مناعة كاملة

Clinical Immunology
Medical Laboratories Techniques

Year 4
Clinical Immunology Lecture No. 1 Prof.Dr.Izzat Al-Rayahi
Year 4
Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies
and a diversity of clinical manifestations. It most commonly presents in women during their child-bearing years, in which the
immune system targets intracellular particles that contain both nucleic acids and nucleic acid binding proteins.
Etiology and Pathogenesis
Although the etiology of SLE is unknown, multiple factors are associated with the development of SLE, including genetic (HLA-
DR2/DR3), racial, hormonal, immune abnormalities and environmental factors (ultraviolet light, viral infection involving molecular
mimicry between organism and self for example anti-Sm autoantibody react with p24 gag protein of retroviruses and that anti- Ro
recognizes a nucleocapsid protein on vesicular stomatitis virus). One proposed mechanism for the development of autoantibodies
involves a defect in apoptosis or clearance of apoptotic cells, leading to a disturbance in immune tolerance. The redistribution of
cellular antigens during apoptosis leads to a display of cytoplasmic and nuclear antigens on the cell surface, enhancing immune
reactivity to antigens, which are normally protected intracellularly. Activation of antigen-presenting cells by IFN-α might promote
presentation of autoantigens to self-reactive T cells. Immune complexes form in the microvasculature, leading to complement
activation and inflammation. Antibody–antigen complexes deposit on the basement membranes of skin and kidneys. In active SLE,
this process has been confirmed based on the presence of complexes of nuclear antigens such as DNA, immunoglobulins, and
complement proteins at these sites.
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Figure : Etiology of SLE.
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Nuclear antigens
Clinical Features
Systemic lupus erythematosus is a multisystem disease and can affect virtually all organs and system; whilst some manifestations
are common, others are rare. Therefore, joint, skin and blood are affected in 80-100% of patients, kidneys, CNS and
cardiopulmonary system in over 50%; while thrombosis, a typical lupus manifestation associated with possession of the
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anticardiolipin antibody, is present in 10% of patients. Systemic manifestations including fatigue, malaise, fever, anorexia, nausea
and weight loss, are present in the great majority of patients.
The symptoms difference according to the infected organ and including arthritis, arthralgia, malar rash, an erythematous rash over
the nasal bridge, photosensitivity, discoid lesions, headache, migraine,nephrotic syndrome, pleuritis and pericarditis.
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General laboratory findings
The most frequent laboratory alteration that is identified is normocromic normocytic anemia of chronic disorders. Occasinally a
Coombs-positive haemolytic anemia is observed. Leukopenia (probably autoantibody mediated), especially lymphopenia, and
thrombocytopenia are frequent. The erythrocyte sedimentation rate is typically elevated, while C-reactive protein tends to be
normal. Urinalysis can show haematuria, proteinuria and renal casts in the presence of glomerulonephritis.
Immunological laboratory findings
All patients in whom SLE is suspected should be tested for antinuclear antibodies, including those to dsDNA and extractable
nuclear antigens (ENA), and for antiphospholipid antibodies, as well as having their serum level of IgG and complement
components, C3 and C4 measured,Antihistone antibodies are also present in patients with drug-induced SLE, most frequently
associated with hydralazine and procainamide therapies.
The sero-immunological hallmark of SLE is antinuclear antibodies (ANA), in the absence of ANA, the diagnosis of SLE is put
into question, even though some 5% of patients may have an ANA-negative serology.ANA is currently detected by an indirect
immunofluorescence technique, where diluted patients serum is applied to frozen tissue, especially liver, of rodent origin and cell
lines of human origin, such as the HEp2 cell line derived from a laryngeal tumor, in which nuclei are prominent, are used as
substrate to detect ANA. If the patient is ANA positive, the autoantibody will bind to nuclei. To reveal this binding, a second
antibody tagged with fluorescent label is add. This second antibody will bind and ANA will then be seen by placing the preparation
under a fluorescence microscope. Four patterns of fluorescence can be seen indicating different types of antinuclear antibodies.
Table. Immunofluorescence Patterns of Antinuclear Antibodies
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ANA is a very sensitive test for SLE, being present in virtually all patients and frequently at high titers; its disease specificity is
relatively low since it is frequently found in other rheumatic diseases, as well as in autoimmune liver disease, during viral infections
and, occasionally, at low titers, in normal subjects.
DNA antibodies are the most important in SLE. They can react with single-stranded DNA (ssDNA) or with double-stranded
DNA (dsDNA).Although anti-ssDNA may be found in many diseases besides SLE, anti-dsDNA autoantibodies are found almost
exclusively in SLE (70%of the patients). While the disease specificity of dsDNA autoantibodies is high, that of ANA is low.
Anti-dsDNA autoantibodies are usually detected by very analytically sensitive technique, such as radioimmunoassay (RIA) or
enzyme linked immunosorbent assay (ELISA).they can also be detected by immunofluorescence staining of an organelle called a
kinotoplast in the flagellate Crithdia luciliae,which contains dsDNA.
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In a patient with lupus nephritis, a kidney biopsy is frequently obtained for diagnostic reasons the glomeruli of such bioptic renal
material contain antigen-antibody complexes. By applying a fluorescent antibody directed against human antibody (similar to that
used in the second step of ANA detection) to frozen section of the kidney biopsy. This one step technique is known as direct
immunofluorescence.
Extractable nuclear antigens (ENA) include Sm (Smith), RNP (ribonucleoprotein), Ro (Robert) also called SS-A (Sjogrens
syndrome antigen A) and anti- La (Lane) or SS-B (Sjogrens syndrome antigen B).
Anti-ENA antibodies are include anti-Sm found almost exclusively in SLE, and anti-RNP more typically associated with mixed
connective tissue disease than with SLE, anti- Ro and anti-L are found in Sjogrens syndrome. Other Anti-ENA antibodies are anti-
Jo-1, anti Scl-70 and anticentromere, which are associated mainly with polmyositis, systemic sclerosis and CREST syndrome
respectively. Anti-ENA antibodies are normally detected by immunodiffusion or ELISA technique.
The lupus anticoagulant causes a prolonged clotting time in vitro but thrombosis in vivo. It is often found in associated with other
autoantibodies to phospholipids, such as anticardiolipin antibodies and false positive tests for syphilis.
Assessment of the complement profile is of importance in management. Serial determinations of CH50, a functional assay measuring
complement hemolytic activity, and of the individual factors C3 and C4, inform on how much immune complexes are consuming
complement.
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Rheumatoid Arthritis
Rheumatoid Arthritis is a chronic systemic inflammatory disease of undetermined
etiology involving primarily the synovial membranes and articular structures of multiple
joints. The disease is often progressive and results in pain, stiffness, and swelling of joints.
In late stages, deformity and ankylosis develop. Women are affected more than men, with a
female: male ratio of 3:1; the disease onset reaches its apex between 35 and 50 years.
Causes
The causes of RA is unknown.
 Genetic: Certain HLA-DR4 molecules associated with RA (e.g. HLA-DR beta

*0401, 0404, or 0405); in addition, HLA-DR1 (HLA-DR beta *0101) carries this
shared epitope and confer risk, particularly in certain southern European areas.
 Environmental: for many decades, numerous infection agents have been suggested
to induce RA. Among these are Mycoplasma organisms, Epstein Barr virus, rubella
virus, cytomegalovirus and herpes virus.
 Hormonal: Sex hormones may play a role, as evidenced by the disproportionate
number of females with RA, its amelioration during pregnancy, its recurrence in the
early postpartum period, and its reduced incidence in women using oral
contraceptives. Hyperprolactinemia may be a risk factor for RA.
Immunopathogensis
Rheumatoid Arthritis is a disease result from immunological response to an antigen within
the joint. This antigen could be self molecules expressed in the joint or could be foreign (e.g.
bacterial or viral) antigen sequestered in joint tissue. The nature of this immunological
response and the target antigen remain uncertain. Unknown antigen stimulates the activation
of T lymphocytes that, in turn activate synovial macrophages. The macrophages secrete the
proinflammatory cytokines, TNF-α and IL-1, which activate osteoclasts and chondrocytes.
This "two-pronged attack" results in the destruction of cartilage and bone. The chondrocytes
begin to produce high quantities of fibroblast growth factor and GM-CSF, which completes
a harmful cycle that can result in reactivation of the macrophage. Also, B cells are activated
by polyclonal stimulation and produce immunoglobulins, especially rheumatoid factors, that
stimulate the activation of complement through immune complex. Moreover,
proinflammatory cytokines, especially TNF-α and IL-1, lead to the increased of proliferation
and activation of fibroblast. This result in synovitis with pannus formation and in
consecutive bone and joint damage.
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Figure: Comparison between normal and RA joints.
Table: autoimmune response identified in patients with RA.
Autoantigen Antibodies in RA T cell response in RA Specificity for RA

IgG Yes: RF No
Type II collagen and Yes: in10-20% Yes: in10-20% No
other cartilage antigens
Citrullinated proteins Yes Probably Yes
(CCP)
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Symptoms of RA Patients
RA usually affects joints on both sides of the body equally. Wrists, fingers, knees, feet, and
ankles are the most commonly affected. The disease often begins slowly, usually with only
minor joint pain, stiffness, and fatigue. Joint symptoms may include:
 Morning stiffness, which lasts more than 1 hour, is common. Joints may feel warm,
tender, and stiff when not used for an hour.
 Joint pain is often felt on the same joint on both sides of the body.
 Over time, joints may lose their range of motion and may become deformed.
Other symptoms include:
 Chest pain when taking a breath (pleurisy).

 Pericarditis.
 Eye burning, itching, and discharge.
 Nodules under the skin (usually a sign of more severe disease).
 Burning in the hands and feet.
 Sleep difficulties.
Laboratory diagnosis
 Synovial fluid analysis
 Inflammatory synovial fluid (WBC count > 2000/µL) is present with WBC counts
generally from 5,000-50,000/µL.
 Usually, neutrophil predominance (60-70%) is observed in the synovial fluid( in
contrast with mononuclear cell predominance in the synovium).
 Because of a transport defect, the glucose levels of pleural, pericardial, and synovial
fluids in patients with RA are often low compared to serum glucose levels.
 Immunological parameters include autoantibodies (e.g., RF, anti-RF33 (nuclear
antigen), anti-CCP, ANA).
 Rheumatoid factor(RF) refers only to the IgM antibody which binds aggregated IgG
as antigen. During the first year of illness, rheumatoid factor is more likely to be
negative with some individuals converting to seropositive status over time. RF is also
seen in other illnesses, for example Sjögren's syndrome, Hepatitis C, chronic
infections and in approximately 10% of the healthy population, therefore the test is
not very specific.
 Anti-cyclic Citrullinated peptide (anti-CCP) is the highly sensitivity (90-96%) for
RA, can identify RA years before symptoms develop and is the most specific test for
RA.
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 Antinuclear antibodies (ANA) are present in approximately 30% of patient with
RA. This test is not routinely performed in the early disease.
 C-reactive protein (CRP) for acute active arthritis.
 Hematological tests
 Complete blood count (CBC) indicate the presence of anemia in normocytic and
normochromic.
 Thrombocytosis may be present.
 Erythrocyte sedimentation rate (ESR) is elevated inapproximately 90% of patient
with RA. This test is not routinely performed in the acute setting
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Ankylosing spondylitis
The term spondyloarthritis (SpA) (otherwise known as spondyloarthropathy) encompasses
a heterogeneous group of inflammatory diseases characterized by spinal and peripheral joint
oligoarthritis, inflammation of the attachments of ligaments and tendons to bones
(enthesitis) and, at times, mucocutaneous, ocular, and/or cardiac manifestations. These
disorders show familial aggregation and are typically associated with genes of the major
histocompatibility complex (MHC), particularly human leukocyte antigen (HLA)-B27 The
SpA include: (1) ankylosing spondylitis (AS); (2) reactive arthritis (ReA)— known
previously as Reiter’s syndrome; (3) psoriatic arthritis (PsA) and/or spondylitis; (4)
enteropathic arthritis and/or spondylitis associated with the inflammatory bowel diseases
(IBD), ulcerative colitis (UC), or Crohn’s disease; and (5) undifferentiated SpA, which
encompasses patients expressing elements of, but failing to fulfill, accepted criteria for one
of the above diseases. In addition, isolated acute anterior uveitis (AAU)1 and spondylitic
heart disease (complete heart block and/or lone aortic regurgitation)2 associated with HLA-
B27 may also be classified within the spectrum of SpA.
Ankylosing spondylitis (AS) is a chronic inflammatory condition of the spine and

sacroiliac joints. It is progressive disease in which restriction of movement is associated
with intervertebral ossification of the ligaments. Men, usually below the age of 40, man
develop the disease three times more frequently than women. Approximately 90% of the
patients are HLA-B*27 positive, while the prevalence of this antigen in the general
population is 7%. Of all the adult HLA-B*27- positive individuals, 1-2% have ankylosing
spondylitis.
The etiology of the disease is unknown, but persistence of specific antigens of the
infecting organisms has been demonstrated in these patients. This has led to suggestion
that AS is also triggered by infection (possibly in the gastrointestinal tract) in susceptible
HLA-B*27- positive individuals.
The onset of AS tends to be insidious with a dull lumbar pain; this persists over 3 months
and is accompanied by morning stiffness relieved by exercise. Arthritis of the peripheral
joints is seen in one third of the patients. Amongst extrarticular manifestation, iritis is the
most troublesome: it tends to be unilateral and accompanied by photophobia pain.
Inflammation of the colon and ileum is frequent but usually asymptomatic.
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Criteria of AS Classification
Inflammatory Spinal Pain: History or present symptoms of spinal pain in back,

dorsal or cervical region with at least 4 of the following: A. Onset at age < 45 years.
B. Insidious onset. C. Improved by exercise. D. Associated with morning stiffness
E. at least for 3 months duration
Synovitis: Asymmetric or Predominantly in the lower limbs. and one of the

followings:
 Positive family history
 Psoriasis
 Inflammatory bowel disease.
 Alternating buttock pain.
 Enthesopathy
 Acute diarrhea
 Urithritis
 Sacroiliiatis
Etiology of AS
Inflammation occurs and persists in different organs and joints in Ankylosing Spondylitis.
Each individual tends to have their own unique pattern of presentation and activity of the
illness. The initial inflammation may be a result of an activation of body's immune system,
perhaps by a preceding bacterial infection or a combination of infectious microbes. Once
activated, the body's immune system becomes unable to turn itself off, even though the
initial bacterial infection may have long subsided. Chronic tissue inflammation resulting
from the continued activation of the body's own immune system in the absence of active
infection is the hallmark of an inflammatory autoimmune disease.
 The tendency to develop Ankylosing Spondylitis is believed to be genetically

inherited, and the majority (nearly 90%) of patients with Ankylosing Spondylitis are
born with the HLA-B27 gene.
Some additional factor(s), perhaps environmental, are necessary for the disease to appear
or become expressed.
Pathophysiology
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 Genetic Predisposing Factor (HLA-B 27) with CD8 T cells
 (TNF α) and IL-1 are also implicated in AS
 Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with AS.
 AS arises from a cross-reaction between HLA-B27 and antigens of the Klebsiella

bacterial strain.
CD4
positive T
lymphocyt Natural
CD8 killer
positive T (NK) cell
lymphocyt
 KIR
receptor
T cell
recept
Free B27 HLA-class
II HLA-B27
homodimers at
HLA-B27
heavy chain (DR, cell surface
DQ, DP) peptide
Endoplasmic Bi Bi ERA
reticulum
B27
BiP P P D
Bi
misfolding, UP
R Gol
gi
B27 folding, assembly

Tapasi HLA-B27:B2M:peptide
B27 heavy chain and loading of n
(HC) trimolecular complex
(B2m) peptide peptide
loading loading
Calnexi Calreticulu
n m BiP B2 Macropha
Riboso m
me
ge
TAP
proteolytic 1,2
degradation peptide
within fragments
Viral,
bacterial or
tumor
Fig. After transcription of the human leukocyte antigen (HLA)-B27 heavy chain on ribosomes in
macrophages, it is inserted into the endoplasmic reticulum (ER), glycosylated, and two pathways ensue.
(A) The B27 heavy chain is retained through binding with calnexin and ERp57, folded into its tertiary
structure and bound to b2- microglobulin. After that calnexin releases the complex and it is associated with
calreticulum, which in turn chaperones the formation of the peptide loading on to the complex of heavy
chain, b2-microglobulin and antigenic peptide, via the TAP proteins and tapasin. The antigenic peptide is
derived from intracellular proteins from viruses, bacteria, tumors, etc., that have been degraded in
proteasomes, and then the peptides are trimmed for optimal length for peptide loading by endoplasmic
reticulum-associated aminopeptidase (ERAP1). Then the trimolecular peptide complex (HLA-B27 heavy
chain, b2-microglobulin and peptide) travels through the Golgi apparatus (A1) to the cell surface, where
the antigenic peptide is presented either to the a:b T-cell receptor on CD8+ T lymphocytes or to the killer
immunoglobulin (KIR) receptor on natural killer (NK)cells (A2); or (B) the HLA-B27 heavy chain misfolds
in the ER, forming B27 homodimers and other misfoldings which are bound to the ER chaperone BiP.
Then, they either (B1) accumulate there, causing either ER-associated degradation (ERAD) or a
proinflammatory ER unfolded protein response (UPR); or (B2) the B27 homodimers migrate to the cell
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surface where they either become antigenic themselves or present peptide to receptors on T cells and natural
killer (NK) cells.
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Clinical Features
o Chronic pain and stiffness in the lower part of the spine.
o An inflammation of the eye (iridocyclitis and uveitis), causing redness, eye
pain, vision loss, floaters and photophobia.
o Generalized fatigue and sometimes nausea
o Less commonly aortitis, apical lung fibrosis and ectasia of the sacral nerve
root sheaths may occur.
o Other forms of spondyloarthropathies are associated with ulcerative colitis,
Crohn's disease, psoriasis, and Reiter's syndrome (reactive arthritis).
Ke y C o n c e p t s
Clinical features of inflammatory back pain
¡ Low-back pain that is present every day for at least 3 months
¡ Age of onset at less than 45 years
¡ Morning stiffness in the back lasting at least 30 minutes
¡ Pain that is relieved by exercise and worsened by rest
¡ Alternating-buttock pain
¡ Relief with nonsteroidal anti-inflammatory agents
The diagnosis of Ankylosing Spondylitis is based on:
 Evaluating the patient's symptoms
 A physical examination
 X-ray findings
 Blood tests
The examination can demonstrate signs of :
Symptoms include pain and morning stiffness of the spine and sacral areas with or
without accompanying inflammation in other joints, tendons, and organs.
1. inflammation and decreased range of motion of joints. This can be particularly

apparent in the spine.
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2. The Schober's test is a useful clinical measure of flexion of the lumbar spine
performed during examination. Flexibility of the low back and/or neck can be
decreased.
3. There may be tenderness of the sacroiliac joints of the upper buttocks.
4. The expansion of the chest with full breathing can be limited because of rigidity of
the chest wall.
Laboratory findings
Blood & Other Tests
 The presence of the blood test genetic marker, the HLA-B27 gene.
 Increase in the blood concentration of CRP & ESR is a nonspecific marker for
inflammation throughout the body and is often elevated in conditions such as
Ankylosing Spondylitis.
 Urine Analysis is often done to look for accompanying abnormalities of the kidney.
Differential Diagnosis of AS
 kidney conditions that may produce back pain that mimics Ankylosing Spondylitis
 Patients are also simultaneously evaluated for symptoms and signs of other related
spondyloarthropathies, such as Psoriasis.
 Venereal disease.
 Dysentery (reactive arthritis or Reiter's disease).
 Inflammatory bowel disease (ulcerative colitis or Crohn's disease).
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Psoriatic Arthritis
Skin involvement exhibits four clinical patterns. The most common type is psoriasis
vulgaris. Nearly as common is guttate psoriasis. The most severe type is the erythrodermic
variety. Finally, pustular psoriasis is the type most closely associated with HLA- B27.
Usually the disease appears coincident with or after the onset of skin manifestations,
although approximately 15–20% of patients will have pre-existent arthritis. The joint disease
likewise occurs in different subtypes, as defined by the Moll and Wright classification (Fig.
1), including oligoarticular, asymmetric, polyarticular, symmetric, distal interphalangeal
(DIP)-predominant, spondylitis (sacroiliitis), arthritis mutilans, inflammation of DIP joints
(often with nail involvement
(~ 80%)), dactylitis: “sausage digits,” and enthesitis. Extra-articular features include nail
pitting (which correlates best with DIP involvement) and uveitis (which occurs in some
series as high as 33% but in most far less). Radiographically, large eccentric erosions are
encountered.
(MCP) and proximal interphalangeal (PIP) joints than the lower extremities, and is more
likely to have a chronic course. The symptoms of peripheral arthritis tend to coincide with
activity of the bowel disease in UC but not in Crohn’s disease. Total colectomy is associated
with remission of arthritis in half of patients. In contrast, axial involvement may precede the
development of IBD, has no gender predilection, and resembles the development of AS. The
axial symptoms do not parallel activity of bowel disease. In addition to spondylitis, an
isolated sacroiliitis occurs that is often asymmetric and not associated with HLA-B27.
Mucocutaneous complications of IBD include erythema nodosum, which occurs in fewer

than 10% of those with Crohn’s disease and is rare in UC; pyoderma gangrenosum, seen in
slightly over 1% of those with Crohn’s disease and rarely occurring in those with UC; and,
rarely, erythema multiforme. Painful aphthous ulcers occur in about 8% of those with UC
and are rare in Crohn’s disease.
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The uveitis with IBD that is bilateral, posterior, insidious in onset, and/or chronic in duration
contrasts with the uveitis associated with other types of SpA, which is predominantly
anterior, unilateral, sudden in onset, and limited in duration. Only 46% of patients with
uveitis associated with IBD are HLA-B27-positive, as opposed to 89% of the patients with
SpA. Episcleritis, scleritis, and glaucoma are more common among patients with IBD than
in those with SpA.
Fig. 1 : Patterns of psoriatic arthritis, showing (A) rheumatoid-like distribution; (B) sausage digits; (C) distal
interphalangeal involvement; and (D) psoriatic arthritis mutilans.
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Psoriatic Arthritis (PsA) is a chronic and inflammatory arthritis in association with skin
psoriasis, characterized by osteolysis and bony proliferation. PsA is classified as one of the
subtypes of spondyloarthropathies. Males and females are equally affected. PsA can range
from mild nondestructive disease to a severely rapid and destructive arthropathy.
Clinical manifestations include skin and nail psoriasis, dactylitis, enthesitis,

osteoperiostitis, large joint oligoarthritis, arthritis mutilans, sacroiliitis, spondylitis and
distal interphalangeal arthritis.
Comorbidities in PsA Patients
 Ocular inflammation (Iritis/Uveitis/ Episcleritis).

 Irritable bowel disease (IBD).
 Metabolic Syndrome (Hyperlipidemia, Hypertension, Insulin resistent,
Diabetes,Obesity ) lead to Higher risk of Cardiovascular disease (CVD)
 Psychosocial burden, Reactive depression, Higher suicidal ideation and Alcoholism.
Two percent of patients with psoriasis develop psoriatic arthropathy; this may affect the
peripheral joints or the spine. The psoriasis generally precedes the arthritis by many years;
in rare cases where the arthritis comes first, diagnosis may be difficult. A family history of
psoriasis is a helpful diagnostic clue and the characteristic nail changes of psoriasis are
present in 80% of patients with psoriatic arthritis. Dactylitis – inflammation of an entire
digit to look like a sausage – is a distinctive feature. Usually rheumatoid factor (RF) negative
and ACPA negative. Radiographic damage can be noted in up to 47% of patients at a median
interval of two years despite clinical improvement with standard DMARD therapy.
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Treatment is similar to that for RA, including the use of anti- TNF drugs. The prognosis is
usually good, although severe joint destruction can occur.
Figure: Main Features of Psoriatic Arthritis
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Sjögren's Syndrome
Sjogren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by
lachrymal and salivary gland dysfunction. It was named after the Swedish
ophthalmologist Henrik Sjo¨gren after he reported 19 cases of keratoconjunctivitis in
1933.1 The hallmark feature of SS is deficient tear and saliva production due to
lymphocytic infiltration of the salivary and lachrymal glands leading to xerostomia (dry
mouth) and xerophthalmia (dry eyes). In addition, SS can involve any organ system and
present with a wide spectrum of clinical features. The autoimmune process seems to
primarily affect the lining epithelium of various organs; in fact some experts propose the
term “autoimmune epithelitis” to be used instead of SS.
 Most individuals with Sjögren's syndrome present with sicca symptoms, such as
Conjunctivitis Sicca (dry eyes), xerostomia (dry mouth), & parotid gland
enlargement.
 In addition, numerous extra glandular features may develop, such as arthralgia,

arthritis, Raynaud's Phenomenon, Myalgia, Pulmonary disease, Gastrointestinal
disease, leukopenia, anemia, lymphadenopathy, neuropathy, vasculitis, renal tubular
acidosis, and Lymphoma.
Epidemiology
Sjo¨gren’s syndrome predominantly effects females (female : male ratio 9:1) in their
fourth and fifth decades of life. However, symptoms can be present for much longer
time and there is usually a 5- to 10-year delay in the diagnosis of SS.
Environmental factors
The inciting event in the pathogenesis of SS is not known, and it may not be a single
event. The strong predominance of females suggests gender-specific predisposing
factors. Although sex hormones are obvious targets, there is no conclusive proof yet
that the difference in the pathogenesis between males and females is due to sex
hormones alone. Estrogens are considered contributors to autoimmunity, whereas
androgens are thought to be protective. But since the peak age of onset in SS occurs
around menopause, characterized by a decrease in estrogens, the increased risk may
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be due to a change in the androgen–estrogen ratio rather than absolute levels of

estrogens.
Viral infections have also been proposed as inciting events. This theory is
strongly supported by the fact that chronic inflammation of the salivary
glands has been observed with chronic hepatitis C, HTLV-1, and human
immunodeficiency virus infections.
Pathophysiology
 Sjögren's syndrome can occur as a primary disease of exocrine gland dysfunction or

as a secondary in association with several other autoimmune diseases (e.g. SLE, RA,
Scleroderma c Sclerosis, Cryoglobulinemia).
 These primary and secondary types occur with similar frequency, but the sicca
complex seems to cause more severe symptoms in the primary form.
Immunopathogenesis
The pathogenesis of SS is still largely unknown. In a genetically predisposed individual,

various environmental factors, such as viral infections, may lead to epithelial cell activation
and a protracted inflammatory response with features of autoimmunity. Autoreactive
lymphocytes and autoantibodies are considered important in this process, although the
pathogenic role of any particular autoantibody is still undefined
Etiology of Sjögren's Syndrome
• Immunological Factors.
• Neurological Factors.
• Apoptotic Mechanisms.
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Immune Mechanism
• Cell-mediated immune mechanisms likely play a central role in the inflammation that
leads to tissue damage in SS.
• CD4 T helper cells predominate in the focal lymphocytic infiltrates that characterize
involved salivary and lacrimal glands.
• Expression of certain HLA molecules on the epithelial cells enhance

hypergammaglobulinemia with the elevation of RF, Ro & La autoantibodies.
Neuroendocrine Mechanism
A. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair

neural release of acetylcholine.
B. In addition, antibodies to acetylcholine (muscarinic) receptors may interfere with the

neural stimulation of local glandular secretion , perhaps by interfering with aquaporin.
C. Moreover, a recent study reports that M3 muscarinic receptor antibodies may cause
autonomic dysfunction in patients with Sjögren syndrome.
Apoptotic Mechanism
A defect in Fas-mediated apoptosis, which is necessary for down-regulation of the

immune response, can result in a chronic inflammatory destruction of the salivary gland,
resembling Sjögren’s Syndrome.
Clinical considerations ¡
¡ Chronic fatigue is a prominent presenting feature of Sjo¨ gren syndrome.

¡ Autonomic and peripheral nervous system involvement is often under recognized.
¡ Mimics of Sjo¨gren’s syndrome include IgG4-related disease (Mikulicz’s disease),
hepatitis C infection, sarcoidosis, and HTLV infection.
¡ Presence of joint erosions and CCP antibody is indicative of secondary Sjo¨ gren
syndrome due to rheumatoid arthritis.
¡ Avoid prolonged use of topical ophthalmic NSAID and steroid preparation due to
increased risk of complications.
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¡ Sudden normalization of previously elevated rheumatoid factor should prompt

evaluation for development of lymphoma.
¡ Identify and treat oral candidiasis. Sjo¨ gren syndrome patients are at a high risk for
oral candidiasis, which can present as oral erythema and/or pain.
¡ Pediatric primary Sjo¨gren syndrome is rare and presents with variable, atypical
features most commonly recurrent tender parotid gland swelling.
Clinical Features:
 Xerostomia
 Conjunctivitis sicca (ocular signs).
 Skin, nose, and vaginal dryness, and may affect other organs of the body,
 including the kidneys, blood vessels, lungs, liver, pancreas, and brain.
 Patients with secondary SS also have signs and symptoms of the associated rheumatic
disorder.
Classification criteria
1. Ocular symptoms
Dry eyes for more than 3 months
Foreign-body sensation
Use of tear substitutes more than 3 times per day
2. Oral symptoms (Xerostomia)
Feeling of dry mouth
Recurrently swollen salivary glands
Frequent use of liquids to aid swallowing
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Year 4
3. Ocular signs (Conjunctivitis Sicca)
 Schirmer test performed without anesthesia (<5 mm in 5 min)
 Positive vital dye staining results
4. Oral signs
Abnormal salivary scintigraphy findings
Abnormal parotid sialography findings
Abnormal sialometry findings (unstimulated salivary flow <1.5 mL in 15

minutes)
5. Positive anti–SSA or anti–SSB antibody results
6. Positive minor salivary gland biopsy findings
Diagnosis
I. Laboratory Studies
1) Complete blood count (CBC) [showed low platelets & WBCs, ESR is elevated in
80%] of patients.
2) Chemistry Tests:
• Creatinine clearance may be diminished in up to 50% of patients.
• A high total protein level or a low albumin level should prompt the clinician to
perform serum protein electrophoresis.
• A high alkaline phosphatase level should prompt consideration for primary biliary
cirrhosis.
• With elevated transaminase levels, consider the possibility of chronic active hepatitis,
which can be associated with sicca symptoms, or hepatitis C, which can cause mild
salivary gland enlargement. However, mild (<2-fold) increases in transaminase levels
have been observed in 22% of patients with Sjögren syndrome.
5
Year 4
• Consider evaluating patients with a low bicarbonate level for type I (distal) renal
tubular acidosis. Less commonly, patients can also develop proximal renal tubular
acidosis with Fanconi syndrome.
• Hypokalemia, occasionally severe enough to lead to periodic paralysis, can be

observed in patients with type I renal tubular acidosis but can also be observed in
patients who have Sjögren syndrome without renal tubular acidosis.
• Schirmer's test
• Serum protein electrophoresis
• Patients with Sjögren syndrome often have a polyclonal gammopathy.
• Loss of a previously detected polyclonal gammopathy can be observed in some

patients with Sjögren syndrome who develop lymphoma.
• Development of a monoclonal gammopathy can also signal the development of a

lymphoma.
• Autoantibodies
• Anti-SS-A and anti-SS-B are present in most cases of primary-type Sjögren's

syndrome, while antisalivary duct antibodies are present in most cases of the
secondary type.
Other autoantibodies, such as anti-nuclear antibodies and rheumatoid factor, are

frequently present in patients with both primary and secondary SS. Although they
lack specificity, they are markers of a systemic autoimmune response and thus can
help distinguish SS from other causes of salivary or lachrymal gland dysfunction.
In recent years, research has focused on identifying antibodies more specific for SS,
such as anti-a-fodrin and anti-muscarinic acetylcholine receptor antibodies, but the
results have been controversial. The major stimulus for saliva production is the
binding of acetylcholine to muscarinic acetylcholine receptors. The hypothesis that
6
Year 4
oral and ocular dryness could result from antibodies antagonizing the muscarinic
acetylcholine receptor-3 is intriguing.
• Antinuclear antibodies of the speckled and homogeneous type are present in most
cases of primary Sjögren's syndrome.
7
Year 4
Behcet's Disease
Behcet's disease is a rare, chronic, lifelong disorder that involves inflammation of blood
vessels throughout the body. It is a form of vasculitis that can lead to ulceration and other
lesions, slightly affecting more men than woman characterized by a triad of symptoms,
including aphthous ulceration of the oral mucous membranes and genitalia and uveitis. Rare
manifestations include oligoarthritis of the lower extremities, vasculitis of the pulmonary
vessels, cerebrovascular symptoms. The etiology of the Behcet's disease is unkown. It is
believed to be partly genetic, an association with HLA-B51 has been found.
Figure: Pathogencity of Behcet's disease
Risk factors
 Age. Behcet's disease most commonly affects men and women in their 20s, 30s and
40s, though children and older adults also can develop the condition. When the
condition occurs at an earlier age, it tends to be more severe.
 Geography. Although the disease occurs worldwide, people from countries in the
Middle East and Asia, including Turkey, Iran, Iraq, Japan and China, are more likely
to develop Behcet's.
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Year 4
 Sex. While Behcet's disease occurs in both men and women, the disease is usually
more severe in men.
 Genes. Having certain genes HLA-B51 is associated with a higher risk of developing
Behcet's.
Clinical features
 Mouth: Painful mouth sores, identical to canker sores, are the most common sign of
Behcet's disease. Sores begin as raised, round lesions in the mouth that quickly turn
into painful ulcers. The sores heal usually in seven to 21 days, though they do recur.
 Skin: Skin lesions may occur in people with Behcet's disease. Skin problems can
vary. Some people may develop acne-like sores on their bodies. Others may develop
nodules on the lower legs.
 Genitals: People with Behcet's disease may develop sores on their genitals. The sores
most commonly occur on the scrotum or the vulva.
 Eyes: Behcet's disease may cause inflammation in the eye — a condition called
uveitis In people with Behcet's disease, uveitis causes redness, pain and blurred vision
in one or both eyes
 Joints: Joint swelling and pain most commonly affect the knee in people with
Behcet's disease.
 Vascular system: Inflammation in veins and large arteries may occur in Behcet's
disease, causing redness, pain and swelling in the arms or legs when a blood clot
results.
 Digestive system: Behcet's disease may cause abdominal pain, diarrhea or bleeding.
 Brain: Inflammation in the brain and nervous system that leads to headache, fever,
disorientation, poor balance or stroke.
Diagnosis
There is no diagnostic test and the diagnosis is entirely clinical. Laboratory findings are
nonspecific and reflect the inflammatory state, C-reactive protein levels, erythrocyte
sedimentation rate (ESR), leukocyte count, complement components, and acute-phase
2
Year 4
reactants may all be elevated during an acute attack. Internationally accepted diagnosis
criteria have been published recently.
International Clinical Criteria for Behcet's Disease

An international group of physicians has established a set of guidelines to aid in the
classification of Behcet's patients. The International Clinical Criteria for Behcet's Disease
classification states patients must present with:
 Recurrent oral ulcerations (apthous or herpetiform) at least three times in one year.
 Additionally, patients must present any two of the following:
o Recurrent genital ulcerations.
o Eye lesions (uveitis or retinal vasculitis) observed by an ophthalmologist.
o Skin lesions (a variety of rashes or acne-like sores) may be caused by
Behcet's disease. Positive
o Positive pathergy test, your doctor inserts a sterile needle into your skin and
then examines the area two days later. If the pathergy test is positive, a small
red bump forms under your skin where the needle was inserted. This
indicates your immune system is overreacting to the minor injury.
Treatment
In the meantime, no specific treatment is available, although corticosteroids may control
symptoms and azathioprine and adalimumab (a humanized antibody to TNF-α) have been
shown to reduce progression of visual loss. In severe cases, ciclosporin, tacrolimus and
infliximab may be effective. Thalidomide may be useful in refractory orogenital ulceration.
3
Year 4
Gluten Sensitive Enteropathy /(GSE) or Celiac Disease
Celiac disease (CD), an immune-mediated mucosal disorder primarily affecting the small
intestine in genetically susceptible individuals, is triggered by the ingestion of dietary
gluten. Gluten is the alcohol-soluble protein component of the cereals wheat, rye and barley.
It is composed of 2 major protein fractions: glutenin and gliadin; most of the toxic activity
exerted by gluten in CD is due to gliadin.
It is, also known as celiac sprue, gluten-sensitive enteropathy, non-tropical sprue,

characterized by inflammation leading to injury to the mucosal lining of the small intestine,
including villous atrophy with crypt hyperplasia, intraepithelial lymphocytosis, and
subsequent nutrient malabsorption.
The disorder is a multifactorial condition, originating from the interplay of genetic and
environmental factors. The necessary environmental trigger is gluten, timing of gluten
introduction into the diet could play a role in pathogenesis, since initial exposure to wheat,
barley, or rye in the first 3 months of life or after the 7th months proved to be related to an
increased risk of CD. Breast-feeding could have a protective effect, since introduction of
gluten to the infant’s diet when infant is still at the age of being breastfed has markedly
reduced the risk of celiac disease. While, the genetic predisposition has been identified in
the major histocompatibility complex region on chromosome 6p21, with over 90% of CD
patients expressing human leukocyte antigens HLA DQ2 and the remaining celiac patients
express DQ8.Some infectious agents could increase the risk of celiac disease, like repeated
infection with rotavirus, the most common cause of childhood gastroenteritis, represent an
1
Year 4
independent risk factor for celiac disease in genetically susceptible individuals. Some
drugs can have a role in enhancing a person’s susceptibility to gluten, a course of
interferon alfa could activate celiac disease in predisposed people.
• Abnormal small intestine lining from injury

• Injury is result of gluten induced inflammation
• It is an autoimmune reaction with common triggers
• The risk is genetically inherited
• Malabsorption occurs as a result
What is Gluten?
• 10-15% extractable protein portion of wheat

• Subdivided into gliadin & glutenin
– Gliadin 15,000 molecular weight
– Active factor in small bowel injury
– Fraction 3, <1,000 mw sub-fraction
What is gluten sensitive enteropathy?
• Protein gluten in wheat, rye, & barley, +/- oats injures sensitive small
intestine
• Chronic small intestine injury
=enteropathy
• Injured small intestine = malabsorption

• Abnormal immune system reaction results in extra-intestinal symptoms &
signs
• Intestinal injury & symptoms resolve with gluten-free die.
Gluten-Sensitive Enteropathy (GSE)
It is the disease of the small intestine characterized by villous atrophy & mal absorption due to
hypersensitivity to cereal grain storage proteins particularly gliadin fraction of gluten in wheat,
barely & rye. This dz either limited to the intestine or associated with a vesicular skin dz.
dermatitis herpetiformis [GSE-DH].
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Year 4
Pathology
 The inflammatory lesions of the GIT are found in the small intestine, the area in great
contact the ingested gliadin.
 Increased No. of lamina propria mononuclear cells underlying normal intestinal crypts &
villi. This progress to further increased in cellular filtrate & development of hypertrophic
crypts which elaborate crypt epithelial cells at a rate that compensates for the loss of
epithelial villous cells.
 With further progression the inflammation reaches a destructive stage of Dz.
characterized by intense mononuclear infiltrate associated with crypt hyperplasia that can
no longer keep pace with the loss of villous cells ; as a result, the villi become shortened
or even flattened & the Pt. now develop the characteristic mal absorption of GSE .
 If the GSE inflammation prolonged, the mature lesion may progress to the fibrotic or
burned stage in which destruction is permanent and the Pt no longer fully recovers when
placed on a gluten-free diet.
What happens in Celiac disease?
• Proteins in wheat, rye, barley resistant to digestion in stomach and by pancreatic

enzymes
• Make way into lining, possibly pre-injured by infection, predisposed by genetic HLA type
• Activate T lymphocytes that release chemicals (cytokines) causing inflammation &
damage
• Damaged lining malabsorbs nutrients & vulnerable to more injury.
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Year 4
Immunological Mechanism
Gluten-Sensitive Enteropathy is due to an immune reactivity to certain cereal storage protein
peptides. The main pathologic stages are:
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Year 4
 Induction of T cells by APC which present gliadin peptides to T cells in the
context of MHC Ags associated with GSE.
 The induced T cells [ TH1] cells produce INF-γ & TNF-α, which then act on
intestinal macrophages to produce proinflammatory cytokines such as IL-1β
& TNF-α
 These cytokines induce fibroblast to produce metallo-proteinases that are
the proximal cause of injury to the LP matrix supporting the villi.
 The 2nd mechanism: T cells with TCR-bearing IEL recognize and lyses
epithelial cells expressing gliadin peptides presented in the context of non-
classical MHC Ags.
 B cells specific for gliadin also occur in lesions and give rise to
characteristic s-IgA antigliadin Ab. Antibody for gliadin & an endogenous
enzyme [transglutaminase] also occur. These entire Abs act to activate
complement which subsequently amplifying the inflammatory process.
 These events seems to be genetically related to certain HLA molecules that
enhance the Dz development and act as a risk factors for the Dz
development such as HLA-B8 , DR3 DQ2 particularly the latter which
observed to participate in gliadin presentation to reactive T cells.
Epidemiology
The likelihood of having gluten-sensitive enteropathy increases to 10 to 20

percent in persons who have a first-degree relative with celiac disease. Genetic
factor enhances the chance for dz development (HLA-B8, DR3 DQ2). In
addition, celiac disease is associated with other autoimmune syndromes. For
example, as many as 7 percent of patients with type I diabetes also have
gluten-sensitive enteropathy.
The clinical manifestations of CD vary markedly with the age of the patient, the duration
and extent of disease, and the presence of extraintestinal pathology. Depending on the
features at the time of presentation, together with the histologic and immunologic
abnormalities at the time of diagnosis, CD can be subdivided into the following clinical
forms.
1. Classical (typical) form
The so-called typical form of CD is present characteristically between 6 and 24 months of
age. Symptoms begin at various times after the introduction of weaning foods containing
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Year 4
gluten. Infants and young children typically present with chronic diarrhea, anorexia,
abdominal distension, abdominal pain, poor weight gain or weight loss and vomiting.
Malnutrition can be severe if the diagnosis is delayed. Behavioral changes are common and
include irritability.
2. Atypical forms
An increasing number of patients, especially at an older age, are being diagnosed with CD
without having typical gastrointestinal manifestations but there are various extraintestinal
manifestations present such as dermatitis herpetiformis, anemia, osteoporosis, autoimmune
hepatitis, dental enamel defects, recurrent aphthous stomatitis, epilepsy, and neuropathy.
Serology for CD is positive and bioptic findings confirm the diagnosis.
3. Silent form
Silent celiac disease patients are those who are asymptomatic but small intestinal biopsy
show villous atrophy. Silent cases are detected by population screening and screening of
first degree relatives of celiac disease, 10% of whom are found to have CD. Serological tests
are positive in them.
4. Latent form
Latent (or “potential”) form is asymptomatic patients, with a normal or minimally abnormal
mucosa. These individuals have a genetic susceptibility to CD and may also have positive
autoimmune serology.
Refractory celiac disease (RCD) is defined by persistent or recurrent malabsorptive

symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for at
least 6–12 months in the absence of other causes of non-responsive treated celiac disease
and overt malignancy
Celiac disease prevalence is increased in at-risk conditions such as family history of celiac
disease, autoimmune diseases, especially type1diabetes (T1D) and thyroiditis, IgA
deficiency, and some genetic syndromes.
The clinical course of GSE is dominated by gastrointestinal tract symptoms

relating to malabsorption. The GIT manifestations are consist of weight loss,
diarrhea, and symptoms due to nutritional deficiencies and in children growth
failure.
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Year 4
TABLE Symptoms of Celiac Disease and Possible Causes
Symptoms Possible causes
Fatigue, malaise Anemia, general immune system

activation
Weight loss Nutrient malabsorption
Accelerated gastrointestinal tract

Diarrhea, abdominal pain transit time, steatorrhea,
malabsorption
Most commonly, iron deficiency;

Anemia less commonly, vitamin B12 and/or
folate deficiency
Bone pain Osteoporosis
Aphthous oral ulcers, glossitis, Vitamin deficiency, "oral" celiac

stomatitis disease
Postulated cause: iron, folate,

Infertility
and/or zinc deficiency
Peripheral insensitivity to
Male impotence, decreased libido
circulating testosterone
Immunologic attack on hair

Alopecia areata
follicles
Demineralization during tooth bud

Dental enamel defects
development in children
Hypoglycemia Delayed absorption of glucose
Secondary digestion of sugars by

Gas, flatus, borborygmus
intestinal flora
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Year 4
Seizures, gluten ataxia, central Increased affinity of celiac
nervous system symptoms antibodies for brain vasculature
Diagnosis
1. Small intestine biopsy

The most relevant feature of the disease was histological change, and histology became the
gold standard for diagnosis. The diagnosis required three small bowel biopsies-the first
during the gluten containing diet, which had to show “flat” mucosa; the second, during
gluten free diet which showed improvement in villous structure, and the third, at gluten
challenge 2 years later which had to show histological relapse.
The degree of the intestinal lesion is defined on the basis of the widely used Marsh-
Oberhuber classification, it ranges from type 0 (Marsh 0) to Marsh type 4:
 Type 0 concerns the normal stage of the small bowel mucosa.

 Type 1 or infiltrative lesion comprises normal mucosal architecture in which the
villous epithelium is infiltrated by small, non mitotic intraepithelial lymphocytes and
it is characteristically present in first-degree relatives of children with celiac disease.
 Type 2, or hyperplastic lesion, consists of a type 1 lesion with enlarged crypts.
 Type 3or destructive lesion is synonymous with the typical flat mucosa of CD and
it is subclassified according to the different degrees of villous atrophy present: Marsh
type 3a, with partial villous atrophy; Marsh type 3b, in the presence of subtotal villous
atrophy; and Marsh type 3c, when total villous atrophy is present.
 Marsh type 4 or hypoplastic lesion (total villous atrophy with crypt hypoplasia)
represents the extreme end of the gluten-sensitivity spectrum and an irreversible
lesion is present in some adult CD patients whose small bowel mucosa is
unresponsive to gluten withdrawal: the so-called refractory CD.
2. Serology tests
Serologic testing is primarily used to identify symptomatic or at-risk individuals who need
to undergo biopsy. Because of their high sensitivity and specificity, serologic tests are
excellent for screening asymptomatic at-risk individuals; they also can be used for
monitoring dietary compliance.
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Year 4
 Anti-gliadin antibodies (AGA) are not specific for CD as they are also found in
healthy individuals and patients with other gastrointestinal diseases such as gastritis,
gastroenteritis and irritable bowel syndrome, except in children younger than 2 years
of age, in whom anti-gliadin antibodies measure is more sensitive test. IgG-AGA is
very sensitive but less specific, and IgA-AGA is less sensitive but more specific.
Their use in combination can give results of a high detection rate. Several methods
have been used to analyze AGA, but currently ELISA is the most used method.
 Anti-endomysial antibodies (EMAs) are used as the “gold standard” for CD screening
because of their high sensitivity and specificity. The test was developed in the early
1980s and rapidly gained use as part of ''a celiac panel'' by commercial labs in
combination with AGA IgG and IgA. IgA-EMA and IgG-EMA are measured by
indirect immunofluorescence, using tissue sections from either monkey esophagus or
human umbilical cord [140]. Its major drawbacks are false negatives in young
children, and in the hands of an inexperienced laboratory because of the subjective
nature of the test. Also IgA-EMA give false negative in patients with IgA deficiency.
 Anti-tissue transglutaminase (tTG) antibodies are more specific have shown to be
correlated with mucosal damage and are used widely in CD screening. IgG-tTG and
IgA-tTG were used in combination as a screening test for celiac disease to assess IgA
deficiency. ELISA is the most used method to analyze tTG. However, it represents
an improvement over the antiendomysial antibody assay because it is inexpensive,
rapid and easy to perform.
 Anti-reticuline antibody is best detected by an indirect immunofluorescent method
using unfixed cryostat sections of rat liver and kidney as antigens. IgA class reticulin
antibodies react with connective tissue fibers and are found in 60% of celiac disease
patients. IgG class reticulin antibodies are occasionally found in other disease states,
especially bullous dermatoses and in some normal subjects.
3. Genetic testing
Up to 95% of patients with celiac disease are positive for HLA-DQ2, and most of the
remaining patients are positive for HLA-DQ8. . However, these alleles are also found in
40% of the general population. Although HLA-DQ2 and HLA-DQ8 are necessary in the
disease process, they alone are not sufficient for celiac disease to develop. HLA testing has
a high negative predictive value and can be useful in certain situations, such as when a
diagnosis is unclear, when serologic testing or biopsy is performed in patients on a gluten-
free diet, or in determining which family members to screen for celiac disease.
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Year 4
Serological Tests:
 Anti-tissue transglutaminase Antibody (TTG)

 IgA anti-endomysial Antibody (EMA) if TTG is positive
 Gliadin antibodies (not recommended, low sensitivity)
 Endoscopy with small bowel biopsy
 Imaging (at time of diagnosis and as warranted)
 Hematological & Biochemical Tests
 Complete Blood Count with platelets
 Iron studies (Serum Iron, TIBC, Ferritin)
 Serum Vitamin B12
 Serum Folate
 Calcium
 Phosphate
 Renal Function tests (Blood Urea Nitrogen, Creatinine)
 Liver Function Tests (AST, ALT, Albumin, Alk Phos).
 Treatment
 The only proven treatment for celiac disease is strict and life-long adherence to a
gluten-free diet. All food and drugs that contain gluten from wheat, rye, barley, and
their derivatives must be eliminated because even small amounts can be harmful.
Differential Diagnosis
 Anorexia Nervosa
 Inflammatory Bowel Disease (e.g. Crohn's Disease)
 Intestinal infection (e.g. Giardiasis, Clostridium difficile, Tropical Sprue)
 Malabsorption (e.g. Lactose Intolerance)
 Mesenteric Ischemia
 Tuberculosis
 Intestinal Lymphoma
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Year 4
 Immunodeficiency (e.g. Human Immunodeficiency Virus,
Hypogammaglobulinemia)
 Whipple's Disease
 Zollinger-Ellison Syndrome
 Irritable Bowel Syndrome
Pernicious Anemia
Pernicious anemia (PA) is a megaloblastic anemia caused by a deficiency of vitamin B12
resulting from malabsorption. Impaired absorption is the result of defective intrinsic factor
(IF) secretion. This is due to atrophy of the gastric mucosa caused by autoimmune reactions
to gastric parietal cells and their products.
Pernicious anemia occurs in equal numbers in both men and women. Most patients with
pernicious anemia are older, usually over 60 years. Occasionally, a child will have an
inherited condition that results in defective intrinsic factor.
Virtually all patients will have gastric parietal cells antibody targeting antigens in the
secretory canaliculi, which are the intracellular channels carrying hydrochloric acid into the
gastric lumen and its major target is the α subunit of the proton pump (H+, K+, ATPase), an
enzyme composed of two transmembrane components, the α and β subunits. In addition,
there are at least two types of antibody against intrinsic factor: blocking and binding
antibodies; the blocking type reacts with the combining site for vitamin B 12 on IF and is
found in most patients (over 70%), while the binding antibody reacts with other epitopes on
IF (whether this is free or complexed to vitamin B12) and is present in some 60% of pateints.
During the course of the digestion of foods containing B 12, the B12 becomes attached to a
substance called intrinsic factor. Intrinsic factor is produced by parietal cells that line the
stomach. The B12-intrinsic factor complex then enters the intestine, where the vitamin is
absorbed into the bloodstream. In fact, B12 can only be absorbed when it is attached to
intrinsic factor.In pernicious anemia, this process is impaired because of loss of parietal
cells, resulting in insufficient absorption of the vitamin. So, the vitamin passes out of the
body as waste. Although the body has significant amounts of stored B12, this will eventually
be used up. At this point, the symptoms of pernicious anemia will develop.
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Year 4
Causes
Intrinsic factor is produced by specialized cells within the stomach called parietal cells.
When these parietal cells shrink in size (atrophy), they produce less intrinsic factor.
Eventually, the parietal cells stop functioning altogether. Other important products of
parietal cells are also lessened, including stomach acid, and an enzyme involved in the
digestion of proteins. Other conditions that interfere with either the production of intrinsic
factor, or the body's use of B12, include conditions that require surgical removal of the
stomach, or poisonings with corrosive substances which destroy the lining of the stomach.
Certain structural defects of the intestinal system can result in an overgrowth of normal
bacteria. These bacteria then absorb B12 themselves, for use in their own growth. A B-12
deficient state, may be caused by infection with the tapeworm Diphyllobothrium latum,
possibly due to the parasite's competition for vitamin B-12.Various conditions that affect
the part of the intestine (the ileum), from which B12 is absorbed, can also cause anemia due
to B12 deficiency. These ileum-related disorders include tropical sprue, Crohn's disease,
tuberculosis.
Symptoms
B12 is required for the proper formation of red blood cells. Without B 12, red blood cell
production is greatly reduced. Those red blood cells that are produced are abnormally large
and abnormal in shape. Because red blood cells are responsible for carrying oxygen around
the body, decreased numbers (termed anemia) result in a number of symptoms see figure.
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Year 4
Figure: Symptoms of Pernicious anemia.

Diagnosis
Tests that may be used to diagnosis pernicious anemia include
 Blood smear reveals abnormally large red blood cells.
 White blood cells and platelet counts may also be decreased in number.
 Reticulocyte count will be low in number.
 Serum vitamin B12 level will be low.
 Schilling test, in this test, a patient is given radioactive B12 under two different sets of
conditions: once alone, and once attached to intrinsic factor. Normally, large amounts
of B12 are absorbed through the intestine, then circulate through the blood, and enter
the kidneys, where a certain amount of B12 is then passed out in the urine. When a
patient has pernicious anemia, the dose of B12 given by itself will not be absorbed by
the intestine, so it will not pass into the urine. Therefore, levels of B12 in the urine will
be low. When the B12 is given along with intrinsic factor, the intestine is able to absorb
the vitamin. Urine levels of B12 will therefore be higher.
 Immunology, specifically anti-parietal cell antibody (APCA) and intrinsic factor
antibody (IFA). APCAs bind to the alpha- and beta-subunits of the membrane-bound
H(+)/K(+)-ATPase. In contrast, IFAs bind directly to intrinsic factor, blocking its
ability to bind vitamin B12 and can be detected by means of immunofluorescence,
enzyme-linked immunosorbent assay - currently the most commonly used method,
and radioimmunoprecipitation assay (RIA). APCA can be found in 85-90% of
patients with PA. Their presence is not sufficient for diagnosis, because they are not
specific for PA as they are also found in the circulation of individuals with other
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Year 4
diseases. APCA are more prevalent in the serum of patients with T1D, autoimmune
thyroid diseases, vitiligo, celiac disease. So that a combination of PCA and IFA
testing was the optimal strategy for the evaluation of patients with suspected PA.
Diabetes mellitus
Diabetes is a state of high blood sugar (hyperglycemia) that can have many underlying
causes and is classified into:
1. Insulin-dependent diabetes mellitus (IDDM) or type1.

2. Non-insulin-dependent diabetes mellitus (NIDDM) or type 2.
3. Gestational diabetes mellitus.
Type 1 diabetes mellitus
Type 1 diabetes mellitus (type 1 DM) is a major clinical problem in both children and adults.
It is an organ-specific autoimmune disease represents 10-15% of all diabetes. Healthy
human islets of Langerhans are composed of a core of some 80% β cells (making the
glucose-regulating hormone insulin), with a mantle of other endocrine cells types, producing
glucogan (α cells), somatostatin (δ cells) and pancreatic polypeptide (PP cells) making up
the remainder.
In type 1 DM, the hyperglycemia results from insufficient insulin secretion by β cells in the
islets of Langerhans of the pancreas.
Causes
1. Genetic: DR3/DQ2 or DR4/DQ8 haplotypes have strong link for the incidence of the
disease, but other genetic associations (non HLA) are CTLA-4 (cytotoxic lymphocyte
associated protein 4) also found in many family that play a role in the onset of type 1
DM.
2. Environmental factors:
 Seasonal variation in the incidence rate (peaks in autumn and winter).
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Year 4
 Infection with pathogens that have specific tropism toward the pancreatic tissue,
mumps and coxsakie viruses. Similarities in the protein sequence of these viruses
and certain islet cell cytoplasmic (ICA), glutamic acid decarboxylase (GAD)
would initiate molecular mimicry mechanism in tolerance breakdown.
Immunopathogenesis
A virus infection in the pancreatic β islets cells leads to inflammation, damaged and
releasing β cells antigens, their recruit antigen presenting cells (dendritic cells) which
capture the virus protein and auto antigens released from the damaged β islets cells to local
lymph node and present them to T cells. T cells are activated to eradicate the virus.
Inadvertently, T cells are activated against β cells and the slow process of β cells damage
starts.
In type 1 DM insulin production is failed due to destruction of β cells in the islets of

Langerhans in pancreatic tissue without any destruction in the other cells as (α or δ cells)
which is mediated by specific immune response).
Features of islet autoantigens in type 1 DM
Autoantigens Islet specific Function Autoantibody

Insulin Yes, and β cells Regulates glucose Insulin autoantibody
specific (IAA)
glutamic acid No, present in other Catalyses glutamic acid
decarboxylase islet cells and CNS synthesis of γ- decarboxylase
amino butyric acid autoantibody
(GABA), a (GADA)
negative
neurotransmitter
probably regulates
insulin release.
Islet tyrosine No, present in other Unknown insulinoma-2
phosphatase islet cells and CNS associated
autoantibody (IA-
2A)
Zinc transport 8 Yes, and β cells Zinc transport Zinc transport 8
specific autoantibody
(ZNT8A)
15
Year 4
Symptoms
Many pre- or subclinical stages occur in the DM patient before clinical diagnosis can be
done:
1. Stage 1: the cell mass and function of β cells is normal but individuals who carry
genetic susceptibility alleles to type 1 suffer exposure to an environmental stimulus
triggering islets inflammation (insulitis). The release of sequestered or altered self
antigens explains in part the later development of islet Autoantibodies that mark the
recognition of stage 2.
2. Stage 2: serological evidence of humoral and cell-mediated autoimmunity indicated
by the appearance of different types of autoantibody as islet cell cytoplasmic
autoantibody (ICA), glutamic acid decarboxylase autoantibody (GADA), insulinoma-
2 associated autoantibody (IA-2A) or insulin autoantibody (IAA). This occurs
without any clinical metabolic signs. However, during this stage, there can be a 50%
decline in β cells mass without detectable abnormalities by any form of glucose
tolerance testing.
3. Stage 3: The earliest functional β cells abnormalities which manifestation by the
intravenous glucose tolerance test (IVGTT) which decrease.
4. Stage 4: intolerance to oral glucose challenges appears as indicated by oral glucose
tolerance test (OGTT).
5. Stage 5: after 1-2 years of glucose intolerance upon oral testing, atypical history of
polyuria, polydipsia, polyphagia with weight lose are identified. Finally by a true
hyperglycemia a full diagnosis can be done.
16
Year 4
Inflammatory bowel disease
It is a chronic inflammatory disease of gastrointestinal tract due to immune response to the

commensal microflora in the lumen of basal consistent and may be divided into two major
groups:
 Crohn's disease
 Ulcerative colitis
Crohn's disease also known as granulomatous colitis and regional enteritis, it is classified
as a type of inflammatory bowel disease, in which the body immune system attacks the
gastrointestinal tract, causing a transmural inflammation, that may affect any part of the
gastrointestinal tract from mouth to anus. It is onset patient between 15-30 year, males and
females are equally affected.
Most gastroenterologists categorize the presenting disease by the affected areas:
 Ileocolic Crohn's diseases, which affect both the ileum (the last part of the small
intestine that connect to the large intestine) and the large intestine, accounts for 50%
of cases.
 Crohn's ileitis, affecting the ileum only, accounts for 30% of cases.
 Crohn's colitis, affecting the large intestine, accounts for the remaining 20% of cases
and may be difficult to distinguish from ulcerative colitis.
1
Year 4
However, individual affected by the disease rarely fall outside these three classification,
being affected in other parts of the gastrointestinal tract such as the stomach and esophagus.
Crohns disease may also be categorized by the behavior of disease as it progresses. There
are three categories of disease presentation in Crohns disease:
 Stricturing disease: narrowing of the bowel which may lead to bowel obstruction or
changes in the caliber of the feces.
 Penetrating disease: creates abnormal passageways (fistulae) between the bowel and
other structures such as the skin.
 Inflammatory disease: cause inflammation without causing stricture or fistulae.
Causes
 Genetic factor: many studies that is suggested relationship between genetic and
Crohns disease such as mutation in gene nucleotide-binding oligomerisation domain
2 (NOD2 gene) on chromosome 16.
 Environmental factor: by diet, smoking, drugs, hormonal contraception.
2
Year 4
 Immune system: abnormalities in immune system causes Crohns disease and the
inflammation that is occur in this disease causes activation of T H1 by an
overproduction of IL-12 by macrophages and of IFN-γ by T lymphocytes.
 Microbes: there are many bacteria causes of Crohns disease such as Mycobacterium
ovum, Yersinia spp and Listeria spp.
Clinical Features
A. Gastrointestinal Features
 Abdominal pain.
 Diarrhea may be bloody or may not be bloody, is different according to the part of
the small intestine or large intestine, in ileitis large-volume watery feces, while, in
colitis small volume semisolid or watery feces.
 Vomiting &nausea.
 Perianal discomfort (itching around the anus).
 Aphthousof mouth (ulceration of mouth).
B. Systemic Features
 In children causes growth failure, acute myelogenous leukemia in blood (myeloid)
and lymphoma (cancer of lymph).
 In adult causes weight loss.
C. Extraintestinal Features
 In the eye, the inflammation of the interior portion of the eye is called uveitis or
white part of the eye called episcleritis, both can lead to loss of vision if untreated.
 In the skin cause erythema nodosum (red nodules or subcutaneous tissue) or
pyodermagangrenosum (ulcerating nodules).
 In the blood causes blood clotting especially painful of the lower legs can be a sign
of deep venous thrombosis.
 Difficult breathing may be a result of pulmonary embolism.
 Autoimmune hemolytic anemia.
 Some neurological disease such as neuropathy & depression.
3
Year 4
 Inflammation of one or more joints (arthritis).
 Osteoporosis increased risk of bone fracture.
Ulcerative colitis
Ulcerative colitis is confined to the colon and affects the mucosal layer only and causing a
continuous inflammation. It is result of immune response to commensal microflora with TH2
profile, through there is an increase of the TH2 cytokine IL- 5. Favouring a TH2 pattern is
the fact that ulcerative colitis is associated with the production of various autoantibodies,
such as perinuclear anti-neutrophil cytoplasmic antibody (PANCA) and anti- tropomyosin.
Clinical Features
A. Gastrointestinal Features
 The clinical presentation of ulcerative colitis depends on the extent of the
disease process. Patients usually present with diarrhea mixed with blood
[Relapsing rectal bleeding] and mucus, of gradual onset.
 They also may have signs of weight loss, and blood on rectal examination.
 The disease is usually accompanied with different degrees of abdominal pain,
from mild discomfort to severely painful cramp [Tenesmus].
B. Extraintestinal Features
 Aphthous ulcers of the mouth
 Ophthalmic (involving the eyes):Iritis or uveitis
 Musculoskeletal: Seronegative arthritis, Ankylosing Spondylitis, Sacroiliiatis
 Cutaneous (related to the skin):Erythema nodosum, Pyoderma gangrenosum
 Deep venous thrombosis and pulmonary embolism
 Autoimmune hemolytic anemia
 clubbing, a deformity of the ends of the fingers
 Primary Sclerosing Cholangitis, a distinct disease that causes inflammation of
the bile ducts
Diagnosis
4
Year 4
1. In both inflammatory bowel diseases, the key diagnostic procedures are radiologic,
endoscopic and histologic.
2. In Crohn's disease, typical laboratory findings include anemia (chronic disease, iron
deficiency, vitamin B12 deficiency, folate deficiency), leukocytosis, thrombocytosis,
elevation of the sedimentation rate, hypoalbuminaemia and electrolyte imbalance in
the presence of severe diarrhea. The measurement of C-reactive protein appears to be
of use in monitoring the progress of the disease.
3. While, in ulcerative colitis, the laboratory findings are mostly non-specific, reflecting
blood loss and inflammation, and include anemia, leukocytosis, elevated
sedimentation rate and C-reactive protein levels. Seventy percent of patients with
ulcerative colitis, but not with Crohn's disease, have been reported to have in their
sera an anti-neutrophil cytoplasmic antibody (ANCA) that give a characteristic
perinuclear staining (PANCA) that can also be seen in primary sclerosing cholangitis.
4. General stool examination for occult blood.
5
Clinical Immunology Prof.Dr.Izzat Al-Rayahi
Year 4
Helicobacter pylori associated Chronic Gastritis & Mucosa-Associated Lymphoid

Tissue Lymphoma (MALT)
Gastritis is a histological term that describes stomach inflammation resulting from toxic
exposures, infection, idiopathic inflammation, and autoimmunity. The most common cause
of gastritis is H pylori infection. Other causes include acid reflux, prolonged use of
nonsteroidal anti-inflammatory drugs (NSAIDS), alcohol use, and tobacco use, all of
which can irritate the lining of the stomach. Severe illness and radiation therapy can also
cause gastritis
Erosive gastritis is most commonly caused by alcohol use, tobacco use, and prolonged
use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS). Severe illness and
consumption of caustic substances have also been associated with the development of
erosive gastritis. The most common cause of chronic, nonerosive gastritis is a stomach
infection caused by Helicobacter pylori (H pylori), a type of bacteria found in up to half of
all people in industrialized nations.
Symptoms
The signs and symptoms of gastritis vary among individuals. If infection with H pylori
bacteria is the cause, symptoms will remain as long as the infection is untreated. H. pylori
is uniquely adapted to the acidic environment of the stomach through its ability to
metabolize urea to ammonia, which provides a buffered microenvironment that allows
.prolonged asymptomatic colonization
Some people with gastritis have no symptoms at all, while others may have burning
abdominal pain, Loss of appetite, nausea with or without vomiting.
In some cases, gastritis can be life threatening, with symptoms including:
▪ Bloody stool (blood may be red, black, or tarry in texture)
▪ Severe abdominal pain
▪ Vomiting blood or black material (resembling coffee grounds)
Although acute infection can cause abdominal pain and dyspepsia, there is typically no
clinical recognition of acute infection. Rather, the burden of H. pylori results from chronic
infection of the stomach.The development of peptic ulcer disease and adenocarcinoma
caused by chronic H. pylori infection correlates with the anatomical distribution of
inflammation. When H. pylori chronic gastritis affects the antrum predominantly, there is
an association with duodenal ulcers, increased serum gastrin levels and excess acid
production, and no gastric mucosal atrophy. However, when H. pylori affects the body and
the antrum in a confluent or patchy manner, intestinal metaplasia develops, oxyntic
mucosa atrophies, and acid production decreases. This latter type of H. pylori chronic
gastritis is associated with gastric ulcerations and increased risk for adenocarcinoma and
mucosa-associated lymphoreticular tissue (MALT) B-cell lymphoma. Although
eradication of H. pylori can reverse the mucosal atrophy and restore acid production in this
setting, mucosal restoration occurs only in a minority of patients and does not necessarily
reverse the intestinal metaplasia.
Immune pathophysiology
Although there are many pieces of evidence to support immune mechanisms for the
persistence of HP infection in the stomach, data suggest that pro-regulatory effects of H.
pylori infection, including local IL-10 production, increases in regulatory T cells (Tregs)
in the gastric mucosa and increased antigen-presenting cell (APC) phagocytosis of
apoptotic cells all contribute to persistence of chronic H. pylori gastritis.
Diagnosis
Active disease can be diagnosed with endoscopic biopsy, which has high sensitivity and
specificity, while simultaneously assessing peptic and malignant complications.
Noninvasive testing for H. pylori infection includes serum antibody detection (best used in
highly endemic areas to predict active infection), urea breath testing (limited by expense
and possible false-positive results), and fecal antigen testing (which has potential
advantages in the setting of intestinal metaplasia and after antibiotic treatment).
Treatment
Once H. pylori infection is diagnosed, there are many effective eradication therapies that
need to be tailored to patients’ drug tolerance and allergy history as well as local antibiotic
resistance patterns. In general, a 14-day course with a proton pump inhibitor (histamine 2
[H2] blockers may be substituted) and two antibiotics (clarithromycin with amoxicillin or
metronidazole) is recommended as first-line treatment.13 Alternative regimens, including
bismuth or sequential therapy, may be needed in cases of antibiotic resistance. Eradication
of infection can be confirmed by either invasive or noninvasive (but not serum antibody)
methods.
1
Year 4
Primary Biliary Cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver that results in
chronic injury to the intrahepatic bile duct epithelium. The gradual inflammatory destruction
of the bile ducts causes cholestasis with the subsequent retention of toxins, inciting further
hepatic injury and resulting in fibrosis, cirrhosis, and eventual liver failure.
It is most common in women over the age of 50. The ratio of affected women to men has
been reported to be as high as 9:1.
Causes
The cause of the disease is unknown, but research indicates that there is immunological
basis for the disease, making it an autoimmune disorder. Most of the patients (>90%)seem
to have anti-mitochondria antibodies (AMAs) against pyruvate dehydrogenase complex
(PDC-E2), an enzyme complex that is found in the inner mitochondria membrane.
Molecular mimicry is the most widely proposed explanation as to the induction of
autoimmunity in PBC. Briefly, a host is infected with a microorganism that contains
antigens similar to antigens present in the host. These microbial antigens induce an
immunologic response when presented to the immune system of the host. As a result, what
began as a pathogen-specific response then cross-reacts with the host antigens and results in
tissue injury and disease.
The predisposing role of the HLA system to the disease has not been fully clarified, although
a weak but significant association with HLA-DR8 has been reported.
The pathogensis of the bile duct damage in PBS is unclear. Bile ducts in PBS patients
express increased densities of adhesion molecules, MHC classII antigens, IL-2 and pyruvate
dehydrogenase compared with normal ducts, and so represent potential targets for the
infiltrating activated T cells (CD4+ and CD8+ ).
Symptoms
The most common presenting symptoms include pruritis and fatigue. Jaundice, darkening
of the skin in exposed areas and manifestations resulting from impaired bile excretion
follow.latter range from steatorhoea to impaired absorption of lipid soluble vitamins ,
1
Year 4
leading to osteomalacia (from vitamin D malabsorption), bruising (vitamin K) and
occasionally night blindness (vitamin A).
Diagnosis
The diagnostic criteria for PBC include an elevation in liver enzymes (most notably alkaline
phosphatase) for a duration of six or more months, histologic findings, and the presence of
antimitochondrial antibodies in the serum. The presence of two criteria is highly suggestive
of the disease while a definite diagnosis requires all three.
Involvement of the liver is heterogeneous, so a biopsy may demonstrate different stages of
disease
 Stage I is characterized by portal inflammation comprised of predominantly
lymphoplasmacytic infiltrates. The pathognomonic lesion of PBC, the florid duct
lesion, represents focal duct obliteration by granuloma formation.
 Stage II there is extension of inflammation to theperiportal areas.
 Stage III. There is formation of fibrous septa that link adjacent portal triads and bile
duct loss (ductopenia).
 Stage IV is defined by frank cirrhosis.
2
Year 4
Primary Sclerosing Cholangitis
Primary Sclerosing Cholangitis(PSC) is a chronic liver disease that is characterized by
chronic inflammation and fibrosis leading to narrowing and dilatation of the intrahepatic or
extrahepatic bile duct, or both.
PSC typically presents in the fourth to fifth decades of life. Men are affected more often
than women.
Although the exact cause of PSC is unknown, it is considered autoimmune due to the
presence of autoantibodies.The condition is associated in the majority of cases with chronic
inflammatory bowel disease, particularly ulcerative colitis.
Patient may present with clinical, biochemical, immunological and histological features
indistinguishable from those of type I autoimmune hepatitis, though they have more
frequently an atypical peri-nuclear anti-neutrophil cytoplasmic antibody. This pANCA is
atypical in that its target antigen appears to be nuclear and not cytoplasmic.
The correct diagnosis can be made only by demonstrating the characteristic bile duct
abnormalities by specialized imaging such as endoscopic retrograde cholangio-
pancreatography or magnetic resonance cholangiography.
3
College of Health and Medical Techniques/ kufa
Clinical immunology
Fourth stage
Lecture :- ( 10 )
Renal disease
Introduction
The glomerulus is the communication point between the bloodstream
and nephron, the functional unit of the kidney. It is composed of the
glomerular capillaries and Bowman’s capsule of the nephron. Fluid from
the blood in the glomerular capillaries passes into the Bowman’s capsule
and then enters the tubules where it is processed to form urine. Each
kidney has about 1 million nephrons that act together to complete the
various functions including removing waste substances from the blood,
regulating blood volume and blood pressure. If a significant number of
nephrons are damaged, these functions will be significantly hampered.
Mesangial cells among the glomerular capillaries regulate the blood flow
in the capillaries. If these cells and layers of the glomerulus are damaged,
glomerular filtration and therefore normal kidney functioning is
impaired.
Renal diseases
Many renal diseases have underlying immunological mechanisms.
Antibody-mediated effects are primarily involved. Other mechanisms may
involve cell-mediated injury or cytotoxic antibodies. Immunological
diseases of the kidney mainly affect the glomerulus, which is most likely
due to its filter function. Circulating antibody-mediated renal diseases are
-: induced in three mechanisms
1- Circulating performed immune complexes accumulate sub-endothelial on
the capillary aspect of the basement membrane
,2- Antibodies may react in situ with the glomerular basement membrane
3- Antigens of the visceral epithelial cells.
Antibody deposits can cause direct damage to epithelial or endothelial cells
of glomerulus due to complement activation and pore formation. On the
other hand, the antibodies can also bind to the FC receptors of monocytes,
macrophages, granulocytes and platelets. This leads to the activation, or in
the case of platelets aggregation of the cells. The glomerular damage can
:cause two distinct symptom complexes
1- The nephrotic syndrome:

2-The nephritis syndrome:
Glomerulonephritis (GN)
Means inflammation in the kidneys either of the small blood vessels or of
the glomeruli but includes a number of disorders that affect the structure
and function of the glomerulus without any prominent inflammation. It is
therefore also referred to as glomerular disease or glomerulopathy. In
glomerulonephritis, various known and unknown causes trigger immune
activity against the glomeruli which damages it.
Diagnosing the pattern of GN is important because the outcome and
treatment differs in different types.
Pathophysiology of Glomerulonephritis
Glomerulonephritis is known to be an immune reaction mediated by
antigen-antibody complexes. An antigen is the trigger substance against
which antibodies are formed by the immune system. The antibodies then
bind with the antigen and this antigen-antibody complex can instigate a
number of immune activities designed to protect the body. In the process,
inflammation arises in whichever tissue that the targeted immune
response is occurring. Although the exact cause of glomerulonephritis is
not always understood, the mechanism by which it occurs is proposed in
two different models –
1-Immune complex deposition

2-Circulating immune complexes.
Other mechanisms may involve
4- cell-mediated injury or
5- cytotoxic antibodies.
In immune complex deposition, it is believed that antibodies are
directed against antigens that are “planted” in the glomerulus or against
antigens that are normal components of the glomerulus, specifically the
glomerular basement membrane (GBM). The immune activity is therefore
specifically targeted at the glomerulus.
With circulating immune complexes, the antigen-antibody

complexes are circulating in the bloodstream and eventually reach the
glomerulus during glomerular filtration. These complexes form in the
backdrop of several autoimmune or infectious diseases and the antigen may
be endogenous (created within the body) or exogenous (from foreign
matter or microorganisms) in nature. In these cases, immune activity is
targeted at the circulating immune complex and can lead to inflammation at
other sites in the body as well as the glomerulus.
In response to the inflammation, different histologic alterations

may be seen in the glomerulus. This includes:
• Increase in the number of cells (capillary endothelium or

mesangial cells)
• Thickening of the basement membrane
• Tissue degeneration – hyalinosis and sclerosis .
Types of Glomerulonephritis
1- Glomerulonephritis may be primary or secondary.
Primary glomerulonephritis arises on its own without any other
underlying disease. Secondary glomerulonephritis occurs as a
consequence of some other disease, which may not even involve the
kidney.
2- Acute and Chronic Glomerulonephritis

In acute glomerulonephritis, the condition starts suddenly and the tissue
damage progresses rapisdly .With chronic glomerulonephritis , the
condition develops gradually and damage becomes extensive after months
or years .
Signs and Symptoms of Glomerulonephritis
• Hematuria (blood in the urine) which may appear as pink-colored or
brownish urine.
• Proteinuria (protein in the urine) which may present as foamy urine
(frothy).
• Edema (swelling) most prominent in the face, hands, abdomen and

feet.
• Hypertension (high blood pressure)
• Azotemia (high urea levels in the blood) which leads to various

additional signs and symptoms (uremia).
Glomerulonephritis may lead to a collection of clinical features grouped

together as glomerular syndromes and includes:
• Nephrotic syndrome – proteinuria (protein in urine),

hypoalbuminema (low blood proteins), edema (swelling due to fluid
retention), hyperlipidemia (high blood lipids), lipiduria (lipids in the urine).
• Nephritic syndrome – hematuria (blood in urine), azotemia (high

urea levels in blood), proteinuria, oliguria (large volume of urine), edema,
and hypertension (high blood pressure).
• Rapidly progressing glomerulonephritis – nephritis (kidney

inflammation), proteinuria, and acute renal failure.
Additional signs and symptoms of glomerulonephritis may include:
• Anemia
• Fatigue
• Nausea and vomiting
• Paleness and/or yellowing of the skin
• Itching of the skin
• Dehydration
2
Clinical immunology
Fourth stage
Lecture :- ( 11 )
Renal disease
Rapidly progressive glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) describes a group of diseases
with aggressive glomerular injury which may be irreversible if not treated
early (e.g. antiglomerular basement membrane disease, anti neutrophil
.(cytoplasmic antibody associated glomerulonephritis
1- Anti-glomerular basement membrane disease

Anti–glomerular basement membrane (anti-GBM) disease is an autoimmune
disorder characterized by the presence of circulating pathogenic
autoantibodies directed against proteins in the glomerular and alveolar
basement membranes. In the kidneys, binding of these autoantibodies with
the GBM results in activation of the complement cascade and can lead
to rapidly progressive glomerulonephritis. In Goodpasture syndrome, (or
anti-GBM disease) is a rare, life-threatening autoimmune disease that affects
the lungs and the kidneys. It happens when the immune system mistakenly
attacks a protein called collagen because it recognizes it as a foreign
substance. In Goodpasture syndrome, the body produces proteins (antibodies)
that attach to the collagen in certain parts of the lungs and the kidneys. When
they attach to the collagen, these antibodies cause severe inflammation and
destruction of those tissues. An early and precise diagnosis of anti-GBM
disease is extremely important for preventing death and preserving renal
function. . If not treated promptly, anti-GBM disease can cause serious
complications, such as
1-Severe kidney inflammation, which can quickly lead to kidney failure
2-Severe bleeding in the lungs, which can cause respiratory failure .
Acute glomerulonephritis mediated by anti-glomerular basement membrane
(anti- GBM) antibody account for about 1-2% of all cases of
glomerulonephritis. Anti-CBM nephritis is more common in men and in those
who possess HLA-DR2 .
The target Ag is the α3 chain of type IV collagen, a major constituent of the
GBM.
Lung damage results from antibodies to antigens common to both alveolar
and glomerular basement membranes. In Goodpasture’s syndrome, respiratory
symptoms often precede renal disease by 1 year or longer. Haemoptysis,
usually leading to anemia, is a prominent feature and the sputum typically
contains haemosiderin-laden macrophages. biopsies show intra-alveolar
haemorrhage and necrotizing alveolitis.
Although the cause is unknown, anti-GBM disease follows upper respiratory
tract infections in 20-60% 0f patients, or exposure to certain hydrocarbons.
These agents may damage alveolar basement membrane, generating new and
potent antigens able to stimulate autoantibody production. Alternatively, the
agent responsible (e.g. a virus may cross-react with basement membrane
.antigens
Treatment
Immunosuppression with high-dose steroids and oral cyclophosphamide,
together with plasmapheresis, is used in the treatment of severe forms of this
disease
2-Anti-neutrophil cytoplasmic antibody associated glomerulonephritis
ANCA vasculitis is an autoimmune disease affecting small blood vessels in

the body. It is caused by autoantibodies called ANCAs, or Anti-
Neutrophilic Cytoplasmic Autoantibodies. ANCAs target and attack a
certain kind of white blood cells called neutrophils. They target a part of
neutrophils called the cytoplasm (the inside of the cell.)
When ANCAs (the autoantibodies) attach to neutrophils, it makes the
neutrophils attack small blood vessels in the body, and the blood vessels
become swollen and inflamed.
When blood vessels in the kidney are affected, it can cause blood and
protein to leak into the urine, as well as kidney damage (kidney function gets
worse)..
Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis

is the most frequent cause of rapidly progressive glomerulonephritis and is
usually classified as a pauci-immune type characterized by glomerular
necrosis and crescent formation.
Autoantibodies in ANCA
There are 2 main kinds of autoantibodies that can be involved in ANCA
vasculitis.
1- P-ANCA is called (perinuclear ANCA). This type of autoantibody
usually targets and attaches to something called MPO
(myeloperoxidase), which is inside of neutrophils.
2- C-ANCA is called (cytoplasmic ANCA). This type is usually targets
and attaches to something called proteinase 3 (PR3), which is also
inside of neutrophils.
Symptoms
There are many different symptoms that can occur in ANCA vasculitis If
the kidneys are affected
• Blood in the urine (may appear red or more often tea-colored)
• Foamy urine (due to protein in the urine)
• New or worsened high blood pressure
• Decreased kidney function or kidney failure – this often does not cause
a lot of symptoms until it is more advanced/severe, but symptoms can
include fatigue, nausea/vomiting, poor appetite, metallic taste
Diagnosis of ANCA
1- Blood tests for kidney function (creatinine), urine tests for blood and
protein, and looking at the urine under a microscope
2-Although a positive ANCA test (on bloodwork) can be very helpful in

pointing to a diagnosis of ANCA vasculitis, it is not a perfect test and cannot
determine the diagnosis alone.
3- A kidney biopsy can confirm the diagnosis.
(A) Light microscopy showing thickened glomerular capillary walls and a

fibrocellular crescent (PAM stain, ×400).
(B) Immunofluorescence staining revealing deposition of IgG along
glomerular capillary walls (×200).
(C) Electron micrograph showing thickened glomerular basement membrane
with diffuse subepithelial deposits and foot process effacement (×6500).
Treatment
In general, treatment for ANCA vasculitis involves 2 parts.
The first part is called induction therapy, which is aimed at trying to get the
disease controlled and into remission.
The second part of treatment is called maintenance therapy. Maintenance
therapy involves continuing immunosuppressive medications to keep the
disease in remission and decrease the chance that it will come back (relapse).
These are some of the treatments/medicines that can be used:
1-Corticosteroids:- Drug works by decreasing the movement of
polymorphonuclear leukocytes (PMNs) to sites of cellular and tissue injury to
decrease inflammation.
2- Cyclophosphamide:- Drugs of this class suppress the natural immune
system including B and T lymphocyte activity and function.
3- Rituximab :- is a medicine that reduces the number of immune cells in the
body
4- Azathioprine :- Drugs of this class alter RNA and DNA, building blocks
of all cells, resulting in blunting of the immune system.
Clinical immunology
Fourth stage
Lecture :- 12 & 13
Membranous Glomerulonephritis
MN is one of the most common causes of nephrotic syndrome. When your
immune system attacks the glomeruli in membranous nephropathy, it causes
changes to the filters that lead you to lose large amount of protein into the
urine. is a specific type of glomerulonephritis also known as membranous
glomerulopathy, Membranous nephropathy and extramembranous
glomerulonephritis . is a slowly progressive disease of the kidney affecting
mostly people between ages of 30 and 50 years, usually white people (i.e.,
those of European, Middle Eastern, or North African ancestry) .
Symptoms
The symptoms of MGN are different for everyone, and you may not have
symptoms at all. If symptoms do develop, they typically include:
• swelling of the hands, feet, or face

• fatigue
• foamy urine
• an excessive need to urinate at night
• weight gain
• poor appetite
• blood in the urine
Causes of membranous nephropathy (MN)
Most cases of MN are now known to be caused by an antibody to a protein
on the podocyte called the phospholipase A2 receptor (PLA2R). In most
people with MN, the body’s immune (defense) system makes an antibody (a
protein that normally helps fight infections). Instead of targeting an
infection, these antibodies attack the podocytes. The podocytes stop
retaining the proteins in the blood stream and allow them to leak into the
urine.
Pathophysiology of Membranous Glomerulonephritis
MGN is caused by immune complex formation in the glomerulus. The
immune complexes are formed by binding of antibodies to antigens in
the glomerular basement membrane. The antigens may be part of the
basement membrane, or deposited from elsewhere by the systemic
circulation.
The immune complex serves as an activator that triggers a response from the
C5b - C9 complements, which form a membrane attack complex (MAC) on
the glomerular epithelial cells. This, in turn, stimulates release of proteases
and oxidants by the mesangial and epithelial cells, damaging the capillary
walls and causing them to become "leaky". In addition, the epithelial cells
also seem to secrete an unknown mediator that reduces nephrin synthesis
and distribution.
Diagnosis of membranous nephropathy (MN)

• Blood test: Taking a sample of blood to measure levels of fat and
protein.
• Glomerular filtration rate (GFR): Studying a blood sample to
measure kidney function.
• Kidney biopsy: Taking a small sample of kidney tissue with a needle
and having a lab examine it to see if it contains an antibody associated
with MN.
• Urine test: Measuring levels of protein and blood in your urine.
• Antibody levels: blood sample to measure the levels of the antibody

against the phospholipase A2 receptor.
Treatment
For treatment of idiopathic membranous nephropathy, the treatment options
include immunosuppressive drugs and non-specific anti-proteinuric
measures such as ACE inhibitors or angiotensin II receptor blockers. Given
spontaneous remission is common, international guidelines recommend a
period of watchful waiting before considering immunosuppressive
treatment.[18] Likelihood of achieving spontaneous remission is much higher
if anti-proteinuric therapy with ace inhibitors or angiotensin II receptor
blockers is commenced.
Post infection Glomerulonephritis
Poststreptococcal glomerulonephritis (GN) is a kidney disorder that occurs
after infection with certain strains of streptococcus bacteria. is mainly seen
in countries in which antibiotics for streptococcal infections are not widely
available and accounts for about a third of cases of acute GMN. It is a
disease of children aged 2–10 years, but adolescents and adults may be
affected. Over 90% of cases are preceded by streptococcal infection of the
throat or skin. Patients typically present with acute nephritis 7–12 days after
a throat infection or about 3 weeks after a skin infection.
Symptoms
Symptoms may include any of the following:
• Decreased urine output

• Rust-colored urine
• Swelling (edema), general swelling, swelling of the abdomen, swelling of
the face or eyes, swelling of the feet, ankles, hands
• Visible blood in the urine
• Joint pain
• Joint stiffness or swelling
Causes
Poststreptococcal GN is a form of glomerulonephritis. It is caused by an

infection with a type of streptococcus bacteria. The infection does not occur
in the kidneys, but in a different part of the body, such as the skin or throat.
The disorder may develop 1 to 2 weeks after an untreated throat infection, or
3 to 4 weeks after a skin infection.
The condition is not common today because infections that can lead to the
disorder are treated with antibiotics.
Pathophysiology
APSGN is an immune complex-mediated disease. Several mechanisms may

participate in the pathogenesis of renal damage. Nephritogenic immune
complexes are formed in circulation and deposited in the glomeruli;
alternately, the antigen and antibody arrive separately and meet in or outside
the glomerular basement membrane, causing in situ immune complex
disease. Immune cell recruitment, production of chemical mediators and
cytokines, and local activation of the complement and coagulation cascades
drive an inflammatory response that is localized in the glomeruli. Glomerular
deposition of circulating immune complexes depends on the antigen load, the
antigen:antibody ratio, and the size of the immune complexes . In
situ formation of immune complexes is favored by cationic antigens that
have a charge-dependent facilitated penetration into the polyanionic
glomerular basement membrane, and tend to occur in conditions of antigen
excess
Diagnosis
Laboratory investigations are the most useful in PSGN assessment.
• Evidence of a preceding streptococcal infection is determined by
measuring anti-streptolysin titer (ASO), and anti-nicotinamide-
adenine dinucleotidase (anti-NAD) which tend to rise following
pharyngitis. Other antibodies such as anti-DNAse B and anti-
hyaluronidase (AHase) are usually elevated after both pharyngitis and
skin infections. ASO titer is the most frequently used test, while the
most sensitive is the streptozyme test; which includes measuring the
titers of all the antibodies mentioned above. ASO titers can be falsely
low in patients treated with antibiotics for streptococcal infections.
• Serum complement level (C3) is usually low due to its consumption in
the inflammatory reaction. Mostly, the decrease in C3 concentration
occurs before serum ASO has risen.Complement levels usually return
to normal levels in 6-8 weeks.
• Urineanalysis: shows macroscopic or microscopic hematuria, RBC
casts, mild proteinuria. Only 5% of patients with PSGN have massive
proteinuria that indicates nephrotic syndrome. White blood cell casts,
hyaline, and cellular casts are usually present in the urine analysis.
• Renal Function Tests: Blood urea nitrogen and serum creatinine
typically elevate during the acute phase. These values usually return
to normal later.
Renal biopsy is not recommended for diagnosing patients with PSGN and is
performed only when other glomerular pathologies are suspected.
Treatment
There is no specific treatment for this disorder. Treatment is focused on

relieving symptoms.
• Antibiotics, such as penicillin, will likely be used to destroy any

streptococcal bacteria that remain in the body.
• Blood pressure medicines and diuretic drugs may be needed to control
swelling and high blood pressure.
• Corticosteroids and other anti-inflammatory medicines are generally not
effective.
You may need to limit salt in your diet to control swelling and high blood
pressure.
IgA Nephropathy
IgA nephropathy is a chronic kidney disease. It progresses over 10 to 20

years, and can lead to end-stage renal disease. It is caused by deposits of the
protein immunoglobulin A (IgA) inside the filters (glomeruli) in the
kidney.It is one of the most common causes of
primary glomerulonephritis in the world .
IgA nephropathy was first described by Berger and Hinglais in 1968, and is
also known as Berger disease.
It accounts for about 10% of all cases of primary glomerular disease in the
USA, 20% of cases in Europe and 30–40% in Asia.
Symptoms
IgA nephropathy usually asymptomatic in the early stages, so the disease

can go unnoticed for years or decades. It's sometimes suspected when
routine tests reveal protein and red blood cells in your urine that can't be
seen without a microscope (microscopic hematuria).
Signs and symptoms of IgA nephropathy include:
• Cola- or tea-colored urine (caused by red blood cells in the urine)

• Repeated episodes of cola- or tea-colored urine, and sometimes visible
blood in your urine, usually during or after an upper respiratory or other
infection and sometimes after strenuous exercise
• Foamy urine from protein leaking into your urine (proteinuria)
• Flank pain :- Pain in the one or both sides of your back below your ribs
• Swelling (edema) in your hands and feet
• High blood pressure (Hypertension)
Pathophysiology
The disease derives its name from deposits of Immunoglobulin A
(IgA) in a granular pattern in the mesangium (by immunofluorescence), a
region of the renal glomerulus. The mesangium by light microscopy may be
hypercellular and show increased deposition of extracellular matrix proteins.
There is no clear known explanation for the accumulation of the

IgA. Exogenous antigens for IgA have not been identified in the kidney, but
it is possible that this antigen has been cleared before the disease manifests
itself. It has also been proposed that IgA itself may be the antigen.
The exact pathogenesis of IgA nephropathy is still not well defined. Current
data implicate an important genetic factor, especially in promoting the
overproduction of an aberrant form of IgA1. The immunochemical
aberrancy of IgA nephropathy is characterized by the undergalactosylation
of O-glycans in the hinge region of IgA1. However, such aberrant
glycosylation alone does not cause renal injury. The next stage of disease
development requires the formation of glycan-specific IgG and IgA
antibodies that recognize the undergalactosylated IgA1 molecule. These
antibodies often have reactivity against antigens from extrinsic
microorganisms and might arise from recurrent mucosal infection. B cells
that respond to mucosal infections, particularly tonsillitis, might produce the
nephritogenic IgA1 molecule. With increased immune-complex formation
and decreased clearance owing to reduced uptake by the liver, IgA1 binds to
the glomerular mesangium via an as yet unidentified receptor. Glomerular
IgA1 deposits trigger the local production of cytokines and growth factors,
leading to the activation of mesangial cells and the complement system.
Emerging data suggest that mesangial-derived mediators following
glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury
via mesangio–podocytic–tubular crosstalk. This Review summarizes the
latest findings in the pathogenesis of IgA nephropathy.
Diagnosis
1- ultrasound of the kidney and cystoscopy are usually done first for an adult
patient with isolated hematuria, to pinpoint the source of the bleeding. In
children and younger adults, the history and association with respiratory
infection can raise the suspicion of IgA nephropathy.
2- A kidney biopsy is necessary to confirm the diagnosis. The biopsy
specimen shows proliferation of the mesangium, with IgA deposits on
immunofluorescence and electron microscopy.
3- A urinalysis will show red blood cells, usually as red cell urinary casts.
Proteinuria, usually less than 2 grams per day, also may be present.
4- Other blood tests done to aid in the diagnosis include CRP or ESR,
complement levels, ANA, and LDH. Protein electrophoresis and
immunoglobulin levels can show increased IgA in 50% of all patients.
Treatment for IgA nephropathy

Treatment for IgA nephropathy includes medication to:
• Control blood pressure with angiotensin-converting enzyme (ACE)
inhibitors, angiotensin receptor blockers (ARBs), or other medicines.
• Remove extra fluid with a diuretic.
• Controlyour immune system to lower kidney inflammation with

prescribed steroids such as prednisone or cyclophosphamide.
• Lower your cholesterol levels with medications such as statins.
Clinical immunology
Fourth stage
Lecture :- 14 & 15
Glomerulonephritis associated with systemic disease
A- Lupus Nephritis
B- Henoch-Schonlein Purpura
A- Lupus Nephritis :- Lupus is an autoimmune disease that triggers

your immune system to attack your tissues. In addition to your kidneys,
lupus can damage your brain, heart, joints, skin and other parts of your body.
Stages of Lupus Nephritis

Based on the kidney biopsy, will know the stages or classification of lupus
nephritis. The six stages, or classes, are based on:
a- Cell changes in the glomeruli as seen under the microscope
b- Immune deposits seen on immunofluorescence
C- Electronic microscopy
Stage 1: Minimal mesangial glomerulonephritis
• Minor kidney damage
• No obvious other signs or symptoms

Stage 2: Mesangial proliferative glomerulonephritis
• Some clear damage to the kidney
• Extra blood or protein in your urine that your health care team can
detect with lab tests
Stage 3 : Focal glomerulonephritis
• More damage that amounts to less than 50% of important blood vessels
in your kidney
• Higher amounts of blood or protein in urine
• Possible high blood pressure
Stage 4: Diffuse proliferative nephritis

• Damage that amounts to more than 50% of important blood vessels in
the kidney
• Blood or protein in urine
• Possible need for dialysis as kidneys stop working properly
Stage 5: Membranous glomerulonephritis

• Thickening of important parts of the kidney
• Blood or protein in urine
• Dialysis or possible kidney transplant
Stage 6: Advanced sclerotic

• Damage to more than 90% of important kidney blood vessels
• When treatment is possible, may need dialysis or kidney transplant
• Plus other signs: Blood or protein in urine and high blood pressure
Symptoms of lupus nephritis

Symptoms of lupus nephritis tend to develop about five years after lupus
symptoms first appear. But lupus nephritis can be the first — and sometimes
the only — manifestation of systemic lupus erythematosus (SLE). Lupus
nephritis can cause:
1. Edema (swelling due to fluid buildup) in your lower body or around
your eyes.
2. Fever with no known cause.
3. Hematuria (blood in the urine).

4. High blood pressure.
5. Increased urination, especially at night.
6. Joint
pain or swelling.
7. Muscle pain.
8. Proteinuria (protein in the urine), which often causes your urine to look
foamy.
9. Red skin rash on the face.
10. Weight gain due to excess fluid in your body.
Causes lupus nephritis

No one knows why some people with SLE develop lupus nephritis. Your
family background and ancestry, medical conditions, and environmental
factors such as exposure to chemicals or pollutants may all play a role in
causing the disease.
Lupus nephritis usually gets worse over time, which can lead to kidney
failure. The cause of lupus in most cases, however, is unknown.
Pathophysiology
Autoimmunity plays a major role in the pathogenesis of lupus nephritis.
The immunologic mechanisms include production of autoantibodies
directed against nuclear elements. The characteristics of the nephritogenic
autoantibodies associated with lupus nephritis are as follows :
1. Antigen
specificity directed against nucleosome or double-stranded
DNA (dsDNA) - Some anti-dsDNA antibodies cross-react with the
glomerular basement membrane
2. Higher-affinity
autoantibodies may form intravascular immune
complexes, which are deposited in glomeruli
3. Cationic
autoantibodies have a higher affinity for the anionic
glomerular basement membrane
4. Autoantibodies of certain isotypes (immunoglobulin [Ig] G 1 and

IgG 3) readily Activate complement
These autoantibodies form pathogenic immune complexes intravascularly,

which are deposited in glomeruli. Alternatively, autoantibodies may bind to
antigens already located in the glomerular basement membrane, forming
immune complexes in situ. Immune complexes promote an inflammatory
response by activating complement and attracting inflammatory cells,
including lymphocytes, macrophages, and neutrophils.
Diagnosis of lupus nephritis

The diagnosis of lupus nephritis depends on
1- blood tests .
2- urinalysis :- a nephritic picture ( i.e symptoms of nephritic ) is found and
red blood cell casts, red blood cells and proteinuria is found.
3- X-rays .
4- ultrasound scans of the kidneys .
5- kidney biopsy.
Treatment of lupus nephritis
1- Corticosteroids :- These strong anti-inflammatory drugs can

decrease inflammation .
2- Immunosuppressive drugs :- These drugs, which are related to the ones
used to treat cancer or prevent the rejection of transplanted organs, work by
suppressing immune system activity that damages the kidneys. They include
azathioprine (Imuran), cyclophosphamide (Cytoxan), voclosporin
(Lupkynis) and mycophenolate (Cellcept).
3- Medications to prevent blood clots or lower blood pressure if needed .
The goals of treatment for lupus nephritis are to:
1- Reduce inflammation in your kidneys .

2- Decrease immune system activity .
3- Block your body’s immune cells from attacking the kidneys directly or
making antibodies that attack the kidneys .
B- Henoch-Schonlein Purpura
(HSP) is an acute immunoglobulin A (IgA)–mediated disorder characterized
by a generalized vasculitis involving the small vessels of the skin, the
gastrointestinal (GI) tract, the kidneys, the joints, and, rarely, the lungs and
the central nervous system (CNS). It most commonly occurs in children. It
most commonly occurs in children.
Symptoms of Henoch-Schonlein Purpura

1- The main symptom is a spotty rash
with numerous small bruises rash
2- joint pain and swelling
3- Abdominal pain
4- Blood in urine.
Before these symptoms begin, patients may have two to three weeks of
fever, headache, and muscular aches and pains. Rarely, other organs, such as
the brain, lungs, or spinal cord may be affected .
Causes and Risk Factors for Henoch-Schonlein Purpura

The exact cause of HSP is not known. The body's immune system is
believed to play a role in targeting the blood vessels involved. An abnormal
immune response to an infection may be a factor in many cases.
Approximately two-thirds of the cases of HSP occur days after symptoms of
an upper respiratory tract infection develop.
Some causes of HSP have been linked to
1- vaccinations for typhoid, cholera, yellow fever, measles, or
hepatitis B
2- foods
3 - Drugs
4- Chemicals
5- Insect bites.
6-Some experts also say that HSP is associated with the colder
weather of fall and winter.
Diagnosis of Henoch-Schonlein Purpura

There is no specific test to diagnose HSP. It is diagnosed based on
recognition of the classic symptoms, and exclusion of other conditions that
can cause a similar rash. In many children with a classic rash, minimal
testing is needed to establish a diagnosis of HSP. The rash is necessary for
the diagnosis of HSP but is not always the first symptom to appear. When
joint pain, swelling, or abdominal pain start before appearance of the rash, it
can cause diagnosis can be challenging.
Tests in children with suspected HSP depend on the patient, but might
include the following:
• Platelet count and coagulation studies to looks for other causes of bleeding.
• Laboratory tests to rule out other causes of vasculitis.
• Evaluation of kidney function by blood pressure check, creatinine level,

electrolytes, and urine sample.
• Insome patients, a biopsy may be taken of the skin, kidney or other tissue.
Biopsies in patients with HSP often show high levels of a specific type of
immune protein, called immunoglobulin A (IgA).
• Imaging of the bowels may be performed if abdominal pain is severe.

Treatment of Henoch-Schönlein purpura
Most of the time, Henoch-Schönlein purpura improves on its own without
treatment. Medical care is more likely to be needed if HSP involves the
kidneys.
To help the children to feel better, the doctor may recommend medicines
such as:
• antibiotics, if an infection is causing the HSP .
• pain relievers (such as acetaminophen) .
• anti-inflammatory medicines (such as ibuprofen) to relieve joint pain and

inflammation .
• corticosteroids (such as prednisone) for severe belly pain or kidney disease

Clinical immunology
Fourth stage
Lecture :- week 17
Respiratory disease
1- Drug-Induced Pulmonary Disease
Drug-induced pulmonary disease is lung disease brought on by a bad reaction to a
medicine. Pulmonary means related to the lungs.
What is the most common drug-induced respiratory

problem?
Interstitial pneumonitis (ie, inflammation of the lung interstitium, such as the
alveolar septa) is the most common manifestation of drug-induced lung disease.
The Common Types of Drug-induced Pulmonary Diseases

There are different types of lung or pulmonary diseases caused by drugs are:
1. Allergic reactions like asthma, hypersensitivity pneumonitis, or
eosinophilic pneumoni
2. -Lymph node swelling
3. Alveolar haemorrhage, i.e. bleeding into lung sacs .
4. Bronchitis, i.e., inflammation of the airways .
5. Pneumonia
6. Pulmonary edema, i.e., fluid accumulation in the lungs .
7. Pleural effusion i.e., fluid accumulation around the lungs .

8. Pulmonary fibrosis i.e., formation of scar tissue in the lungs .
9. Pulmonary arterial hypertensioni.e defined as a mean pulmonary

arterial pressure greater than 25 mm Hg at rest or greater than 30 mm Hg
during exercise .
10- Lung failure .
Many medicines and substances are known to cause lung disease in some
people. These include:
• Antibiotics, such as nitrofurantoin and sulfa drugs
• Heart medicines, such as amiodarone
• Chemotherapy drugs such as bleomycin, cyclophosphamide, and methotrexate
• Street drugs
Symptoms
Symptoms may include any of the following:
• Bloody sputum
• Chest pain
• Cough
• Fever
• Shortness of breath
• Wheezing
Diagnosis of Drug-induced Pulmonary Diseases

It has always been a challenge for pulmonologists to diagnose drug-induced
pulmonary disease. The medications can cause reactions in varied forms, which
makes it difficult for pulmonologists to identify the drug or its reaction.
Tests that could detect changes in the lungs include the following:
1. Imaging tests like chest x-ray and chest CT scan .
2. Lung function tests : The primary purpose of pulmonary function testing is to

identify the severity of pulmonary impairment. The tests measure lung
volume, capacity, rates of flow, and gas exchange.
3. Bronchoscopy : is a procedure to look directly at the airways in the lungs
using a thin, lighted tube (bronchoscope). The bronchoscope is put in the nose
or mouth. It is moved down the throat and windpipe (trachea), and into the
airways .
4. Blood tests to rule out SLE-like reactions as a cause of the lung disease
5. Lung Biopsy, in rare cases
Clinical immunology
Fourth stage
Lecture :- week 18
Respiratory disease
2- Eosinophilic Pneumonia
Chronic eosinophilic pneumonia (CEP) is an idiopathic disorder

characterized by an abnormal and marked accumulation of eosinophils in the
interstitium and alveolar spaces of the lung causing inflammation and
damage. Causes include smoking, allergic reactions and parasitic infections.
EP may occur suddenly or worsen slowly.
What are the types of eosinophilic pneumonia?
There are three main types of eosinophilic pneumonia. They include:

• Acute eosinophilic pneumonia: This type worsens quickly as
your blood oxygen level falls. Most patients with AEP completely
recover with treatment.
• Chronic eosinophilic pneumonia: This type worsens slowly, over
days or weeks. If untreated, it may persist over weeks or months and
result in severe symptoms.
• Löffler syndrome (simple pulmonary eosinophilic, or
SPE): This form of eosinophilic pneumonia may cause no symptoms
or only mild symptoms such as a dry cough. Löffler syndrome occurs
due to a parasitic infection (roundworms). With treatment, the
condition typically resolves within one month.
Causes of Eosinophilic pneumonia

Eosinophilic pneumonia has many causes, both infectious and noninfectious.
But healthcare providers don't always know the exact cause.
Common noninfectious triggers include:
• Allergic reactions.
• Fungus (usually aspergillosis).

• Inhaled toxins, such as chemical fumes or particulate metals (found in
the air) or dust.
• Medication, including commonly used antibiotics, nonsteroidal anti-
inflammatory drugs (NSAIDs) or selective serotonin reuptake
inhibitors (SSRIs).
• Smoking, especially if you've had a change in cigarette smoking habits
(starting smoking for the first time or smoking more often).
• Underlying conditions, including cancer, autoimmune disease or
inflammatory disease.
The symptoms of eosinophilic pneumonia
Signs of eosinophilic pneumonia vary, depending on the type and cause.
Common symptoms include:
• Cough.
• Fever.
• Shortnessof breath (dyspnea).

Acute eosinophilic pneumonia can worsen quickly, often within two weeks.
Symptoms are usually more severe in people who smoke and may include:
• Chest pain.
• Chills.
• Fatigue.
• Muscle aches or muscle pain (myalgia).
Without prompt diagnosis and treatment, the oxygen in your blood may fall
to dangerously low levels. This can lead to acute respiratory failure in a few
hours, requiring emergency treatment.
Common symptoms include:

• Shortnessof breath that worsens.
• Night sweats.
• Unexplained weight loss.
• Wheezing.
Pathogenicity of Chronic Eosinophilic Pneumonia

The pathophysiological role of eosinophils in autoimmune diseases is not
well defined; however, it has been shown that the production of pro-
inflammatory cytokines stimulates and activates different cell groups, and
can simultaneously induce autoantibodies and/or increased infiltration of
eosinophils in various tissues, without an underlying autoimmune disease.
A proposed model for the pathogenesis of acute eosinophilic pneumonia. IL-
33 may be released by damaged epithelial cells responding to noxious
stimulants such as allergens, infectious pathogens, and other inhalational
toxins, including cigarette smoke. IL-33 and vascular endothelial grow
factor (VEGF) may also be released by endothelial cells after drug-induced
injury. In addition to IL-33, acute exposure to cigarette smoking induces
epithelial cell release of IL-8, which mediates recruitment and activation of
neutrophils. An additional source of IL-33 in the lung may be the activation
of innate type 2 lymphoid cells, which have the capacity to rapidly generate
IL-33 in response to certain stimuli. Subsequent generation and binding of
IL-33 to cells expressing its receptor (ST2), including macrophages and
dendritic cells, may lead to recruitment and activation of T-helper cell type 2
(Th2)-polarized T lymphocytes and production of cytokines like IL-5, which
further promote recruitment and activation of eosinophils in the lung tissue.
Eosinophils may also migrate into the lung because of chemokine gradients
and increased permeability in the context of endothelial injury.
Diagnosed of Eosinophilic pneumonia
• medical history and travel.
• physical exam.
• Blood tests, including a complete blood count, to detect abnormalities.

• Broncho alveolar lavage (BAL) is the most important test to diagnose
EP. Uses a flexible tube (bronchoscope) to collect fluid from your
lungs to look for signs of disease.
• Chest x-ray and CT scan.
• Peripheral blood eosinophilia count , peripheral eosinophilia is often

present in chronic eosinophilic pneumonia.
• Sedimentation rate (ESR)
The treatment for eosinophilic pneumonia

It may not treat a mild case of EP.
The three main types of eosinophilic pneumonia are treated with
.medications to control the underlying cause and its symptoms
Corticosteroids to reduce swelling (inflammation) are the standard
therapy and highly effective.
In severe cases of AEP, providers may recommend other treatments to
prevent respiratory failure:
• Supplemental oxygen.
• Glucocorticoids (a type of corticosteroid).

People with CEP often take steroids for an extended period, usually months.
Some may require longer treatment.
Clinical immunology
Fourth stage
Lecture :- week 18
Respiratory disease
3- Occupational lung diseases
Occupational or work-related lung diseases are lung conditions that have
been caused or made worse by long-term exposure to certain irritants in the
workplace. Dust particles, chemicals, fungal spores, and certain animal
droppings are examples of exposures that may increase your risk of
developing occupational lung disease.
There is no cure for occupational lung diseases. Controlling your exposure

to lung irritants and treatment can help slow the disease progression, lessen
symptoms, and improve your quality of life. If you smoke, quit. Smoking
can cause or worsen lung disease.
The symptoms of an occupational lung disease
• Coughing
• Shortness of breath
• Chest pain
• Chest tightness
• Abnormal breathing pattern .

Types of occupational lung diseases
• Asthma.
• Bronchiolitisobliterans.
• COPD.( Chronic obstructive pulmonary disease )
• Hypersensitivity pneumonitis.
• Lung cancer.
• Mesothelioma.
• Pneumoconiosis.
The difference between inorganic and organic dust
Inorganic refers to any substances that do not contain carbon, excluding
certain simple carbon oxides, such as carbon monoxide and carbon dioxide.
Organic refers to any substances that do contain carbon, excluding
simple carbon oxides, sulfides, and metal carbonates .
Exposure to environmental and occupational lung

irritants may put you at risk of developing chronic lung
disease, including:
1. Silicosis is caused by breathing in tiny bits of silica, a mineral found in sand,
quartz, and many other types of rock. Silicosis mainly affects workers
exposed to silica dust in jobs such as construction and mining.
2. Coccidioidomycosis or Valley fever is an infection caused by breathing

in the spores of the fungus Coccidioides found in the soil. Valley fever
mainly affects workers exposed to dust storms or areas where contaminated
soil is being disturbed, in jobs like construction or farming.
3. Hypersensitive pneumonitis is caused when you breathe in a specific

substance (allergen) that triggers an allergic reaction in the body.
4. Histoplasmosis is caused by breathing fungal spores from soil that has

been contaminated by bird or bat droppings. Some occupations that may
expose workers to spores are farmers, pest control workers, poultry keepers,
construction workers and landscapers.
5. Asbestosis is a naturally occurring mineral used as an insulation material

and as a fire retardant. The main group at risk for asbestosis is people who
worked in mining, milling, manufacturing, installation, or removal of
asbestos products .
6. Coal workers pneumoconiosis, commonly known as black lung disease,

occurs when coal dust is inhaled. Continued exposure to coal dust causes
scarring in the lungs.
7. Mesothelioma is a rare type of cancer that occurs in the lining of the lungs
and less commonly the lining of the abdomen. Asbestos exposure is the
primary risk factor for mesothelioma. Occupations such as mining or
milling, electricians, plumbers, pipe-fitters, insulators, or even remodelers of
older homes still have a high risk of exposure.
8.Work-related asthma:- Men working in forestry and minerals
and women working in service industries (waitresses, cleaners, and
dental workers) are most likely to develop occupational asthma.
Diagnose of an occupational lung disease

• Pulmonary function tests: diagnostic tests that help to measure the
lungs' ability to move air into and out of the lungs effectively. The
tests are usually performed with special machines into which the
person must breathe.
• Microscopic examination from biopsy or autopsy of tissue, cells,
and fluids from the lungs
• Measurement of respiratory or gas exchange functions
Examination of airway or bronchial activity
•
How can occupational lung diseases be prevented?

The best prevention for occupational lung diseases is avoidance of the
inhaled substances that cause lung diseases and Do not smoke. Smoking can
actually increase the risk for occupational lung disease.
Clinical immunology
Fourth stage
Lecture :- week 19
Respiratory diseases
4- Asthma
A chronic disease in which the bronchial airways in the lungs become
narrowed and swollen, making it difficult to breathe. Symptoms include
wheezing, coughing, tightness in the chest, shortness of breath, and rapid
breathing. An asthma attack may be brought on by pet hair, dust, smoke,
pollen, mold, exercise, cold air, or stress.
Asthma signs and symptoms include:
1. Shortness of breath
2. Chest tightness or pain
3. Wheezing when exhaling, which is a common sign of asthma in
children
4. Trouble sleeping caused by shortness of breath, coughing or wheezing
5. Coughing or wheezing attacks that are worsened by a respiratory virus,

such as a cold or the flu
Types of asthma
1. Allergic asthma
2. Seasonal asthma
3. Non allergic asthma
4. Exercise induced asthma
5. Difficult asthma
6. Childhood asthma
Causes
It isn't clear why some people get asthma and others don't, but it's probably
due to a combination of environmental and inherited (genetic) factors.
Exposure to various irritants and substances that trigger allergies (allergens)
can trigger signs and symptoms of asthma. Asthma triggers are different
from person to person and can include:
1. Airborne allergens, such as pollen, dust mites, mold spores, pet dander
or particles of cockroach waste
2. Respiratory infections, such as the common cold
3. Physical activity
4. Cold air
5. Air pollutants and irritants, such as smoke
6. Certain medications, including beta blockers, aspirin, and nonsteroidal

anti-inflammatory drugs, such as ibuprofen (Advil, Motrin IB, others)
and naproxen sodium (Aleve)
7. Strong emotions and stress
8. Sulfitesand preservatives added to some types of foods and beverages,
including shrimp, dried fruit, processed potatoes .
9. Gastroesophageal reflux disease (GERD), a condition in which stomach
acids back up into your throat
Pathophysiology
There are two phases of an asthma exacerbation, which include the
early phase and late phase. The early phase is initiated by IgE
antibodies that are sensitized and released by plasma cells. These
antibodies respond to certain triggers in the environment, such as the
risk factors listed above. IgE antibodies then bind to high-affinity mast
cells and basophils. When a pollutant or risk factor gets inhaled, the
mast cells release cytokines and eventually de-granulate. Released
from mast cells are histamine, prostaglandins, and leukotrienes.
Simultaneously, cytokines derived from the mast cell will signal other
inflammatory cells and their mediators to the lung. The result is airway
inflammation, increased vascular permeability, mucus secretion,
bronchospasm, and wheezing. These events are referred to as the early
asthmatic response because they occur within minutes. A major component
of the early response is bronchospasm.
The late asthmatic response is delayed by hours. It is caused by a multitude
of inflammatory cells continuing the inflammatory process. Of the
inflammatory cells, the T cells play an important role. Antigen presenting
cells may present a variety of allergenic antigens to chronically activated
T helper cells. These cells then secrete multiple cytokines that maintain and
intensify the local inflammatory response. Many other inflammatory cells,
including mast cells and eosinophils, will respond to the T cells' cytokines.
These inflammatory cells will produce cytokines, which amplify the cellular
response and the inflammatory reaction. There is a migration of
inflammatory cells from the circulation into the pulmonary vasculature and
the airway submucosa. A central component to the inflammatory process as
well as treatment is the arachidonic acid pathway, which leads to the
generation of leukotrienes.
Diagnosis
1- Physical exam
2- Lung function tests :- These are also called (pulmonary function tests.)
Lung function tests detect how well you inhale (breathe in) and exhale
(breathe out) air from your lungs. These tests measure breathing.
Lung function tests are often done before and after inhaling a medication
known as a bronchodilator. This medicine opens the airways. If lung
function improves a lot with a bronchodilator, the patient likely has asthma.
Common Lung function tests used to assess airways

include:
a. Spirometry: A type of lung function test that measures how much you
breathe in and out and how fast you breathe out.
b. FeNO test (exhaled nitric oxide): A test that helps assess
inflammation in the airways.
c. Bronchial provocation or “trigger” tests: Tests that measure if lungs
are sensitive to certain irritants or triggers such as methacholine or
histamine.
d. Diffusion Capacity: Diffusion capacity measures how well oxygen

flows from the lungs into your blood. Poor diffusion indicates damage
to the lung where the oxygen and blood meet in the lungs. Diffusion
capacity is usually normal in asthmatics.
3- Allergy tests
Blood tests: measured the levels of immunoglobulin E (IgE) and -4
.Eosinophil . If the levels are high, this could be a sign of severe asthma
5-Chest X-Ray :- in asthma, the chest X-ray is likely to show air

trapping or hyper-expansion.
Treatment of asthma
• Bronchodilators: These medicines relax the muscles around your
airways. The relaxed muscles let the airways move air. They also let
mucus move more easily through the airways. These medicines
relieve your symptoms when they happen and are used for intermittent
and chronic asthma.
• Anti-inflammatory medicines: These medicines reduce

swelling and mucus production in your airways. They make it easier
for air to enter and exit your lungs.
• Biologic therapies for asthma: These are used for severe

asthma when symptoms persist despite proper inhaler therapy.
Clinical immunology
Fourth stage
Lecture :- week 20
Respiratory disease
5- Non-allergic bronchitis
It is a form of lower respiratory tract infection occurs due to a viral or

bacterial infection. Some people develop non-allergic bronchitis after a cold,
for instance. Bronchitis can be acute or chronic. Acute form leads to cough,
which may contain mucus, while in case of chronic bronchitis, cough last for
more than a few months. Air pollution and smoking are some major causes
of bronchitis.
Symptoms of Acute Bronchitis

Each person is different, and symptoms will vary depending on the cause of
inflammation. The symptoms associated with acute bronchitis are similar to
those of the cold and flu and last less than 3 weeks .
• Coughing with or without mucus
• A runny nose
• A sore throat
• Sneezing
• Fever & chills
• Breathing difficulties
• Extreme fatigue
• Mild headache
• Mild body ache
Causes
A virus usually causes acute bronchitis. Bacteria can sometimes cause acute
bronchitis. But, even in these cases, taking antibiotics is NOT advised and
will not help you get better.
Diagnosis
1. Spirometry :- A test that measures lung function as breathe in and

out of a mouthpiece that is attached to a device called a spirometer.
2. Peak expiratory flow :- A test that measures the force of air
breathe out (exhale) into the mouthpiece of a device called a peak
expiratory flow meter
3. Chest X-ray :- A radiology test that produces images of the chest to

look for evidence of other conditions that could be causing your
coughand breathing problems.
4. Complete blood count (CBC) with differential
5. Procalcitonin levels (to distinguish bacterial from nonbacterial

infections)
6. Sputum cytology (if the cough is persistent)
7. Blood culture (if bacterial superinfection is suspected)
8. Chest radiography (if the patient is elderly or physical findings

suggest pneumonia)
9. Bronchoscopy (to exclude foreign body aspiration, tuberculosis,

tumors, and other chronic diseases)
10.Influenza tests
11. Laryngoscopy (to exclude epiglottitis)
Treatment
Treatment of acute bronchitis is typically divided into two categories:
antibiotic therapy and symptom management.
Clinical immunology
Fourth stage
Lecture :- week 23
Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemia (or autoimmune haemolytic anaemia;

AIHA) occurs when antibodies directed against the person's own red blood
cells (RBCs) cause them to burst (lyse), leading to an insufficient number of
oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs
is reduced from the normal 100–120 days to just a few days in serious cases.
The intracellular components of the RBCs are released into the circulating
blood and into tissues, leading to some of the characteristic symptoms of this
condition. The antibodies are usually directed against high-incidence
antigens, therefore they also commonly act on allogenic RBCs (RBCs
originating from outside the person themselves, e.g. in the case of a blood
transfusion). AIHA is a relatively rare condition, affecting one to three
people per 100,000 per year.
Autoimmune hemolytic anemia is a group of disorders characterized by a

malfunction of the immune system that produces autoantibodies, which
attack red blood cells as if they were substances foreign to the body.
Types :-There are two classifications for AIHA:

1- warm and cold (The classification depends on the type of antibodies
involved.)
2- a. Primary AIHA is when there is no sign of any underlying condition.

b. Secondary AIHA is when there is a link with another condition.
Warm AIHA
Also called warm hemolysis, this involves IgG antibodies. These bind red
blood cells at 98.6°F (37°C), or normal body temperature. This accounts
for 80–90 percent of cases.
Cold AIHA
This is also called cold hemolysis. In this type, IgM autoantibodies, or cold
agglutinins, bind red blood cells when the blood is exposed to cold
temperatures, specifically 32° to 39.2°F (0° to 4°C). This accounts for 10–20
percent of cases.
Symptoms :- Common symptoms of AIHA include:

•a low-grade fever
• weakness and tiredness
• difficulty thinking and concentrating
• paleness
• rapid heartbeat
• shortness of breath
• yellowing skin, or jaundice
• dark urine
• muscle pains
• headaches
• nausea, vomiting, and diarrhea

• lightheadedness when standing up
• difficulty breathing
•a sore tongue
• heart palpitations or a rapid heartbeat
Diagnosis
1- Complete blood count
2-Coombs tests :- These blood tests look for antibodies that may
affect the red blood cells.
Positive: A clumping of the red blood cells (agglutination) during the test.
Agglutination of blood cells during a direct Coomb’s test suggests that
antibodies may be present on red blood cells of the patient and that the
condition of hemolysis may persist.
Agglutination of blood cells during an indirect Coomb’s test suggest the
presence of antibodies circulating in bloodstream that could cause the
immune system to react to any red blood cells that are considered foreign to
the body — particularly those that may be present during a blood
transfusion.
3- Reticulocyte test
This blood test measures the levels of reticulocytes, which are slightly
immature red blood cells. It can determine whether the bone marrow is
creating red blood cells at a suitable rate.
The range will be higher if the body has low hemoglobin levels due to
bleeding or red cell destruction. High red blood cells production can be a
sign of anemia.
4- Bilirubin test
The liver produces bilirubin, a yellow-colored substance that is present in

bile. A blood test can measure the amount of bilirubin in the blood.When
blood cells die, hemoglobin enters the bloodstream. Hemoglobin, in turn,
breaks down into bilirubin. This leads to jaundice, when the eyes and skin
take on a yellowish color.High bilirubin levels in the blood can be a sign of
anemia, liver damage, or another disease.
5- Haptoglobin test
Haptoglobin is a protein that the liver produces. Within the body, it connects
a specific type of hemoglobin within the blood.The amount of haptoglobin
in the blood shows how fast red blood cells are being destroyed.
Treatment
Treatment options for AIHA depend on a number of factors. If the anemia is

mild, it often passes without treatment. Between 70 and 80 percent of people
need no treatment or minimal intervention.
1-corticosteroids is the first type of treatment for people with primary AIHA,
and it can help to improve symptoms in many common types of AIHA.
2-immunosuppressive therapy In severe cases .
3- Surgery : The spleen is responsible for removing abnormal red blood

cells from the bloodstream, including those with antibodies attached.
Removing the spleen can enable the body to preserve those red blood
cells. This can help to prevent anemia.
4- Blood transfusion
Clinical immunology
Fourth stage
Lecture :- week 24
ECZEMA & CONTACT DERMATITIS

eczema, is a group of diseases that results in inflammation of the skin. These
diseases are characterized by itchiness, red skin, and a rash. In cases of short
duration there may be small blisters while in long-term cases the skin may
become thickened. The area of skin involved can vary from small to the
entire body.
Dermatitis is a group of skin conditions that includes atopic dermatitis,
allergic contact dermatitis, irritant contact dermatitis, and stasis dermatitis.
The exact cause of dermatitis is often unclear. Cases may involve a
combination of irritation, allergy, and poor venous return.
Dermatitis of the hand. Rash symptomatic More severe eczema

of dermatitis
Rash symptomatic of dermatitis Complex eczema
Classification:-
A. Exogenous eczemas – are related to clearly defined external triggering
factors , although inherited tendencies can also play a part , this group
include :
1. Irritant contact dermatitis (ICD) .
2. Allergic contact dermatitis (ACD) .
3. Photo-contact dermatitis .
5. Infective dermatitis .
6. Dermatophytide .
7. Post-traumatic eczema .
B. Endogenous eczema – It implies that the condition is not a result of
exogenous or external environmental factors , i.e. is mediated by processes
originating within the body , include :
1. Atopic dermatitis (AD) .
2. Hand eczema and pompholyx .
3. Asteatotic eczema .
4. Discoid eczema .
5. Exudative discoid and lichenoid dermatitis .
6. Chronic superficial scaly dermatitis .
7. Pityriasis alba .
Symptoms
Although every type of dermatitis has different symptoms, there are
certain signs that are common for all of them, including :-
1- Redness of the skin,
2- Swelling,
3- Itching and skin lesions.
4- Sometimes oozing and scarring.
5- Typical affected skin areas include the folds of the arms, the
back of the knees, wrists, face and hands.
Causes :-
The cause of eczema is unknown but is presumed to be a combination of
genetic and environmental factors.
1-Environmental :-The hygiene hypothesis postulates that the cause of

asthma, eczema, and other allergic diseases is an unusually clean
environment.
2-Genetic :-A number of genes have been associated with eczema,

Eczema occurs about three times more frequently in individuals with celiac
disease .
Pathophysiology
The pathophysiology of atopic dermatitis is complex and multifactorial,
involving elements of barrier dysfunction, alterations in cell mediated
immune responses, IgE mediated hypersensitivity, and environmental
factors. The imbalance of Th2 to Th1 cytokines observed in atopic
dermatitis can create alterations in the cell mediated immune responses and
can promote IgE mediated hypersensitivity, both of which appear to play a
role in the development of atopic dermatitis. One must additionally take into
consideration the role of the environment on the causation of atopic
dermatitis and the impact of chemicals such as airborne formaldehyde, harsh
detergents, fragrances, and preservatives. Use of harsh alkaline detergents in
skin care products may also unfavorably alter the skin’s pH causing
downstream changes in enzyme activity and triggering inflammation.
Environmental pollutants can trigger responses from both the innate and
adaptive immune pathways.
Diagnosis
Diagnosis of eczema is based mostly on the history and physical
examination. However, in uncertain cases, skin biopsy may be useful. Those
with eczema may be especially prone to misdiagnosis of food allergies.
Patch tests are used in the diagnosis of allergic contact dermatitis.
An atopy patch test can be used to determine whether or not a specific
allergen is the cause of the rash. The test involves applying a series of
allergens to the skin surface and evaluating the results in one to three days.
A patch test is a method used to determine whether a specific
substance causes allergic inflammation of a patient's skin. Any individual
suspected of having allergic contact dermatitis or atopic dermatitis needs
patch testing.
Medications
• Medicated products applied to the skin. Many options are available to
help control itching and repair the skin. Products are available in
various strengths and as creams, gels and ointments.
Drugs to fight infection: -Antibiotics are used to treat the infection.

• Pills that control inflammation. Options might include
cyclosporine, methotrexate, prednisone, mycophenolate and
azathioprine. These pills are effective but can't be used long term
because of potential serious side effects.
• Other options for severe eczema. The injectable biologics

(monoclonal antibodies) dupilumab (Dupixent) and tralokinumab
(Adbry) might be options for people with moderate to severe disease
who don't respond well to other treatment.
Clinical immunology
Fourth stage
Lecture :- week 21 & 22
Hypersensitivity Diseases
Hypersensitivity (also called hypersensitivity reaction or intolerance) is a set
of undesirable reactions produced by the normal immune system, including
allergies and autoimmunity. They are usually referred to as an over- reaction
of the immune system and these reactions may be damaging, uncomfortable,
or occasionally fatal. Hypersensitivity reactions require a pre-sensitized
(immune) state of the host. They are classified in four groups after the
proposal of P. G. H. Gell and Robin Coombs in 1963.
Type I: IgE mediated immediate reaction
Type II: Antibody-mediated reaction (IgG or IgM antibodies)
Type III: Immune complex-mediated reaction
Type IV: Cytotoxic, cell-mediated, delayed hypersensitivity reaction .
The antigen-specific IgE antibodies can then bind to high-affinity receptors

located on the surfaces of mast cells and basophils. Reexposure to the
antigen can then result in the antigen binding to and cross-linking the bound
IgE antibodies on the mast cells and basophils. This causes the release and
formation of chemical mediators from these cells.
The major mediators and their functions are described as follows:
1. Histamine: This mediator acts on histamine 1 (H1) and histamine 2
(H2) receptors to cause contraction of smooth muscles of the airway
and GI tract, increased vasopermeability and vasodilation, enhanced
mucus production, pruritus, cutaneous vasodilation, and gastric acid
secretion.
2. Tryptase: Tryptase is a major protease released by mast cells. Its role is

not completely understood, but it can cleave C3, C3a, and C5 in
addition to playing a role in airway remodeling. Tryptase is found in all
human mast cells but in few other cells and thus is a good marker of
mast cell activation.
3. Proteoglycans: Proteoglycans include heparin and chondroitin sulfate.
The role of the latter is unknown; heparin seems to be important in
storing the preformed proteases and may play a role in the production
of alpha-tryptase.
4. Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis

causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis
results in neutrophil chemotaxis. Eosinophils release major basic
protein and, together with the activity of neutrophils, can cause
significant tissue damage in the later phases of allergic reactions.
Diagnosis of hypersensitivity
Laboratory testing may include:
1- Allergen-specific IgE blood testing: this is testing that is used to

help diagnose allergies. The test measures the amount of allergen-specific
IgE antibodies in the blood in order to detect an allergy to a particular
substance.
The RAST (Radioallergosorbent test) is a laboratory test performed on
blood. It tests for the amount of specific IgE antibodies in the blood which
are present if there is a "true" allergic reaction.
Note: The traditional method for blood testing was the RAST
(radioallergosorbent test), but it has been largely replaced with newer
IgE-specific immunoassay methods. Some health practitioners, however,
still refer to all IgE allergy blood tests as RAST even though it is not the
methodology that the laboratory uses.
Other types of allergy tests:
1. Skin prick or scratch tests are done in an allergist's or dermatologist's

office and must be done by a trained professional. They are often used to
detect airborne allergies such as pollens, dust, and molds. Because of the
potential for a severe reaction, skin prick tests are not usually used for
food allergies. The person being tested must not have significant eczema
or be taking antihistamines or certain antidepressants for several days
before the skin prick test. False positives can arise with even a non-
allergic person if the dosage of the allergen is high enough.
2. Intradermal allergy skin tests, using injections that form a bubble
under the skin, may be done but they are not widely accepted because of
a high false-positive rate.
3. Patch testing:- Delayed hypersensitivity skin and patch tests are the
easiest methods of testing for type IV delayed hypersensitivity. A
concentration of the suspected allergen is applied to the skin under a
nonabsorbent adhesive patch and left for 48 hours. If burning or itching
develops more rapidly, the patch is removed. A positive test consists of
redness with some hardening and swelling of the skin and sometimes
vesicle (blister-like) formation. Some reactions will not appear until after
the patches are removed, so the test sites are also checked at 72 and 96
hours.
4- Oral food challenges are considered the "gold standard" for

diagnosing food allergies. They are labor-intensive and require close
medical supervision because reactions can
be severe, including life-threatening anaphylaxis. Food challenges

involve giving a person small amounts of unmarked potential food
allergens in capsule or intravenous form and watching for allergic
reactions. Negatives are confirmed with larger meal-sized portions of
food.
5- Food elimination is another way to test for food allergies:

eliminating all suspected foods from the diet, then reintroducing them
one at a time to find out which one(s) are causing the problem.
2- Total IgE testing is sometimes done to look for an ongoing allergic

process. It is a blood test that detects the total amount of IgE protein
(including allergy antibodies) but does not identify specific allergens.
Conditions besides allergies can also cause the IgE level to rise.
3- Complete blood count (CBC) and WBC differential—these
tests include the measurement of eosinophils, a type of white blood cell. The
level of eosinophils may be increased in a person with allergies.
4- Histamine and/or tryptase blood tests may be used to help

diagnose anaphylaxis or mast cell activation.
6- The MELISA® test (Memory Lymphocyte Immuno Stimulation

Assay) measures hypersensitivity to numerous metals, including
mercury, by placing a series of metals into contact with the white
blood cells of the person being tested and then monitoring the
reaction. An innovative diagnostic tool.
Treatment
The treatment of immediate hypersensitivity reactions includes the
management of anaphylaxis with intramuscular adrenaline (epinephrine),
oxygen, intravenous (IV) antihistamines, support blood pressure with IV
fluids, avoid latex gloves and equipment in patients who are allergic, and
surgical procedures such as tracheotomy if there is severe laryngeal edema.
Clinical immunology
Fourth stage
Immunological Thyroid Disease
AITD are the more frequent pathological conditions of the thyroid gland.
Although appearing as a single pathologic entity, the AITD comprise two
main clinical presentations: Graves’ disease and Hashimoto’s thyroiditis.
Both conditions are characterized by lymphocytic infiltration of the
thyroid parenchyma.
In Graves’ disease, the infiltration is mild and induces the production of
anti-TSH receptor antibodies that stimulate the growth and the function
of thyroid follicular cells, ultimately leading to hyperthyroidism.
In Hashimoto’s thyroiditis, the lymphocytic infiltration is more severe
and causes the destruction of the thyroid follicles and subsequent
hypothyroidism. It is a typical T cell-mediated autoimmune disease,
characterized by the ectopic formation of tertiary lymphoid follicles
within the thyroid gland.
Causes of autoimmune thyroid diseases
1.Genetic susceptibility
2. Envionmental factors
Aside the genetic factors, the remaining 20% or so contribution to the
occurrence of AITD is thought to be due to environmental factors.
Several factors have been identified and proposed. These include
radiation, iodine status, smoking, infection, stress and drugs such as
lithium and interferon .
3. Radiation
External radiation for Hodgkin’s disease triggers the subsequent
occurrence of antithyroid antibodies and AITD, hypothyroid thyroiditis as
well as Graves’ disease. Similarly, radioiodine treatment of toxic goitre
may be followed, years later, by the occurrence of Graves’ disease, even

Graves’ ophthalmopathy . In a different context, children exposed to
radiation from Chernobyl showed a greater incidence of thyroid
autoantibody positivity, with no increase in the incidence of
hypothyroidism .
4. Stress:- As early as one of the first description of the disease, stress has
been considered as a trigger factor for Graves’ disease onset. An abundant
literature is devoted to that question , the approach of which remains
relatively uncertain in the absence of objective markers.
5. Drugs:- Lithium treatment is associated with an increased prevalence

of thyroid antibodies, hypothyroidism and, to a lesser extent, of Graves’
disease. However, lithium-induced AITD must be differentiated from the
inhibitory effect of lithium on thyroid secretion . Interferon-induced
thyroiditis can manifest as classical autoimmune thyroiditis or, rarely,
Graves’ disease, but also as non-autoimmune thyroiditis. Whether the
hepatitis C virus itself plays a role in the disease remains questionable.
Symptoms
The symptoms may vary depending on the thyroid function, i.e.
hyperthyroidism or hypothyroidism.
Hyperthyroidism can cause sweating, rapid heart rate, anxiety, tremors,
fatigue, difficulty sleeping, sudden weight loss, and protruding eyes.
Hypothyroidism can cause weight gain, fatigue, dry skin, hair loss,
intolerance to cold, and constipation. The effects of this disease may be
permanent but can sometimes be transient.
Symptoms may come and go depending on whether the person

receives treatment.
1- Tiredness
2- Sensitivity to cold
3- Puffy face
4- Trouble pooping
5- Enlarged tongue
6- Pale, dry skin and brittle nails
7- Hair loss
8- Weight gain
9- Muscle aches and joint pain
10- Depression
11- Memory lapse
12- Heavy menstrual bleeding
Pathogenesis of AITD
Thyroid autoantibodies appear mostly with the presence of lymphocytes in the
targeted organ. Lymphocytes produce antibodies targeting three different
thyroid proteins: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin
Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies
(TRAb). Some patients who are healthy may be positive for more than one of
these antibodies. Doctors who attend to such patients will most likely do routine
follow-ups on the patient’s health since, even though it is highly unlikely that
they will present any thyroid problems, there is still a chance that they will
develop some type of dysfunction with time.
AITD is characterized by lymphocytic infiltration in the thyroid gland and the
production of pathogenic thyroid autoantibodies . Autoantibodies against
various thyroid antigens such as thyroid peroxidase (TPO), Tg, sodium iodide
symporter, and pendrin are detected in the sera from patients with Hashimoto's
thyroiditis . Production of TSAb against TSHR result is Graves'
hyperthyroidism . It is clear that the production of autoantibodies requires
disruption of self-tolerance and an adaptive immune response.
Diagnosis
For thyroid function evaluation, thyrotropin (TSH) is the usual starting point.
TSH shows an exponential response to changing peripheral thyroid hormone
levels, thereby providing high clinical detection sensitivity. Thyroxine (T4) or
triiodothyronine (T3) is frequently measured alongside, mostly as free
hormones (FT4 and FT3), to assess disease severity or treatment response.
Some diseases require additional testing to determine the cause of observed
abnormalities or to clarify contradictory results of TSH and T4/T3 testing.
Thyroid autoantibody testing is important in this context.
Testing for structural thyroid disease centers on tumor markers, mainly

thyroglobulin (Tg), calcitonin, and carcinoembryonic antigen, all of which are
primarily used for follow-up. Tg immunoassays are not infrequently
compromised by anti-Tg autoantibody interferences, which can be partially
overcome by mass spectrometry (MS) Tg measurements.
Various tests can be chosen depending on the presenting symptoms. Doctors

may search for Thyroid peroxidase Antibodies (TPOAb) when a person has
symptoms of hypothyroidism, or when a person will be started on a drug
therapy associated with risks of developing hypothyroidism, such as lithium or
Interferon alfa. This antibody is related to Hashimoto's thyroiditis and Graves'
disease. If the person presents symptoms of hyperthyroidism, doctors are more
likely to test for Thyroid stimulating hormone receptor Antibodies (TRAb), and
monitor the effects of anti-thyroid therapy, also associated with Graves' disease.
Doctors may check Thyroglobulin Antibodies (TgAb) also, whenever a

thyroglobulin test is performed to see if the antibody is interfering. TgAb may
also be ordered in regular intervals after a person has been diagnosed with
thyroid cancer, and just like TPOAb, it can be associated with Hashimoto’s
thyroiditis.
*
Clinical immunology
Fourth stage
Clinical immunology
Fourth stage
Lecture :- week 27& 28
Tumors and Tumor Markers

Tumor immunology
The proliferation of normal cells is carefully regulated. However, such cells
when exposed to chemical carcinogens, irradiation and certain viruses may
undergo mutations leading to their transformation into cells that are capable
of uncontrolled growth, producing a tumor or neoplasm.
The tumor may be:
• Benign, if it is not capable of indefinite growth and the host survives.
• Malignant, if the tumor continues to grow indefinitely and spreads

(metastases). This uncontrolled growth may be due to up regulation of
oncogenes (cancer-inducing genes) and/or down regulation of tumor
suppressor genes (that normally inhibit tumor growth often by inducing cell
death).
Tumor associated antigens
There are 2 main types of tumor antigens:
• Tumor-specific transplantation antigens (TSTA) which are unique to tumor
cells and not expressed on normal cells.
• Tumor associated transplantation antigens (TATA) that are expressed by
tumor cells and normal cells.
Tumor-associated developmental antigens or onco-fetal antigens:-
These include alpha-fetoprotein (AFP) and carcino-embryonic antigen
(CEA) found secreted in the serum. AFP is found in patients with
hepatocellular carcinoma whereas CEA is found in colon cancer. These are
important in diagnosis. AFP is produced only as a secreted protein
whereas CEA is found both on cell membranes and in secreted fluids.
Viruses that cause human tumors include:
DNA viruses
• Papova (papilloma, polyoma) viruses: Papilloma virus causes cervical
cancer.
• Hepatitis virus: Hepatitis B virus causes hepatocellular cancer.
• Adenoviruses may also be tumorigenic
• Certain types of Herpes Virus ( CMV and EBV )
RNA viruses
• Retroviruses: Human T- lymphotropic viruses (HTLV-I and HTLV-II)
causes T-cell leukemias.
Immunity against Tumor :There is several anti-tumor immune reactivity in
human;
1. Cell-mediated immunity plays a critical role in tumor rejection.
2. The T helper (Th) cells recognize the tumor antigens that may be shed
from tumors and internalized, processed and presented in association with
class II MHC on antigen presenting cells. These Th cells, will produce
cytokines. provide help to B cells in antibody production.
3. Cytokines such as IFN-gamma γ may also activate macrophages to be
tumoricidal
4. The Th cells also provide help to tumor-specific cytotoxic T cells (CTLs)
+
CD8 and NK cell by inducing their proliferation and differentiation.
5. The CTLs recognize tumor antigens in the context of class I MHC and
mediate tumor cell lysis.
6. In tumors with decreased MHC antigens, natural killer (NK) cells are
important in mediating tumor rejection.
Tumor Marker (TM):-
T.M or also known as biomarkers are indicators of cellular, biochemical,
molecular, or genetic alterations by which neoplasia can be recognized. It is
measurable biochemical that are associated with a malignancy, they are
substances found at higher than normal levels in some peoples with
cancer.
Classification:- The T.M. is either produced by the tumor cells (tumor
derived) or by the body in response to tumor cells (Tumor associated).
1. Tumor Specific Antigens: - Present on tumor cells and not on any normal
cells.
2. Tumor Associated Antigens: - Are present on tumor cells and also on
some normal cells in response to the tumor.
Clinically associated useful of TMs :-
• Diagnostic and distinguish benign from malignant disease
• Correlate with the amount of tumor present (so-called tumor burden)
• Allow subtype classification to more accurately stage patients
• Be prognostic, either by the presence or absence of the marker or by its
concentration
• Guide choice of therapy and predict response to therapy
Type of T.Ms. (specific and /or sensitive)
As like other laboratory Testing, T.Ms. test must be both specific and
sensitive.
Specificity: - If either the T.Ms. it self or the test used to detect or measure it
is not specific enough, there is a chance that the results could suggest a tumor
is presents, or growing despite treatment, when it is not (a false positive).
High specificity – not present in other diseases, non-tumors and in healthy
subjects
Sensitivity: - If the T.Ms. or the test is not sensitive enough, the result may
suggest a tumor is not present when it actually is or that is responding to
treatment, when it is not (A false Negative). High sensitivity – detectable at
the beginning of the disease
Main Examples of T.Ms. in cancers:-
Protein Tumor Markers :
- Carcinoembryonic antigen (CEA)
- α- Fetoprotein ( AFP ) .
- Carbohydrate Antigen ( CA . 19-9) . ( CA . 125). monitoring of ovarian
CA
- Prostate-Specific Antigen ( PSA ) .
- CA 15-3 – monitoring of breast CA
- CA 72 CA 72-4– monitoring of gastric CA
- CA 19 CA 19-9 9 for monitoring of pancreas CA (and bile ducts)
- Human Chorionic Gonadotropin in Testicular Germ Cell Tumors
The following examples for T.Ms. often associated with cancer:-

1. Carciniembryonic Antigen (CEA) :- It is an oncofetal protein that is
normally present during fetal life but can be seen in low concentration in
healthy adults. This may be found at elevated levels in patients with cancer of
the colon and rectum. CEA itself is secreted into the circulation and is also
found in the mucous secretions of the stomach, small intestine, and biliary
tree.
2. α- Fetoprotein(AFP):- It is an oncofetal antigen synthesized by
hepatocytes and endodermally , it is used for the detection of Hepatocellular
carcenoma (HCC) .It raised in testicular cancer. Elevated levels are also seen
in hepatitis, inflammatory bowel disease, and cirrhosis. Prognosis The AFP
concentration reflects tumor size.
3. Prostate – Specific Antigen (PSA):- Is a serine protease that is formed

in the prostatic epithelium and secreted into the prostatic ducts. Its function is
to digest the gel that is formed in seminal fluid after ejaculation. Normally
only small amounts of PSA leak into the circulation . PSA levels are high in
man with prostate cancer, prostatitis or being prostatic hyperplasia (BPH).
4. Carbohydrate Antigen – 125 (CA-125):- This protein is found on the

surface of ovarian cancer cells and can be detected with a blood test , An
increased in CA -125 may be caused by another type of cancer , including
endometrial, peritoneal of fallopian tube cancer or anon- cancerous condition
, pelvic inflammatory diseases , cirrhosis.
5. Carbohydrate Antigen 19-9: Serum marker for pancreas cancer But its
use is limited to monitoring response to therapy, not as a diagnostic marker.
Because CA 19-9 epitope is normally present within the biliary tree.
6. DNA-Based Markers:
Specific mutations in oncogenes , tumor -suppressor genes, and mismatch
repair genes can serve as biomarkers. These mutations may be germline .
e.g. proto-oncogene , or somatic mutations such p53 mutations. RB gene
mutation
7. Human Chorionic Gonadotropin (HCG) :

A glycoprotein hormone , Normally secreted by placental tissue with highest
circulating levels occurring at 60 days of gestation. elevation occurs during
pregnancy and in patients with trophoblastic neoplasms.. Maybe elevated in
some benign conditions – peptic ulcer disease, inflammatory intestinal
disease and cirrhosis .
8. Other types of Tumor markers
a. Tissue and organ specific antigens :- PSA , Thyroglobulin (TG) ,

Squamous cell carcinoma ( SCC) , Hormone receptors , C- Peptide .
b. Nonspecific antigens (Paraneoplastic production):- Ferritin , Lactate

dehydrogenase ( LDH) , B2- Micro globulin , ACTH , ADH and Parathyroid
hormones.
Clinical immunology
Fourth stage
Transplantation
Immunology of transplantation
Graft or Transplant: Transfer of living cells, tissues and organs from one part
of the body to another or from one individual to another.
The transplantation mainly based on:
1. Organ or tissue transplanted
2. Anatomical site of origin of transplant & site of its placement:
a. Orthotopic: normal sites
b. Heterotopic: abnormal sites
3. Genetic compatibility and antigenic relationship.

4. Fresh or stored transplanted tissue :
Types of Transplantation:-
1. Autologous .
2. Syngeneic.
3. Allogenic .
4. Xenogeneic .
Auto grafting ( Autologous ) -
Transfer of self-tissue from one body site to another in the same individual,
it should:
• Genetic homology of the tissue- immune system does not respond
(Skin,hiar grafts) Auto graft acceptance epidermis:-
1. After 3- 7 days have revascularization of blood vesicles.
2. 7 – 10 days healing.
3. 12 -14 neutrophil resolution,
Allograft reaction:-
First Set Response :- Skin graft from a genetically unrelated animal of
same species . Initial acceptance , Thrombosed and necrosed Mainly by T
lymphocytes .
- After 3- 7 days have revascularization of blood vesicles .
- 7 – 10 cellular infiltration ,
- 10 -14 thromboses and necrosis ,
- > 14 day damaged blood vesicles and rejection the implanted tissues.
Second Set Response :- If an animal has rejected a graft by the first set response,
another graft from the same donor is applied – rejected in an accelerated manner ,
Mainly by antibodies
Effecter mechanism of allograft rejection:-
• Hyper acute Rejection
a. Pre-existing specific antibodies in high titers in the host circulation bind
to donor endothelial antigens.
b. Activates Complement Cascade.

c. Characterized by thrombotic occlusion of graft
d. Graft remains pale
e. Rejected within minutes or hours, even without an attempt at
vascularization
Immunological Enhancement: -
Humoral antibodies can act in opposition to CMI by inhibiting graft
rejection.
- Afferent inhibition: Combine with antigens released from graft so that
they are unable to initiate an immune response
- Central inhibition: Antibodies may combine with lymphoid cell, by a

negative feedback, render them incapable of responding to the
antigens of the graft.
- Efferent inhibition: By coating the surface of cells in the graft so that

sensitized lymphocytes are kept out of contact with them .
Acute Rejection: -
- Vascular and parenchymal injury mediated by T cells and antibodies
that usually begin after first week of transplantation if no
immunosuppressant therapy
- Incidence is high (30%) for the first 90 days.

Chronic Rejection :-
- Occurs in most solid organ transplants
- Heart, Kidney, Lung, Liver
- Characterized by :
a. Fibrosis
b. Vascular abnormalities
c. Loss of graft function over a prolonged period.
Histocompatibility antigens.
Antigens that participate in graft rejection are called transplantation or
histocompatibility antigens :
- ABO blood group
- HLA system (MHC restricted allograft Rejection )
Histocompatibility Testing :-
- ABO blood grouping
- HLA compatibility:
- Tested by HLA typing and tissue matching
- HLA typing identifies the HLA antigens expressed on the surface of
leucocytes
Methods of HLA – Typing :-
- Microcytotoxicity test .
- Molecular methods
a. RFLP with southern blott
b. PCR using sequence specific primers.
- Tissue matching .
Micro Cytotoxicity: -
Tests for complement mediated lysis of peripheral blood lymphocytes
with a standard set of typing sera. Micro-cytotoxicity assay, utilizes
serum with known anti-HLA antibodies that recognize particular HLA
loci (HLA-A, HLA-B, HLA-C, HLA-DQ, HLA-DR /not DP) in order to
match genetically similar individuals in hopes of performing a tissue
transplantation.
Graft-versus-host (GVH) reaction: -
Graft rejection is due to the reaction of the host to the grafted tissue,
Host-versus-graft response , The contrary situation, in which the graft
mounts an immune response against the antigens of the host, is known as:
Graft-versus-host (GVH) reaction.
Essential Component Required for (GVH)
The GVH reaction occurs when the following conditions are present:
1. The graft contains immunocompetent T cells.
2. The recipient possesses transplantation antigens that are absent in the
graft.
3. The recipient must not reject the graft.
When grafted tissue has mature T cells, they will attack host tissue leading
to GVHR. Major problem for bone marrow transplant.
Methods to overcome GVHR :
- Treat bone marrow to deplete T cells.
- Use autologous bone marrow.
- Use umbilical cord blood.
Caused by the reaction of grafted mature Tcells in the marrow inoculum
with alloantigens of the host
- Acute GVHD :- Characterized by epithelial cell death in the skin,
GI tract, and liver .
Chronic GVHD :- Characterized by atrophy and fibrosis of one or -

+more of these same target organs as well as the lungs

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Clinical Immunology

Medical Laboratories Techniques

Systemic lupus erythematosus

Figure : Etiology of SLE.

General laboratory findings

 Genetic: Certain HLA-DR4 molecules associated with RA (e.g. HLA-DR beta

Figure: Comparison between normal and RA joints.

Table: autoimmune response identified in patients with RA.

Autoantigen Antibodies in RA T cell response in RA Specificity for RA

Other symptoms include:

 Chest pain when taking a breath (pleurisy).

Ankylosing spondylitis (AS) is a chronic inflammatory condition of the spine and

Inflammatory Spinal Pain: History or present symptoms of spinal pain in back,

Synovitis: Asymmetric or Predominantly in the lower limbs. and one of the

 Positive family history

 Inflammatory bowel disease.

 Alternating buttock pain.

 The tendency to develop Ankylosing Spondylitis is believed to be genetically

 (TNF α) and IL-1 are also implicated in AS

 Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with AS.

 AS arises from a cross-reaction between HLA-B27 and antigens of the Klebsiella

B27 folding, assembly

The diagnosis of Ankylosing Spondylitis is based on:

 Evaluating the patient's symptoms

The examination can demonstrate signs of :

1. inflammation and decreased range of motion of joints. This can be particularly

3. There may be tenderness of the sacroiliac joints of the upper buttocks.

Blood & Other Tests

Mucocutaneous complications of IBD include erythema nodosum, which occurs in fewer

Clinical manifestations include skin and nail psoriasis, dactylitis, enthesitis,

Comorbidities in PsA Patients

 Ocular inflammation (Iritis/Uveitis/ Episcleritis).

Figure: Main Features of Psoriatic Arthritis

 In addition, numerous extra glandular features may develop, such as arthralgia,

be due to a change in the androgen–estrogen ratio rather than absolute levels of

 Sjögren's syndrome can occur as a primary disease of exocrine gland dysfunction or

The pathogenesis of SS is still largely unknown. In a genetically predisposed individual,

Etiology of Sjögren's Syndrome

• Expression of certain HLA molecules on the epithelial cells enhance

A. Proinflammatory cytokines released by epithelial cells and lymphocytes may impair

B. In addition, antibodies to acetylcholine (muscarinic) receptors may interfere with the

A defect in Fas-mediated apoptosis, which is necessary for down-regulation of the

¡ Chronic fatigue is a prominent presenting feature of Sjo¨ gren syndrome.

¡ Sudden normalization of previously elevated rheumatoid factor should prompt

 Conjunctivitis sicca (ocular signs).

Dry eyes for more than 3 months

Use of tear substitutes more than 3 times per day

2. Oral symptoms (Xerostomia)

Feeling of dry mouth

Recurrently swollen salivary glands

Frequent use of liquids to aid swallowing

3. Ocular signs (Conjunctivitis Sicca)

 Schirmer test performed without anesthesia (<5 mm in 5 min)

 Positive vital dye staining results

Abnormal salivary scintigraphy findings

Abnormal parotid sialography findings

Abnormal sialometry findings (unstimulated salivary flow <1.5 mL in 15

5. Positive anti–SSA or anti–SSB antibody results

6. Positive minor salivary gland biopsy findings

• Creatinine clearance may be diminished in up to 50% of patients.