Immunology

Innate Immunity
Jason Ryan, MD, MPH

Barriers to Infection
Connexions/Wikipedia
Skin/ Innate Adaptive

Mucous Immune Immune
Membranes System System
Immune Systems
Innate Adaptive
• Fast-acting system • Slow-acting (days)
• Non-specific reaction • Highly specific
• Same cells, same reaction • Unique cells activated to
to many invaders respond to a single
• No memory invader
• 2nd infection same • Memory
response as 1st infection • 2nd infection: faster
response
Antigen Presentation
• Innate system can be activated by “free” antigen
• Pathogenic molecules detected freely in blood, tissue
• Adaptive system requires “antigen presentation”
• Pathogens must be engulfed by cells, broken down
• Pieces of protein transported to surface
• Antigen “presented” to T-cells for activation
Cytokines
• Cell signaling proteins
• Often released by immune cells
• Stimulate inflammatory response
• Various subsets
• Chemokine: Attracts immune cells (chemotaxis)
• Interleukins: IL-1, IL,2, etc
• Tumor necrosis factor (TNF): Can cause tumor death
• Transforming growth factor (TGF)
• Interferons: Named for interfering with viral replication
Cluster of Differentiation (CD)
• Cellular surface molecules
• CD3, CD4, CD8
• Found on many immune cells (T-cells, B-cells)
• Used to identify cell types
• Some used as receptor/cell binding
Innate Immune System
• Phagocytes
• Macrophages (hallmark cell)
• Neutrophils
• Complement
• Natural Killer Cells
• Eosinophils
• Mast cells and Basophils
Innate Immunity
General Principles
• Recognize molecules that are “foreign”

• “Pathogen-associated molecular patterns” (PAMPs)
• Present on many microbes
• Not present on human cells
• Pattern recognition receptors
• Key receptor class: “Toll-like receptors” (TLRs)
• Macrophages, dendritic cells, mast cells
• Recognize PAMPs → secrete cytokines
Innate Immunity
Pattern Recognition
• Endotoxin (LPS)
• LPS binds LPS-binding protein (found in plasma)
• Binds CD14 on Macrophages
• Triggers TLR4
• Cytokine production: IL-1, IL-6, IL-8, TNF
• Peptidoglycan cell wall
• NOD receptors (intracellular)
• Nucleotide-binding oligomerization domain
• Cytokine expression
Innate Immunity
Pattern Recognition
• Mannose (polysaccharide on bacteria/yeast)

• Mannose-binding lectin (MBL) from liver
• Activates lectin pathway of complement activation
• Lipoteichoic acid on Gram-positive bacteria
• Double stranded RNA
• Unmethylated DNA
Monocytes and Macrophages
• Macrophages: guardians of innate immunity
• Produced in bone marrow as monocytes
• Circulate in blood ~3 days
• Enter tissues → macrophages
• Kupffer cells (liver)
• Microglia (CNS)
• Osteoclasts (bone)
Dr Graham Beards/Wikipedia
Monocytes and Macrophages
• Three key functions:
• Phagocytosis
• Cytokine production
• Antigen presentation
Phagocytosis
• Macrophages engulf pathogens into phagosome
• Phagosome merges with lysosome
• Lysosomes contain deadly enzymes
• Death of bacteria, viruses
Graham Colm/Wikipedia
Phagocytosis
• Reactive oxygen species (superoxides)
• Produced by NADPH Oxidase (respiratory burst)
• Generate hydrogen peroxide H2O2 and O2-
• Reactive nitrogen intermediates
• NO (nitric oxide) + O2− (superoxide) → ONOO− (peroxynitrite)
• Enzymes:
• Proteases
• Nucleases
• Lysozymes (hydrolyze peptidoglycans)
Lysosome Enzyme Secretion
Lung Abscess
Yale Rosen/Wikipedia
Phagocytosis
• Some pathogens block this process
• Tuberculosis modifies phagosome
• Unable to fuse with lysosome
• Proliferation inside macrophages
• Protection from antibodies
• Chediak-Higashi Syndrome
• Immune deficiency syndrome
• Failure of lysosomes to fuse with phagosomes
• Recurrent bacterial infections
CDC/Public Domain/Wikipedia
Macrophages
• Macrophages can exist in several “states”
• Resting: Debris removal
• Activated (“primed”): more effective
• Major activators (via surface TLRs):
• LPS from bacteria
• Peptidoglycan
• Bacterial DNA (no methylation)
• Also, IFN-γ from T-cells, NKC
• Attracted by C5a (complement)
Macrophages
Key Surface Receptors
Macrophages
Cytokines
• Key cytokines are IL-1 and TNF-α

• Others: IL-6, IL-8, IL-12
IL-1 and TNF-α
• Both ↑synthesis endothelial adhesion molecules
• Allows neutrophils to enter inflamed tissue
• IL-1
• “Endogenous pyrogen” (causes fever)
• Acts on hypothalamus
• TNF-α
• Can cause vascular leak, septic shock
• “Cachectin:” Inhibits lipoprotein lipase in fat tissue
• Reduces utilization of fatty acids → cachexia
• Kills tumors in animals (“tumor necrosis factor”)
• Can cause intravascular coagulation → DIC
IL-6, IL-8, IL-12
• IL-6
• Fever
• Stimulates acute phase protein production in liver (CRP)
• IL-8
• Attracts neutrophils
• IL-12
• Promotes Th1 development (cell-mediated response)
Neutrophil
• Derived from bone marrow
• Granules stain pink with Wright stain
• Eosinophils=red, Basophils=blue
• Circulate ~5 days and die unless activated
• Drawn from blood stream to sites of inflammation
• Enter tissues: Phagocytosis
• Granules are lysosomes (bactericidal enzymes)
• Provide extra support to macrophages
Neutrophil
Blood stream exit
• Rolling
• Selectin ligand neutrophils (Sialyl-Lewis X)
• Binds E-selectin or P-selectin endothelial cells
• Crawling (tight binding)
• Neutrophils express integrin
• Bind ICAM on endothelial cells
• Transmigration
• Neutrophils bind PECAM-1 between endothelial cells
• Migration to site of inflammation
• Chemokines: C5a, IL-8
Neutrophil
Blood stream exit
PMN
SL
Selectin
Step 1:
IL-1 and TNF stimulate expression selectin
PMNs bind selectin via selectin ligand
Neutrophil
Blood stream exit
PMN
INT
ICAM
Step 2:
LPS or C5a stimulates integrin on PMNs
Integrin binds ICAM on endothelium
Neutrophils
• Small granules (specific or secondary)
• Alkaline phosphatase, collagenase, lysozyme, lactoferrin
• Fuse with phagosomes → kill pathogens
• Also can be released in extracellular space
• Larger (azurophilic or primary)
• Acid phosphatase, myeloperoxidase
• Fuse with phagosomes only
• Band forms
• Immature neutrophils
• Seen in bacterial infections
• “Left shift”
A. Rad/Wikipedia
Neutrophil
• Do not present antigen
• Phagocytosis only
• Contrast with macrophages: APCs and phagocytes
• Chemotaxins (attracters of neutrophils)
• IL-8 (from macrophages)
• C5a
• Opsonin: IgG (only antibody that binds neutrophils)
Complement
• Complement proteins produced by liver
• Most abundant is C3
• Frequent, spontaneous conversion C3 → C3b
• C3b binds amino and hydroxyl groups
• Commonly found on surface of pathogens
• Failure of C3b to bind leads to rapid destruction
Complement
• C3b → MAC formation
• Membrane attack complex
• Forms pores in bacteria
leading to cell death
Wikipedia/Public Domain
Natural Killer Cells
• Two key roles:
• Kill human cells infected by viruses
• Produce IFN-γ to activates macrophages
• MHC Class I
• Surface molecule of most human cells
• Presents antigen to CD8 T-cells
• Activates adaptive immunity against intracellular pathogens
• Some viruses block MHC class I
• NKC destroy human cells with reduced MHC I
• CD16 on surface
• Binds Fc of IgG → enhanced activity
• Antibody-dependent cell-mediated cytotoxicity
• CD56
• Also called NCAM (Neural Cell Adhesion Molecule)
• Expressed on surface of NK cells (useful marker)
• Also found in brain and neuromuscular junctions
• Aids in binding to other cells
ADCC
Antibody-dependent cellular cytotoxicity
• Antibodies coat pathogen or cell

• Pathogen destroyed by immune cells
• Non-phagocytic process
• Classic examples: NK cells and Eosinophils
Satchmo2000/Wikipedia
ADCC
Antibody-dependent cellular cytotoxicity

• IgG binds to pathogen-infected cells
• CD16 on NK binds Fc of IgG
• NKC kills cell
• Eosinophils
• IgE binds to pathogens, especially large parasites
• Eosinophils bind Fc of IgE
• Release of toxic enzymes onto parasite
• Lymphocytes (same lineage as T-cells and B-cells)
• Do not mature in thymus
• No memory
• Do not require antigen presentation by MHC
Eosinophils, Mast Cells, Basophils
• All contain granules with destructive enzymes
• All can be activated/triggered by IgE antibodies
• Important for defense against parasites (helminths)
• Too large for phagocytosis
• Release of toxic substances kills parasite
• Main medical relevance is in allergic disease
Eosinophil
• Granules appear red with Wright stain
• Major basic protein in eosinophils: (+) charge
• Eosin dye: (-) charge
• Discharge contents (cytotoxic enzymes) onto parasites
• Major basic protein (MBP)
• Eosinophilic cationic protein (ECP)
• Eosinophil peroxidase (EPO)
• Eosinophil-derived neurotoxin (EDN)
Bobjgalindo/Wikipedia
Eosinophil
• Activated by IgE
• Antibody-dependent cellular cytotoxicity
• Stimulated by IL-5 from Th2 cells
• ↑eosinophil count characteristic of helminth infection
• Normal % eosinophils <5% or <500 eosinophils/microL
• Also seen in many allergic diseases
Mast cells and Basophils
• Granules appear blue with Wright stain
• Basophils: blood stream
• Mast cells: Tissue
• Bind Fc portion of IgE antibodies
• IgE molecules crosslink → degranulation
• Histamine (vasodilation)
• Enzymes (peroxidases, hydrolases)
Innate Immune System
• Phagocytes
• Macrophages (hallmark cell)
• Neutrophils
• Complement
• Eosinophils
• Mast cells and Basophils
Adaptive Immune System
• T-cells
• CD4: Cytokine production
• CD8: Destruction infected human cells
• B-cells
• Antibody production
• Inter-related with innate immunity
• Cytokines
• Antigen presentation
Dendritic Cells
Langerhans Cells
• Skin and mucosal membranes

• Antigen presenters
• Migrate to lymph nodes
• Activate T-cells
Wikipedia/Judith Behnsen
Immune Cell Terminology
Eosinophil Basophil Neutrophil
Mast Cell
Granulocytes
Agranulocytes
Lymphocytes Monocytes
Natural Killer T-cells B-cells Macrophage

Cells
Immune Cell Lineage
A. Rad/Wikipedia
T-cells
Jason Ryan, MD, MPH
T-cells
• Part of the adaptive immune system
• Millions of T-cells in the human body
• Each recognizes a unique antigen via T-cell receptor
• Emerge from thymus as “naïve” T-cells
• Once they encounter antigen: “mature” T-cells
• Key fact: T-cells only recognize peptides
Antigen Presentation
• T-cells only recognize antigen when “presented”
• Antigen presenting cells
• Produce peptide fragments on their surfaces
• Major histocompatibility complexes (MHC)
• Fragments placed on MHC molecules (I or II)
• T-cell react only to antigen when placed on “self” MHC
• “MHC restriction”
T-cell Receptor
• Two chains: alpha and beta
• Surrounded by CD3 complex
• Signaling complex
• Transmits “bound” signal into cell
Anriar/Wikipedia
T-cell Receptor
• Formed by similar process to antibody heavy chains
• Encoded by genes that rearrange for diversity
• V (variable)
• D (diversity)
• J (joining)
• C (constant)
• Hypervariable domains
T-cells
• Two key subsets: CD4 and CD8
• CD4 T-cells (helper T-cells)
• Produce cytokines
• Activate other cells
• Direct immune response
• CD8 T-cells (cytotoxic T-cells)
• Kill virus-infected cells (also tumor cells)
CD4 T-cells
• Activated by:
• Antigen presenting cells (APCs)
• MHC Class II (binds CD4)
• APCs:
• Dendritic Cells
• Macrophages
• B-cells
Sjef/Wikipedia
MHC Class II
• Binds TCR and CD4
• Expressed only on APCs
• Two protein chains: α and β
• Bind “invariant” chain in ER
• Prevents binding intracellular proteins
• Must merge with acidified lysosome
• Peptide fragments in lysosome
• Invariant chain released
• Antigen binds to MHC II → surface
atropos235 /Wikipedia
CD4 T-cell Co-Stimulation
• B7 protein on APC → CD28 on CD4 T-cells
B7 CD28
APC
MHCII
ATG
TCR
T-
CD4 Cell
CD4 T-cell Activation
• Stimulate B-cells
• More effective antibody production
• Class switching
• Stimulate CD8 T-cells
• Activate macrophages
Th1 and Th2 cells
• Two subpopulations CD4 T-cells
• Th1 cells
• “Cell-mediated” immune response
• Activate CD8 T-cells, macrophages
• IL-12 (macrophages) drives Th1 production
• Promotes specific IgG subclasses (opsonizing/complement)
• Th2 cells
• “Humoral” immunity
• Activate B-cells to produce antibodies (IgE, IgA)
Th1 Cytokines
• IL-2
• Mostly from Th1 cells (some from Th2)
• T-cell growth factor
• Stimulates growth CD4, CD8 T-cells
• Also activates B-cells and NK cells
• Aldesleukin (IL-2) for renal cell carcinoma and melanoma
• IFN-γ
• Activates Th1 cells/suppresses Th2 production
• Activates macrophages (phagocytosis/killing)
• More MHC Class I and II expression
Th2 Cytokines
• IL-4 (major Th2 cytokine)
• Activates Th2 cells/suppresses Th1 production
• Promotes IgE production (parasites)
• IL-5
• Activates eosinophils (helminth infections)
• Promotes IgA production (GI bacteria)
• IL-10
• Inhibits Th1 production
• “Anti-inflammatory” cytokine only
• No pro-inflammatory effect
Th1/Th2 Production
Mϕ
IL-12
Th2
IL-4 +Th1
Th1 Th2
+Th2 Th2
Th1
Th1 Th1 Th1
Th2
IL-10 Th2 Th1
Th1 INF-γ
-Th1 Th2
-Th2
Th1 and Th2 cells
IL-4
Bcell
Th2
CD4 IL-10
IFN-γ
IL-4
IL-2
APC
IL-12
Th1
CD8
Mϕ
IFN-γ
Martin Brändli /Wikipedia

Th1 and Th2 cells
• Th1 versus Th2 varies by infection
• Th1 important for many intracellular infections
• M. Tuberculosis
• Intracellular infection macrophages
• Antibodies not effective
• Need strong Th1 response
• Listeria
• Facultative intracellular organism
• Weaker (relatively) Th1 response certain populations
• Newborns/elderly: Risk for listeria meningitis
• Pregnancy: Granulomatosis Infantiseptica
Granulomatous Diseases
• Inflammation with macrophages, giant cells
• Giant cells formed from macrophages
• Th1 cells secrete IFN-γ → activate macrophages
• Macrophages secrete TNF-α → promote granulomas
Sources: Cavalcanti et al, Pulmonary Medicine, Volume 2012 (2012)

Granulomatous Diseases by Dov L. Boros, Ph.D., Sanjay G. Revankar, M.D. Wikipedia/Public Domain
Leprosy
• Tuberculoid: Limited skin lesions
• Strong cell-mediated TH1 response
• Contains infection Wikipedia/Public Domain
• Lesions show granulomas, few bacteria
• Lepromatous: Diffuse skin lesions
• Th2 response (humoral immunity)
• Depressed cell-mediated immunity
• Antibodies cannot reach intracellular bacteria
Inflammatory Bowel Disease
• Crohn’s disease
• Noncaseating granulomas
• Th1 mediated
• Ulcerative colitis
• Crypt abscesses/ulcers with bleeding
• No granulomas
• Th2 mediated
Th1 Cells and Macrophages
IL-12
Th1
M-phage
T-cell
IFN-γ
IL-12 Receptor Deficiency
• IL-12 cannot trigger differentiation T-cells to Th1 cells
• Loss of activated Th1 cells to produce IFN-γ
• Weak Th1 response and low levels IFN-γ
• Increased susceptibility:
• Disseminated mycobacterial infections
• Disseminated Salmonella
• Disseminated Bacillus Calmette-Guerin (BCG) after vaccine
• Treatment: IFN-γ
IFN-γ Receptor Deficiency
• Severe disseminated mycobacterial disease
• Also salmonella infections (and others)
• Infancy or early childhood
• IFN-γ not effective
• Treatment:
• Continuous anti-mycobacterial therapy
• Stem cell transplant (restore receptors)
CD8 T-cells
• Many similarities to CD4 cells
• React to unique antigens
• Require antigen presentation
• TCR associated with CD3 for signal transmission
• Antigen presented by MHC Class I
• Found on all nucleated cells (not RBCs)
• Most human cells are antigen presenters for CD8
• Main role is to detect and kill virus-infected cells
MHC Class I
• Binds TCR and CD8
• One “heavy chain” plus β-microglobulin
atropos235 /Wikipedia
CD8 T-cell Activation
IL-2 from Th cells
APC
MHCI
ATG
TCR
T-
CD8 Cell
CD8 T-cell Functions
Killing of virus infected cells
• Insert perforins
• Forms channels in cell membrane → cell death
• Insert granzymes
• Proteases → degrade cell contents
• Activate caspases to initiate apoptosis
CD8 T-cell Functions
Killing of virus infected cells
• Insert granulysin
• Lyses bacteria
• Induces apoptosis
• Produce Fas ligand
• Binds to Fas (CD95) on surface of cells
• Activation caspases in cytosol
• Cellular breakdown
• Apoptosis (cell death with no significant inflammation)
• “Extrinsic pathway” of apoptosis
Regulatory T-cells
• Suppress CD4 and CD8 functions
• All express CD25 (classical marker)
• Composed of alpha subunit of IL-2 receptor
• Also have CD4 and CD3
• Produce anti-inflammatory cytokines
• IL-10
• TGF-β
Th17 Cells
• Subset of CD4 T cells (distinct from Th1 and Th2)
• Important for mucosal immunity (GI tract)
• Produce IL-17
• Recruit neutrophils and macrophages
• Loss of these cells: GI bacteria in bloodstream
• E. coli, other enteric gram negatives
• Emerging evidence of role in autoimmune disease
Memory T-cells
• Most T-cells involved in immune reaction die
• Antigen withdrawal
• Loss of stimulation (IL-2)
• Apoptosis
• Some remain as memory T-cells
• Live for many years
• Secondary response requires less antigen
• Secondary exposure produces more cytokines
• Results: Faster, more vigorous response
PPD Test
Purified protein derivative
• Injection tuberculin protein under skin

• Memory Th1 cells activated
• Secrete IFN-γ
• Activate skin macrophages
• Local skin swelling/redness if prior TB exposure
• No prior exposure, no memory T cells: No reaction
• Delayed-type hypersensitivity reaction
Superantigens
• Activate a MASSIVE number of Th-cells
T-Cell T-Cell
TCR TCR
A
A
MHC MHC
APC APC
Normal Antigen Super Antigen

Superantigens
• Typical antigen response: <1% T-cells
• Superantigen: 2-20% T-cells
• HUGE release of cytokines
• Especially IFN-γ and IL-2 from Th1 cells
• Massive vasodilation and shock
Superantigens
• Superantigens cause toxic shock syndrome
• Staph aureus
• Toxic shock syndrome toxin (TSST-1)
• Strep pyogenes (group A strep)
• Pyrogenic exotoxin A or C
Thymus
• Anterior mediastinal structure
• Site of T-cell “maturation”
• Immature T-cells migrate bone marrow to thymus
• In thymus, express TCR
• Only those with ideal TCR survive
• Bind to self MHC Class I and II
• Does not bind in presence of self antigens
• Many undergo apoptosis
Thymus
Public Domain/Wikipedia
Thymus
• Cortex:
• Positive selection
• Thymus epithelial cells express MHC
• T-cells tested for binding to self MHC complexes
• Weak binding: apoptosis
• Medulla
• Negative selection
• Thymus epithelial cells and dendritic cells express self
antigens
• T-cells tested for binding to self antigens and MHC
• Excessive binding: apoptosis
Thymus
Subcapsular Zone
CD8- TCR-
CD4- CD3-
Cortex
TCR+ Weak Binding
CD8+
CD3+ CD4+ MHC I and II Death
Medulla
Strong Binding Strong Binding
CD8+ CD4+
Self-antigens Death
Death Self Antigens
AIRE Genes
• Autoimmune regulator (AIRE)
• Genes responsible for expression self antigens
• Mutations → autoimmune disease
• Clinical consequences:
• Recurrent candida infections
• Chronic mucocutaneous candidiasis
• Hypoparathyroidism
• Adrenal insufficiency
B-cells
Jason Ryan, MD, MPH
B cells
• Part of adaptive immune system
• Lymphocytes (T-cells, NK cells)
• Millions of B cells in human body
• Each recognizes a unique antigen
• Once recognizes antigen: synthesizes antibodies
• Antibodies attach to pathogens → elimination
Mgiganteus/Wikipedia
B cell Receptor
Fab
Light Light
Fc
Heavy Heavy Fvasconcellos /Wikipedia

B Cell Receptor
VH NH3
NH3
NH3 CH1 NH3
VL
SS
CL COOH
CH2
CH2 :Complement
CH2- CH3:
CH3
Macrophages
Protein A
COOH
B cell Diversity
• Millions of B cells with unique antigen receptors
• More unique receptors than genes
• If one gene = one receptor, how can this be?
• Answer: Rearrangements of genetic building blocks
B Cell Receptor
VH NH3
NH3
NH3 CH1 NH3
VL
SS
CL COOH
CH2
CH2 :Complement
CH2- CH3:
CH3
Macrophages
Protein A
COOH
VDJ Rearrangement
Heavy Chain
VDJ Rearrangement
• Heavy chain
• V (~50 genes), D (~25 genes), J (~6 genes)
• Chromosome 14
• Light chain
• V/J gene rearrangements
• Random combination heavy + light = more diversity
• Key point: Small number genes = millions receptors
B cell Activation
B cell Activation
• Two types of activation
• T-cell dependent (proteins)
• T-cell independent (non-proteins)
• For T-cell dependent, two signals required:
• #1: Crosslinking of receptors bound to antigen
• #2: T cell binding (T-cell dependent activation)
Receptor Crosslinking
Pathogen
B Cell
B Cell
T Cell Dependent Activation
• B cell can present antigen to T-cells via MHC Class II
• Binds MHC Class II to T cell receptor
• Other T-cell to B-cell interactions also occur
• CD40 (B cells) to CD40 ligand (T cell)
• Required for class switching
• B7 (B cells) to CD28 (T cell)
• Required for stimulation of T-cell cytokine production
CD40L CD40
TCR
T Cell CD4
MHC2
B Cell
B7
CD28
CD40
B Cell
CD40L
TCR
T Cell CD4
MHC2
Mϕ
B7
CD28
T Cell Independent Activation
Pathogen
Key Point #1
Very important for non-
protein antigens,
B Cell especially polysaccharide
capsules of bacteria
and LPS
Key Point #2
Weaker response
Mostly IgM
No memory
B Cell Activation
Important for
polysaccharide capsules
of bacteria and LPS
Conjugated Vaccines
• Polysaccharide antigen
• No T-cell stimulation
• Poor B cell memory
• Weak immune response → weak protection
• Conjugated to peptide antigen
• B-cells generate antibodies to polysaccharide
• Protein antigen presented to T-cells
• T-cells boost B-cell response
• Strong immune response → strong protection
Conjugated Vaccines
• H. Influenza type B (Hib)
• Neisseria meningitidis
• Streptococcus pneumoniae
B Cell Surface Proteins
• Proteins for binding with T cells
• CD40 (binding with T-cell CD40L)
• MHC Class II
• B7 (binds with CD28 on T cells)
• Other surface markers
• CD19: All B cells
• CD20: Most B cells, not plasma cells
• CD21 (Complement, EBV)
Antibody Classes
Antibody class
determined by
Fc portion

Antibody Functions
• #1: Opsonization
• Mark pathogens for phagocytosis
• #2: Neutralization
• Block adherence to structures
• #3: Activate complement
• “Classical” pathway activated by antibodies
Protein A
• Key virulence factor of Staph Aureus
• Part of peptidoglycan cell wall
• Binds Fc portion of IgG antibodies
• Prevents Mϕ opsonization phagocytosis
• Prevents complement activation
Class Switching
• Activated B cells initially produce IgM
• Can also produce small amount IgD
• Significance of IgD not clear
• As B cell matures/proliferates, it can switch class
• Gene rearrangements produces IgG, IgA, IgE
• NOTE: No change in antibody specificity
• Triggers for class switching:
• Cytokines (IL-4, IL-5 in Th2 response)
• T-cell binding (CD40-CD40L)
VDJ Rearrangement
Heavy Chain
V1 V2 V3 D1 D2 J1 J2 Cm Cd Cγ Cα Cε
Immature
B cell
DNA
V1 D2 J1 J2 Cm Cd Cγ Cα Cε Mature
B cell
DNA
V1 D2 J2 Cm Cd Cγ Cα Cε
mRNA
IgM
• First antibody secreted during infection
• Excellent activator of complement system
• Classical pathway
• 10 binding sites (most of any antibody)
• Greatest avidity of all antibodies
• Prevents attachment of pathogens
• Weak opsonin
• Receptors cannot bind Fc
• Can activate complement and use C3b as opsonin
• Cannot cross placenta

IgG
• Two antigen binding sites (divalent)
• Four subclasses: IgG1, IgG2, IgG3, IgG4
• Major antibody of secondary response
• Only antibody that crosses placenta
• Most abundant antibody in newborns
• Excellent opsonin
• IgG1 and IgG3 are best opsonins
• Longest lived of all antibody type (several weeks)
• Most abundant class in plasma

IgG
• Very important for encapsulated bacteria
• Capsule resists phagocytosis
• Coating with IgG → opsonization → phagocytosis

IgA
• Found on mucosal surfaces, mucosal secretions
• GI tract, respiratory tract, saliva, tears
• Monomer in plasma
• Crosses epithelial cells by transcytosis
• Transported through cell
• Linked by secretory component from epithelial cells
• Becomes dimer in secretions

IgA
• Does not fix complement
• Excellent at coating mucosal pathogens
• Ideal for mucosal surfaces
• Coat pathogens so they cannot invade
• Pathogens swept away with mucosal secretions
• No complement = no inflammation
• Secreted into milk to protect baby’s GI tract

IgA
Secretory Component
Synthesized by epithelial cells
Allows secretion across mucosa
Joining
Segment
Public Domain /Wikipedia

IgA Protease
• Enzymes that cleave IgA secretory component
• Allows colonization of mucosal surfaces
• S. pneumonia
• H. influenza
• Neisseria (gonorrheae and meningitidis)
IgE
• Bind to mast cells and eosinophils
• Designed for defense against parasites
• Too large for phagocytosis
• IgE binds → mast cell or eosinophil degranulation
• Low concentration in plasma
• Does not activate complement
• Mediates allergic reactions
• Seasonal allergies
• Anaphylactic shock

IgE
Mast
Cell

Somatic Hypermutation
• Late event during inflammation/infection
• Often after class switching
• High mutation rate in portions of V, D, J genes
• Re-stimulation required for ongoing proliferation
• Strongest binding BCR proliferate the most
• “Affinity maturation”
• Receptors mutate: Stronger antigen binding over time
Somatic Hypermutation
Bcell
Bcell Bcell Bcell

Weak
Strong Weak
Bcell Bcell Bcell

B Cell Fate
• After activation B cells become:
• Plasma cells (make antibodies)
• Memory B cells
• Plasma cells
• Usually travel to spleen or bone marrow
• Secrete thousands of antibodies per second
• Die after a few days
• More created if infection/antigen persist
• Memory B cells
• Only produced in T-cell dependent activation
B Cell Development Timeline
Bone Marrow
Pre-infection Bcell VDJ Rearrangement
Lymph Nodes
During Infection Class Switching
Bcell
Bcell Somatic Hypermutation
Post-infection
Bcell Memory Cell
B Cell Memory
Primary response: slower, weaker

Secondary response: Faster, stronger
Antibodies
IgG
IgM
7-10days Second antigen exposure

Primary antigen exposure
Vaccines
• B cell and T cell response without overt infection
• Protection via immune memory
• Various types:
• Live attenuated
• Killed
• Oral/intramuscular
Vaccines
• Live attenuated
• Pathogens modified to be less virulent
• Can induce a strong, cell-mediated response
• Some risk of infection (especially immunocompromised)
• If given <1yo, maternal antibodies may kill pathogen
• MMR
• Killed
• Pathogen killed but antigens remain intact
• Strong humoral response (antibodies)
• Weaker immune response than live, attenuated
• No risk of infection
Vaccines
• Oral
• Stimulate GI mucosal immunity
• Largely IgA response
• Oral polio, rotavirus
• Intramuscular
• Stimulate tissue response
• Large IgG
Vaccines
• Passive Immunization
• Administration of antibodies
• Short term protection (weeks)
• No memory or long term protection
• Used for dangerous, imminent infections
• Rabies, Tetanus
• Also maternal antibodies → fetus
• Sometimes passive and active done simultaneously
• Rabies immune globulin plus rabies vaccine
The Complement
System
Jason Ryan, MD, MPH
Complement System
• Proteins circulating in blood stream
• Can bind to pathogens, especially bacteria
• Binding results in bacterial cell death
• Various names of proteins
• C3, C5, C6
• C3a, C3b
C3
• Most abundant complement protein
• Synthesized by liver
• Can be converted to C3b
• C3b binds to bacteria → bacterial death
• All complement activation involves C3→C3b
Complement System
Membrane
Attack
Complex
C3 → C3b → Bacteria
3 Pathways
Alternative
Classical
Lectin
Alternative Pathway
• C3 spontaneously converts to C3b
• C3b rapidly destroyed unless stabilized by binding
• C3b binds amino and hydroxyl groups
• Commonly found on surface of pathogens
• Surfaces that bind C3b:
• Bacterial lipopolysaccharides (LPS)
• Fungal cell walls
• Viral envelopes
C3b
• Stable C3b can bind complement protein B
• Complement protein D clips B bound to C3b
• Forms C3bBb = C3 convertase
• Result: Stable C3b can cleave more C3 → C3b
• Rapid accumulation of C3b on surfaces
C3b
C3b C3bBb
(stable)
C3
B, D
Factor H
• Plasma glycoprotein synthesized in liver
• Blocks alternative pathway on host cells
• Accelerates decay of C3 convertase (C3bBb)
• Cleaves and inactivates of C3b
• Used by cancer cells and bacteria
• Allows evasion of alternative pathway
• Key pathogens:
• H. Influenza
• N. Meningitidis
• Many streptococci
• Pseudomonas
Ferreira V et al. Complement control protein factor H: the good, the bad, and the inadequate
Mol Immunol. 2010 Aug; 47(13): 2187–2197.
Lectin Pathway
• Mannose-binding lectin (MBL)
• Produced by liver → blood and tissues
• Circulates with MASPs
• Mannose associated serine proteases
• Binds surfaces with mannose (many microbes)
• Cleaves C2 → C2b
• C2b4b is a “C3 convertase”
• Converts C3 → C3b
Classical Pathway
• Antibody-antigen complexes
• Bind C1
• C2b4b is a “C3 convertase”
• Converts C3 → C3b
C1
• Large complex
• C1q, C1r, C1s, C1-inhibitor
• Must bind to two Fc portions close together
• C1inhibitor falls off
• C1r and C1s become active
• Create C3 convertase (C2b4b)
Cr Cs
C1i
C Reactive Protein (CRP)
• “Acute phase reactant”
• Liver synthesis in response to IL-6 (Macrophages)
• Can bind to bacterial polysaccharides
• Activates early classical pathway via C1 binding
• Consumes C3, C4
• Generates C3b
• Does not active late pathway
• Little consumption of C5-C9
Biro et al. Studies on the interactions between C-reactive protein and complement proteins.
Immunology. 2007 May; 121(1): 40–50.
C3a and C3b
Anaphylatoxin
Histamine Release Mast Cells
C3a Increased Vascular Permeability
C3
C3b MAC
MΦ (opsonin)
Complement System
Membrane
Attack
Complex
Alternative
C2 → C2b C4b  C4
Spontaneous
Lectin Classic
MBL C1
Membrane Attack Complex
• Stable C3b leads to formation of the MAC
• MAC formed from C5, C6, C7, C8, C9
C5a
Anaphylatoxin
C5a Neutrophil Chemotaxis
C5
C5b MAC
Complement System
C3a, C5a
Membrane
Attack
Complex
Alternative
C2 → C2b C4b  C4
Spontaneous
Lectin Classic
MBL C1
Inhibition of Complement
• Membrane proteins protect human cells
• Decay Accelerating Factor (DAF/CD55)
• MAC inhibitory protein (CD59)
• DAF disrupts C3b attachment
• CD59 disrupts MAC
• Especially important for protecting RBCs
• Deficiency of DAF or CD59 leads to hemolysis
PNH
Paroxysmal Nocturnal Hemoglobinuria
Binds
Nitric Oxide
Anemia RBC Lysis
Hemoglobinuria
Free plasma Hgb NO depletion
Renal Failure
↑ Smooth Muscle
Thrombosis Tone
Erectile Dysphagia Abdominal

Dysfunction Pain
PNH
Paroxysmal Nocturnal Hemoglobinuria
• Classically causes sudden hemolysis at night

• Fatigue, dyspnea (anemia)
• Abdominal pain (smooth muscle tension)
• Thrombosis
• Leading cause of death
• Usually venous clots
• Unusual locations: portal, mesenteric, cerebral veins
Inherited C3 Deficiency
• Recurrent infections encapsulated bacteria
• Pneumococcal and H. flu pneumonia
• Begins in infancy
• Immune complex (IC) deposition
• IC cleared when they bind complement
• Macrophages have complement receptors
• C3 deficiency: glomerulonephritis from IC deposition
• Other type III hypersensitivity syndromes can occur
C5-C9 Deficiency
Terminal complement pathway deficiency
• Like C3, impaired defense against encapsulated bugs

• Still have C3a (anaphylatoxin)
• Also have C3b (opsonin for macrophages)
• Recurrent Neisseria infections
• Most often meningitis
Hereditary Angioedema
• Deficiency of C1 inhibitor protein
• Many functions beyond complement system
• Breaks down bradykinin (vasodilator)
• Deficiency leads to high bradykinin levels
• Episodes of swelling/edema
Hereditary Angioedema
• Recurrent episodes swelling without urticaria
• Begins in childhood
• Swelling of skin, GI tract, upper airway
• Airway swelling can be fatal
• Diagnosis: Low C4 level
• Lack of C1 inhibitor
• Consumption of C4
• Can treat with C1 inhibitor concentrate
ACE Inhibitors
Cough
Bradykinin Angioedema
AI
X X
ACE Inhibitors
A2
Inactive
Metabolite
NEVER give ACE-inhibitors to patients

with Hereditary Angioedema
C3 Nephritic Factor
• Autoantibody
• Stabilizes C3 convertase
• Overactivity of classical pathway
• Found in >80% patients with MPGN II
• Leads to inflammation, hypocomplementemia
Hypocomplementemia
• CH50
• Patient serum added to sheep RBCs with antibodies
• Tests classical pathway
• Need all complement factors (C1-C9) for normal result
• Normal range: 150 to 250 units/mL
• C3 or C4 level
• Low in many complement mediated diseases (consumption)
• Lupus and lupus nephritis
• MPGN
• Post-streptococcal glomerulonephritis
Lymph Nodes and
Spleen
Jason Ryan, MD, MPH
Lymph
• Interstitial fluid from tissues
• Drains into lymphatic system
• Circulates through lymph nodes
• Eventually drains into subclavian veins
Lymphoid Organs
• Primary lymphoid organs
• Sites of lymphocyte formation
• Bone marrow, Thymus
• Create B and T cells
• Secondary lymphoid organs
• B cells and T cells proliferate
• Lymph nodes
• Spleen
• Peyer’s patches
• Tonsils
Lymph Nodes Follicle
Cortex
Medulla
(cords)
Medulla
(sinus)
Paracortex
Artery/Vein
Afferent
Lymph
Vessel
Efferent
Lymph
Vessel
Lymph Nodes
• Lymph fluid drains from site of infection
• Dendritic cells activated
• Express MHC I, MHC II, B7
• Enter lymph carrying processed antigens
• Free antigens also carried with lymph
• Lymph enters nodes
• Many B and T cells waiting for matching antigen
• Dendritic cells present to T cells
• APCs in lymph nodes to process antigen
• B cells react to antigen
• Result: Generation of adaptive immune response
Lymphoid Follicles
• Found in cortex of lymph nodes
• Site of B-cell activation
• Contain follicular dendritic cells
• Different from tissue dendritic cells
• Permanent cells of lymph nodes
• Surface receptors bind complement-antigen complexes
• Allows easy crosslinking of B cell receptors
• Special note: FDCs important reservoir for HIV
• Early after infection large amounts HIV particles in FDCs
Lymphoid Follicles
• Primary follicles
• Inactive follicles
• Follicular dendritic cells and B cells
• Secondary follicles
• “Germinal center”
• B cell growth and differentiation, class switching
• Nearby helper T cells can bind → more growth
Lymphoid Follicles
Gleiberg/Wikipedia
Paracortex
• Two key features:
• #1: Contain T cells activated by dendritic cells and antigen
• #2: Contain high endothelial venules
• Vessels that allow B/T cell entry into node
• Engorged in immune response (swollen nodes)
• Underdeveloped in rare T-cell deficiency disorders
• DiGeorge syndrome
Medulla
• Medullary sinuses (cavities)
• Contain macrophages
• Filters lymph → phagocytosis
• Medullary chords (tissue between cavities)
• Contain plasma cells secreting antibodies
Spleen
• Filters blood (no lymph)
• All blood elements can enter
• No high endothelial venules
• No selective entry T and B cells
Spleen Marginal PALS
Follicle
Zone
Sinusoids
Artery
Spleen
• White pulp
• Exposure to B and T cells
• Exposure to macrophages
• Red pulp
• Filters blood in sinusoids
• Removes old RBCs (red)
• Stores many platelets
White Pulp
• Marginal zone
• Macrophages
• Remove debris
• Dendritic cells process antigen
• Follicles
• B cells
• Periarteriolar lymphocyte sheath (PALS)
• T cells
Sinusoids of Spleen
• Red pulp lined by vascular “sinusoids”
• Open endothelium → cells pass in/out
• Capillaries → cords → sinusoids
• Cords contain macrophages (filtration)
Splenic Dysfunction
• Increased risk from encapsulated organisms
• Loss of marginal zone macrophages → ↓ phagocytosis
• Also loss of opsonization:
• ↓ IgM and IgG against capsules (splenic B cells)
• Loss of IgG opsonization
• ↓ complement against encapsulated bacteria
• ↓ C3b opsonization
Splenic Dysfunction
• Strep pneumo is predominant pathogen for sepsis
• Death in > 50% of patients
• Others: H. flu (Hib), Neisseria meningitidis
• Less common: Strep pyogenes, E coli, Salmonella
• Also malaria and babesia (RBC infections)
Ram e al; Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy
Clin Microbiol Rev. 2010 Oct; 23(4): 740–780.
Splenic Dysfunction
• Splenectomy
• Trauma
• ITP (spleen site of phagocytosis of platelets)
• Hereditary spherocytosis (minimizes anemia)
• Functional asplenia
• Sickle cell anemia
Splenic Dysfunction
• Howell Jolly Bodies
• Some RBCs leave marrow with nuclear remnants
• Normally cleared by spleen
• Presence in peripheral blood indicates splenic dysfunction
• Target cells
• Also seen in liver disease, hemoglobin disorders
• From too much surface area (membrane) or too little volume
• Too much surface area: liver disease
• Too little volume: hemoglobin disorders
• Thrombocytosis
• Failure of spleen to remove platelets
Splenic Dysfunction
Howell-Jolly Bodies
Target Cells
Paulo Henrique Orlandi Mourao /Mikael Häggström Dr Graham Beards

Hypersensitivity
Jason Ryan, MD, MPH
Hypersensitivity
• Immune response that causes disease
• Exaggerated or inappropriate
• Allergic reactions = subtype of hypersensitivity
Hypersensitivity
• First contact with antigen “sensitizes”
• Generation of immune response
• Antibodies, Memory cells
• Second contact → hypersensitivity
• Symptoms from overreaction of immune system
• Four patterns of underlying immune response
• Type I, II, III, IV
Type I
• Immediate reaction to an antigen (minutes)
• Pollen, pet dander, peanuts
• Pre-formed IgE antibodies (primary exposure)
• Antibodies bound to mast cells
• Antigen binds and cross links IgE
• Mast cell degranulation
Allergen
Mast
Cell
Type I Immunology
• Susceptible individuals make IgE to antigens
• Majority of people make IgG
• IgG does not trigger hypersensitivity response
• IgE results from:
• B cell class switching
• Driven by Th2 cells (humoral response)
• IL-4 is key cytokine for IgE production
• No complement
• IgE does not activate complement
Type I Symptoms
• Skin: Urticaria (hives)
• Respiratory tract
• Rhinitis
• Wheezing (asthma)
• Eyes: Conjunctivitis
• GI tract: Diarrhea
James Heilman, MD/Wikipedia

Anaphylaxis
• Systemic type I hypersensitivity reaction
• Itching, diffuse hives/erythema
• Respiratory distress from bronchoconstriction
• Hoarseness (laryngeal swelling/edema)
• Vomiting, cramps, diarrhea
• Shock and death
• Treatment: Epinephrine
Atopy
• Genetic predisposition to localized hypersensitivity
• Urticaria, rhinitis, asthma
• Usually positive family history of similar reaction
Type I Examples
• Asthma
• Penicillin drug allergy
• Seasonal allergies (allergic rhinitis)
• Allergic conjunctivitis
• Peanut allergy (children)
• Shellfish (food allergy)
Type I
• Early symptoms
• Occur within minutes
• Degranulation → release of pre-formed mediators (histamine)
• Synthesis/release of leukotrienes, prostaglandins
• Edema, redness, itching
• Late symptoms
• ~6 hours later
• Synthesis/release of cytokines
• Influx of inflammatory cells (neutrophils, eosinophils)
• Induration
Type I Mediators
• Histamine
• Vasodilation (warmth)
• Increased permeability venules (swelling)
• Smooth muscle contraction (bronchospasm)
• Leukotrienes, prostaglandins and thromboxanes
• Derived from arachidonic acid
Eicosanoids
Lipids (cell membranes)
Phospholipase A2
Arachidonic acid
Lipoxygenase
Cyclooxygenase
Leukotrienes
Thromboxanes
Prostaglandins
Eicosanoids
Type I Hypersensitivity
Ricciotti E, FitzGerald G; Prostaglandins and Inflammation

Arterioscler Thromb Vasc Biol. 2011 May; 31(5): 986–1000.
Other Type I Mediators
• ECF-A
• Eosinophil chemotactic factor of anaphylaxis
• Preformed in mast cells
• Attracts eosinophils (various roles)
• Serotonin
• Preformed in mast cells, causes vasodilation
• Platelet activating factor
• Bronchoconstriction
• Neutral proteases (chymase, tryptase)
• Heparin (anticoagulant)
IgE, Mast Cells, Basophils, and Eosinophils. J Allergy Clin Immunol. 2010 Feb; 125(2 Suppl 2): S73–S80.
Testing and Desensitization
• Testing for IgE
• Pinprick/puncture of skin
• Intradermal injection
• Positive response: wheal formation
• Desensitization
• Gradual administration of increasing amounts of allergen
• Response changes IgE → IgG
• IgG antibodies can “block” mediator release
• “Modified Th2 response”
Type II
• Antibodies (IgG/IgM) directed against tissue antigens
• Binding to normal structures
• Three mechanisms of tissue/cell damage
• Phagocytosis
• Complement-mediated lysis
• Antibody-dependent cytotoxicity
Tissue/Cell
Type II
• Phagocytosis
• Fc receptors or C3b receptors on phagocytes
• Complement
• IgM or IgG → classical complement cascade
• Formation of MAC → cell death
• ADCC
• Antibody-dependent cell-mediated cytotoxicity
• Natural killer cells bind Fc portion IgG
Type II Examples
• Rheumatic fever
• Strep antibodies cross-react with cardiac myocytes
• Exposure to wrong blood type
• RBC lysis by circulating IgG
• Erythroblastosis fetalis
• Autoimmune hemolytic anemia
• Methyldopa and penicillin: drugs bind to surface of RBCs
• Mycoplasma pneumonia: Induces RBC antibodies
Type II Examples
• Pemphigus vulgaris
• Antibodies against desmosomes in epidermis
• Goodpasture syndrome
• Nephritic syndrome and pulmonary hemorrhage
• Type IV collagen antibodies
• Myasthenia gravis
• Antibodies against Ach receptors
Type III
• Antigen-antibody (IgG) complexes form
• Activate complement → tissue/cell damage
• Generalized: Serum sickness
• Localized: Arthus reaction

Generalized Type III
Serum sickness
• IC in plasma → systemic disease

• Usually IgG or IgM (complement activators)
• Deposit in various tissues
• Skin
• Kidneys
• Joints
• Trigger immune response
• Complement activation
• Activation of macrophages and neutrophils (Fc receptors)
Serum sickness
• Historical description:
• Horse plasma used for passive immunization
• ~5-10 days later triad: Fever, rash, arthralgias
• Antibodies to horse serum antigens
• IC deposits in skin, joints
Serum sickness
• Urticaria or palpable purpura

• Low serum complement levels
• Elevated sedimentation rate
• Diffuse lymphadenopathy
• Acute glomerulonephritis
Serum sickness
• Classic serum sickness

• Rabies or tetanus anti-toxin
• Rarely penicillin: drug acts as a “hapten”
• Monoclonal antibodies (rituximab, infliximab)
• Other Type III diseases
• Post-strep glomerulonephritis
• Systemic lupus erythematosus (Anti-DNA antibodies)
• Polyarteritis nodosa (Hep B antigens)
Localized Type III
Arthus Reaction
• Local tissue reaction, usually in the skin

• Injection of antigen
• Preformed antibodies in plasma/tissue
• Formation of immune complexes
Localized Type III
Arthus Reaction
• Local immune complexes form

• 4-10 hours after injection
• Contrast with Type I reaction in minutes
• Complement activation, edema, necrosis
• Immunofluorescent staining
• Antibodies, complement in vessel walls
Localized Type III
Arthus Reaction
• Reported with skin injections:

• Tetanus, diphtheria, hep B vaccines
• Insulin
• Swelling, redness at site hours after injection
• Hypersensitivity pneumonitis
• Farmer’s lung
• Hypersensitivity reaction to environmental antigen
Type IV
Delayed-type hypersensitivity
• Cell-mediated reaction
• No antibodies (different from I, II, III)
• Memory T-cells initiate immune response
Type IV
Delayed-type hypersensitivity
• Classic example: PPD test (tuberculosis)

• Tuberculin protein injected into skin
• Previously exposed person has memory T-cells
• CD4 T-cells recognize protein on APCs (MHC II)
• Th1 response
• IFN-γ activates macrophages
• IL-12 from macrophages stimulates Th1 cells
• Result: Redness, induration 24 to 72 hours later
Type IV Examples
• Immune response to many pathogens:
• Mycobacteria
• Fungi
• Contact dermatitis (i.e. poison ivy)
• Chemicals (oils) attach to skin cells
• Involves CD8 T-cells that attack skin cells
• Erythema, itching
• 12 to 48hrs after exposure (contrast with type I)
• Multiple sclerosis
• Myelin basic protein
Transplants
Jason Ryan, MD, MPH
Organ Transplants US 2014
Usually indicated when organ has failed

Bone Marrow Transplants
• About 17,000 per year in united states
• Abolish bone marrow with chemotherapy
• Reconstitute all cell lines with donor marrow
• Sometimes autotransplant
• Blood type can change!
• Malignancy (leukemia/lymphoma)
• Inherited red cell disorders
• Pure red cell aplasia, sickle cell disease, beta-thalassemia
• Marrow failure (aplastic anemia, Fanconi anemia)
• Metabolic disorders
• Adrenoleukodystrophy, Gaucher’s disease
• Inherited immune disorders
• Severe combined immunodeficiency, Wiskott-Aldrich
Transplant Vocabulary
Matching
• Goal is to “match” transplanted tissue
• Recipient and donor tissue same/similar
• Failure to match leads to rejection of transplant
• Immune system attacks transplant as foreign
Features of a Good Match
• Same blood type
• Same (or close) MHC I and II molecules
• Negative cross-matching screen
• Test of donor cells against recipient plasma
• Screen for antibodies
Self Self
Antigen Antigen
Self Donor
MHC MHC
Self Donor
APC APC
MHC Matching
• Donor cells express MHC I
• If different from recipient, CD8 cells will react
• MHC Class II also expressed
• Donor APCs may be carried along
• Vascular endothelial cells may express MHC II
Human Leukocyte Antigens
HLAs
• Antigens that make up MHC class I and II molecules

• If different between donor-recipient, immune system
will classify donor tissue as foreign
HLA Matching
• Genes on chromosome 6 determine “HLA type”
• MHC Class I
• Genes: HLA-A, HLA-B, HLA-C
• MHC Class II
• HLA-DR, -DM, -DO, -DP, -DQ
• Highly polymorphic
• Many HLA antigens (i.e. more than 50 HLA-A)
• Subtypes numbered: A1, A2, A3, etc.
• If donor-recipient do not match: rejection
HLA Subtypes
• Some associated with autoimmune diseases
• Example: B27
• Higher risk of ankylosing spondylitis
• Also psoriasis, inflammatory bowel disease, Reiter’s syndrome
• Example: A3
• Higher risk of hemochromatosis
HLA Matching
• Two sets of HLA genes per patient
• All HLAs transferred en bloc from each parent
• 1 set from mother (i.e. A2, B3, etc.)
• 1 set from father
• Sibling has 25% chance of perfect match
MHC Matching
Father
Mother
F1 genes (A2, B4…)
M1 genes
F2 genes (A1, B3…)
M2 genes
Patient
F1, M2 25% chance of F1/M2
The “Perfect” Match
• Two-haplotype match
• Still some degree of incompatibility
• Minor histocompatibility antigens
• Identical twins
• Only time when true “perfect” match exists
MHC Matching
• Most important HLA genes for solid organ transplants:
• HLA-A, HLA-B, HLA-DR
• Sometimes called a “6 out of 6 match”
• More genes sometimes tested
• If HLA-C and HLA-DQ tests, “10 out of 10 match”
Source: American Society for Histocompatibility and Immunogenetics (ASHI)

• Chemotherapy to abolish recipient bone marrow
• Grafted cells must replenish all cell lines
• Matched for HLA-A, -B, -DR, also HLA-C
• Sometimes also -DQ, -DP
• Two problems with mismatch:
• Rejection of new cells
• Graft versus host disease
Graft Versus Host Disease
• Mostly a complication of bone marrow transplant
• Donated (grafted) T-cells (CD8) react to recipient cells
• See recipient cells as foreign
• Opposite of rejection
• Symptoms GVHD
• Skin: Rash
• GI Tract: Diarrhea, abdominal pain
• Liver: ↑LFTs, ↑bilirubin
Graft Versus Host Disease
• Small degree GVHD may be good
• New WBCs kill residual cancer cells
• Graft-vs-leukemia (GVL) effect
• Associated with increased overall survival (less relapse)
Rejection
• Hyperacute (minutes)
• Acute (weeks-months)
• Chronic (years)
Hyperacute Rejection
• Within minutes of transplantation
• Caused by preformed antibodies in recipient
• Against ABO or HLA antigens
• Antibodies formed from previous exposure foreign antigens
• Pregnancy, blood transfusion, previous transplantation
• Prevented by cross-matching screen
MULLEY W, KANELLIS J. Understanding crossmatch testing in organ transplantation:

A case-based guide for the general nephrologist. Nephrology 16 (2011) 125–133
Hyperacute Rejection
• Blood vessels spasm
• Intravascular coagulation
• Ischemia (“white rejection”)
• Rare, usually not treatable
Acute Rejection
• Weeks/months after transplant
• Recipients T cells react to graft (via HLA)
• Cell-mediated immune response
• CD8 T-cells very important
• Biopsy: Infiltrates of lymphocytes/mononuclear cells
• Treatable with immunosuppression
Chronic Rejection
• Months or years after transplant
• Inflammation and fibrosis, especially vessels
• Kidneys: fibrosis of capillaries, glomeruli
• Heart: Narrowing coronary arteries
• Lungs: bronchiolitis obliterans
• Complex, incompletely understood process
• Involves cell-mediated and humoral systems
Immune Deficiency
Syndromes
Jason Ryan, MD, MPH
Immune Deficiency
General Principles
• Loss of T-cells, B-cells, Granulocytes, Complement

• Acquired: HIV, Chemotherapy
• Genetic/Congenital:
• Usually presents in infancy with recurrent infections
X-linked Agammaglobulinemia
Bruton’s Agammaglobulinemia
• X-linked
• Failure of B cell precursors to become B cells
• Light chains not produced
• Defect in Bruton tyrosine kinase (BTK) gene
• Symptoms begin ~6 months of age
• Loss of maternal antibodies
• Recurrent respiratory bacterial infections

• Loss of opsonization by antibodies
• H. Flu, Strep pneumo are common
• Classic presentation: Recurrent otitis media +/- sinusitis/PNA
• GI pathogen infections (loss of IgA)
• Enteroviruses (echo, polio, coxsackie)
• Giardia (GI parasite)
• Key findings:
• Mature B cells (CD19, CD20, BCR) absent in peripheral blood
• Underdeveloped germinal centers of lymph nodes
• Absence of antibodies (all classes)
• Treatment: IVIG
Selective IgA Deficiency
• Very common syndrome in US (~1 in 600)
• Defective IgA B-cells (exact mechanism unknown)
• Most patients asymptomatic
• Symptomatic patients:
• Recurrent sinus, pulmonary infections
• Otitis media, sinusitis, pneumonia
• Recurrent diarrheal illnesses from Giardiasis
• Blood transfusions → anaphylaxis
• IgA in blood products
• Antibodies against IgA in IgA deficient patients
• SLE and RA are common (20-30%)
Selective IgA Deficiency
• Diagnosis:
• Serum IgA < 7mg/dl
• Normal IgG, IgM
• Treatment:
• Prophylactic antibiotics
• IVIG
• Special features: False positive β-HCG test
• Heterophile antibodies produced in IgA deficiency
• Lead to false positive β-HCG
• Up to 30% IgA deficient patients test positive for β-HCG
CVID
Common Variable Immunodeficiency
• Defective B cell maturation

• Loss of plasma cells and antibodies
• Many underlying genetic causes
• Most cases due to unknown cause
• 10+ genes mutations associated with CVID
• Often sporadic – no family history
• Normal B cell count, absence of antibodies
• Usually IgG
• Sometimes IgA and IgM (variable)
CVID
Common Variable Immunodeficiency
• Similar to X-linked Agammaglobulinemia

• Recurrent respiratory bacterial infections
• Enteroviruses, Giardiasis
• Key differences:
• Not X-linked (affects females)
• Later onset (majority 20-45 years old)
• ↑ frequency other diseases:
• RA, pernicious anemia, lymphoma
B Cell Disorders
Thymic Aplasia
DiGeorge Syndrome
• Failure of 3rd/4th pharyngeal pouch to form

24-28 Day Old Embryo
Thymic Aplasia
DiGeorge Syndrome
• Most cases: 22q11 chromosomal deletion

• Key point: Not familial
• Classic triad:
• Loss of thymus (Loss of T-cells, recurrent infections)
• Loss of parathyroid glands (hypocalcemia, tetany)
• Congenital heart defects (“conotruncal”)
• Heart Defects:
• Abnormal aortic arch
• Truncus arteriosus
• Tetralogy of Fallot
• ASDs/VSDs
Thymic Aplasia
DiGeorge Syndrome
• Immune symptoms
• Recurrent infections
• Viral, fungal, protozoal, intracellular bacteria
• Immune symptoms sometimes improve
• Cleft palate, mandible problems also common
Thymic Aplasia
Key Findings
• No thymus shadow on CXR

• Thymus large in newborns
• Faint white shadow on chest x-ray
• Also seen in SCID (without ↓Ca, facial/heart abnormalities)
• Low T-cell count
• Underdeveloped T-cell structures
• Paracortex in lymph nodes
• Peri-arteriolar sheaths in spleen
• Treatment:
• Thymic transplantation
• Hematopoietic cell transplantation
Hyper-IgE Syndrome
Job’s Syndrome
• Rare syndrome, poorly understood

• Immune symptoms with skin/bone findings
• Defective CD4+ Th17 cells
• Failure to produce IL-17
• Loss of attraction of neutrophils
• Defects of STAT3 signaling pathway
• Signal transducer and activator of transcription
• Activated by cytokines
• Overproduction IgE, loss of IFN-γ
• Characteristic labs: ↑IgE, ↓IFN-γ
Hyper-IgE Syndrome
Job’s Syndrome
• Skin findings
• First few weeks of life
• Diffuse eczema (also crusted lesions, boils, etc.)
• Histamine release → itching
• Staph abscesses face, scalp
• Classically “cold” - lacking warmth/redness of inflammation
• Loss of cytokine production
• Recurrent sinusitis, otitis (often without fever)
• Facial deformities (broad nasal bridge)
• Retained primary teeth (two rows of teeth!)
Hyper-IgE Syndrome
Job’s Syndrome
• Classic case:
• Newborn baby
• Deformed face/teeth
• Diffuse rash
• Skin abscesses that are “cold”
• Recurrent infections without fever
• Labs: Elevated IgE
Chronic mucocutaneous
candidiasis
• Defect in autoimmune regulator (AIRE) genes
• AIRE Function #1:
• Associates with Dectin-1 receptor
• Dectin-1 responds to Candida antigens
• Result of defect: Recurrent candida infections
• AIRE Function #2:
• Promotes self antigens production in thymus
• Self antigens presented to T-cells (negative selection)
• Result of defect: Autoimmune T-cells
• Endocrine dysfunction (parathyroid/adrenal)
candidiasis
• T-cell dysfunction (cell-mediated defect)
• Th1 cytokines: ↓IL-2, ↓IFN-γ
• ↑IL-10 (anti-inflammatory cytokine)
• NOT due to antibody or B-cell deficiencies
• T cells fail to react to candida antigens
D Lilic. New perspectives on the immunology of chronic mucocutaneous candidiasis.

Curr Opin Infect Dis. 2002; 15(2):143-7
candidiasis
• Chronic skin, mucous membrane candida infections
• Thrush
• Skin
• Esophagus
• Associated with endocrine dysfunction:
• Hypoparathyroidism
• Adrenal failure
• Classic case:
• Child with recurrent thrush, diaper rash
Candida Infections
• T-cells important for mucosal defense
• Example: HIV patients often get thrush (↓CD4)
• Neutrophils important for systemic defense
• HIV patients rarely get candidemia
• No candidemia in CMC
• Chemo patients at risk for candidemia (neutropenia)
SCID
Severe Combined Immunodeficiency
• Loss of cell-mediated and humoral immunity

• Usually primary T cell problem
• Loss of B-cells, antibodies usually secondary
SCID
• T-cell/B cell areas absent/diminished:

• Loss of thymic shadow
• Loss of germinal centers in nodes
• Susceptible to many infections
• Thrush, bacterial, viral, fungal
• Babies: Thrush, diaper rash, failure to thrive
• Death unless bone marrow transplant
SCID
• Most common forms are X-linked (boys)

• Mutation of γ subunit of cytokine receptors
• Gene: IL2RG (interleukin-2 receptor gamma gene)
• Also caused by adenosine deaminase gene deficiency
• Newborn screening:
• Maternal T-cells may falsely indicate normal counts
• TRECs (T-cell receptor excision circles)
• Circular DNA formed in normal T-cells in the thymus
• Mandated in many states
SCID
• Classic case:
• Infant with recurrent infections
• Multiple systems: otitis, GI, candida (skin)
• Absent thymic shadow
• Normal calcium/heart (contrast with DiGeorge)
ADA
Adenosine Deaminase Deficiency
• Excess dATP
• Believed to inhibit ribonucleotide reductase
• Ribonucleotides synthesized first (A, G, C, U)
• Converted to deoxyribonucleotides by RR
• Result: ↓ DNA synthesis → B/T cell dysfunction
ADA
Adenosine Inosine
dATP
Ataxia Telangiectasia
• Autosomal recessive genetic disorder
• Defective ATM gene on chromosome 11
• Ataxia Telangiectasia Mutated gene
• Repairs double stranded DNA breaks
• Nonhomologous end-joining (NHEJ)
• Result: Failure to repair DNA mutations
• Hypersensitivity of DNA to ionizing radiation
Nonhomologous end-joining
NHEJ
Double Strand Break NHEJ

(ionizing radiation)
• Mix of systems involved with varying findings
• CNS (ataxia)
• Skin (telangiectasias)
• Immune system (infections, malignancies)
• Presents in childhood with progressive symptoms
• Usually begins with gait and balance problems
• Cerebellar atrophy
• Ataxia in 1st year of life
• Telangiectasias
• Dilation of capillary vessels on skin
• Repeated sinus/respiratory infections
• Low levels immunoglobulins, especially IgA and IgG
• High risk of cancer (lymphomas)
• Commonly identified lab abnormalities:
• Most consistent lab finding: ↑AFP
• Low IgA level
Hyper-IgM Syndrome
• Class switching disorder
• Failure of B cells (CD40) to T cell (CD40L) binding
• 70% cases: Defective CD40L gene (T-cell problem)
• B cells make IgM only
• Labs show ↑IgM, all other antibodies absent
• Most common form X-linked (boys)
CD40L CD40
TCR
T Cell CD4
MHC2
B Cell
B7
CD28
Hyper-IgM Syndrome
• Recurrent bacterial infections in infancy
• Sinus and pulmonary infections
• Pneumonia, sinusitis, otitis media
• Mostly caused by encapsulated bacteria (S. pneumo, H. flu)
• Also opportunistic infections
• Pneumocystis, Cryptosporidium, Histoplasmosis
• Loss of IgG opsonization
Wiskott-Aldrich Syndrome
• X linked disorder of WAS gene (WAS protein)
• WASp absence/dysfunction
• Necessary for T-cell cytoskeleton maintenance
• This forms “immunologic synapse”
• T-cells cannot properly react to APCs
• Can worsen with age
• Immune dysfunction, ↓platelets, eczema
• Elevated IgE and IgA common (eczema)
• Treatment: Bone marrow transplant
Wiskott-Aldrich Syndrome
• Classic case
• Male infant
• 6 months old (maternal antibodies fade)
• Eczema
• Bleeding, petechiae (low platelets)
• Recurrent infections
Leukocyte Adhesion Deficiency
• Defective neutrophil/lymphocyte migration
• Most common type: Type 1
• Autosomal recessive defect in CD18
• Also called Lymphocyte function associated antigen-1 (LFA1)
• Forms beta subunit of several integrins (adhesion molecules)
• WBCs (especially PMNs) cannot roll, migrate
Leukocyte Adhesion Deficiency
• Delayed separation of the umbilical cord
• After cord cutting, inflammation occurs
• Cord stump normally falls off 2-3 days
• Delayed in LAD (sometimes 30+ days)
• Classic presenting infection: omphalitis (stump infection)
• Other findings:
• Elevated WBCs (neutrophilia) – especially during infections
Chediak-Higashi Syndrome
• Failure of lysosomes to fuse with phagosomes
• Mutation: lysosomal trafficking regulator (LYST) gene
• Causes microtubule dysfunction
• Especially Staph and Strep
• Oculocutaneous albinism
• Fair skin, blond hair, light blue eyes
• Children who survive → severe neuro impairment
• Peripheral neuropathy: weakness and sensory deficits
• Often wheelchair bound
CGD
Chronic Granulomatous Disease
• Loss of function of NADPH oxidase

• Phagocytes use NADPH oxidase to generate H2O2 from
oxygen (respiratory burst)
• Catalase (-) bacteria generate their own H2O2 which
phagocytes use despite enzyme deficiency
• Catalase (+) bacteria breakdown H2O2
• Host cells have no H2O2 to use → recurrent infections
• Five organisms cause almost all CGD infections:
• Staph aureus, Pseudomonas, Serratia, Nocardia, Aspergillus
Source: UpToDate
CGD
NADPH
O2 Oxidase O2· H2O2 Bacteria
CGD
NADPH
Catalase (-)
Bacteria
CGD
NADPH
Catalase (+) H2O

Bacteria O2
CGD
• Nitroblue tetrazolium test

• Dye added to sample of neutrophils
• Absence of NADPH oxidase → cells do not turn blue
• A “negative” test indicates lack of enzyme
• More blue, more NADPH oxidase present
Innate Immunity Defects
Glucocorticoids and
NSAIDs
Jason Ryan, MD, MPH
Glucocorticoids/NSAIDs
• Anti-inflammatory/immune suppression
• Used in many, many conditions
Eicosanoids
Phospholipase A2
Arachidonic acid
Lipoxygenase
Cyclooxygenase
Leukotrienes
Thromboxanes
Prostaglandins
Eicosanoids
Ricciotti E, FitzGerald G; Prostaglandins and Inflammation

Arterioscler Thromb Vasc Biol. 2011 May; 31(5): 986–1000.
Cyclooxygenase (COX)
• Two isoforms
• COX-1
• Constitutively expressed
• Important for GI mucosal function
• COX-2
• Inducible in inflammatory cells
NSAIDs
• NSAIDs
• Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac
• COX-2 inhibitors
• Celecoxib
• Aspirin
NSAIDs
Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac
• Reversibly inhibit COX-1 and COX-2

• Benefits
• ↓ pain, redness, swelling (inflammation)
• Adverse effects
• ↓ platelet aggregation (risk of bleeding)
• ↓ renal blood flow (ischemia)
• ↓ GI mucosa (ulcers/bleeding)
• Interstitial nephritis
Acute Interstitial Nephritis
• Inflammation of “interstitium”
• Space between cells
• Not disease of nephron itself
• Hypersensitivity (allergic) reaction
• Usually triggered by drugs
• Sometimes infections or autoimmune disease
• Classic finding: Urine eosinophils
Acute Interstitial Nephritis
• Classic presentation
• Days to weeks after exposure to typical drug
• Fever, rash
• Oliguria
• Increased BUN/Cr
• Eosinophils in urine
COX-2 Inhibitors
Celecoxib
• Reversibly inhibit COX-2 only

• Benefits
• ↓ pain, redness, swelling (inflammation)
• Less risk GI ulcers/bleeding
• Adverse effects
• ↑ CV events (MI, stroke) in clinical trials
• Sulfa drugs (allergy)
Glucocorticoids
Prednisone, methylprednisolone, hydrocortisone, triamcinolone,
dexamethasone, beclomethasone
• Diffuse across cell membranes
• Bind to glucocorticoid receptor (GR)
• GR-steroid complex translocates to nucleus
• Effects via altering gene expression
Glucocorticoids
Mechanisms of action
• Inactivation NF-KB
• Key inflammatory transcription factor
• Mediates response to TNF-α
• Controls synthesis inflammatory mediators
• COX-2, PLA2, Lipoxygenase
Eicosanoids
Phospholipase A2
Arachidonic acid
Lipoxygenase
Cyclooxygenase
Leukotrienes
Thromboxanes
Prostaglandins
Glucocorticoids
• Many, many immunosuppressive effects
• Neutrophilic leukocytosis (↑WBCs)
• Impaired neutrophil migration
• ↓ circulating eosinophils, monocytes, lymphocytes
• ↓ expression many cytokines
• Interleukins, IFN-γ, TNF-α, GM-CSF
Glucocorticoids
Selected side Effects
• Skin: skin thinning and easy bruising

• Cushingoid appearance/weight gain
• Truncal obesity, buffalo hump, moon face
• Osteoporosis
• Hyperglycemia
• ↑ liver gluconeogenesis
• ↓ glucose uptake fat tissue
Glucocorticoids
Selected side Effects
• Cataracts
• Myopathy (muscle weakness)
• skeletal muscle catabolism (amino acids) for gluconeogenesis
• Gastritis/peptic ulcers
• Gastric hyperplasia
• ↑ acid secretion
• ↓ mucus synthesis
Avascular Necrosis
Osteonecrosis
• Bone collapse
• Most commonly femoral head
• Mechanism poorly understood Jmarchn/Wikipedia
• Interruption of blood flow (infract)
• Demineralization/bone thinning
• Collapse
• Commonly associated with long term steroid use
• Other risk factors:
• Lupus
• Sickle cell
• Alcoholism
• Trauma
Adrenal Insufficiency
• Long term steroid use suppresses HPA axis
• Hypothalamus-Pituitary-Adrenal axis
• Abrupt discontinuation → adrenal insufficiency
• Symptoms (adrenal crisis):
• Dominant feature: Hypotension/shock
• Anorexia, nausea, vomiting, abdominal pain
• Weakness, fatigue, lethargy
• Fever
• Confusion or coma
Immunosuppressants
Jason Ryan, MD, MPH
Immune Suppression
• Commonly used drugs:
• NSAIDs, Steroids
• Less commonly used drugs:
• Cyclosporine/Tacrolimus
• Sirolimus
• Methotrexate
• Mycophenolate
• Cyclophosphamide
• Azathioprine
• TNF-α inhibitors
• Hydroxychloroquine
Cyclosporine & Tacrolimus
• Both drugs inhibit calcineurin
• Calcineurin activates (via dephosphorylation) NFAT
• Nuclear factor of activated T-cells
• Important transcription factor for many cytokines
P IL-2
NFAT NFAT Nucleus

Calcineurin
Other
Cytokines
• Cyclosporine: binds to cyclophilins
• Complex inactivates calcineurin
• Tacrolimus: binds to FK-506 binding protein
• Complex inactivates calcineurin
• Autoimmune diseases, organ transplants
• Similar side effects
• Both drugs metabolized P450 system
• Many drug-drug interactions
• Can raise/lower levels/effects
• Nephrotoxicity
• Most important and limiting side effect
• Vasoconstriction of the afferent/efferent arterioles
• Hypertension
• Via renal vasoconstriction (salt/water retention)
• Diltiazem drug of choice
• Impairs cyclosporine metabolism (↑ drug levels)
• Treats HTN and allows lower dose cyclosporine to be used
• Hyperuricemia and gout
• Hyperglycemia (may impair insulin secretion)
• Neurotoxicity (usually tremor)
Cyclosporine
• Two unique side effects
• Not reported with tacrolimus
Lesion/Wikipedia
• Gingival hyperplasia
• Hirsutism
Sirolimus
Rapamycin
• Kidney transplant, drug-eluting stents

• Inhibits mTOR (mechanistic target of rapamycin)
• Binds FK binding protein
• Same target as Tacrolimus
• Does NOT inhibit calcineurin
• Inhibits mTOR
• Blocks response to IL-2 in B/T cells
• Blocks signaling pathways
• Cell cycle arrest in the G1-S phase
• No growth/proliferation
Sirolimus
Rapamycin
• Anemia, thrombocytopenia, leukopenia

• Hyperlipidemia
• inhibition of lipoprotein lipase
• Hyperglycemia
• Insulin resistance
Coronary Stents
• “Drug-eluting stents” (DES)
• Coated with anti-proliferative drug
• Blunts scar tissue growth (restenosis)
• Sirolimus
• Everolimus
• Paclitaxel
Methotrexate
• Chemotherapy, autoimmune diseases
• Mimics folic acid - inhibits dihydrofolate reductase
dUMP dTMP
Thymidylate
Synthase
N, N Methylene-THF DHF
Dihydrofolate
THF Reductase
Methotrexate
Side Effects
• Myelosuppression
• Reversible with leucovorin (folinic acid )
• Converted to THF
• Does not require dihydrofolate reductase
• “Leucovorin rescue”
• Stomatitis/Mucositis (mouth soreness)
• Occurs with many chemo agents
• DNA damage → cytokine release
• Cytokines damage epithelium
• Loss of mucosal integrity → pain, bacterial growth
• Abnormal LFTs, GI upset
The pathobiology of mucositis. Sonis ST. Nat Rev Cancer. 2004;4(4):277

Mycophenolic acid
CellCept
• Inhibits IMP dehydrogenase

• Rate-limiting step in purine synthesis in lymphocytes only
• Also, preferentially binds type II isoform IMP dehydrogenase
• Type II Expressed by activated lymphocytes
• ↓ nucleotides → ↓ DNA synthesis in T/B cells
• Bone Marrow Suppression
• GI: Nausea, cramping, abdominal pain
Inosine-MP Guanosine-MP
IMP
Dehydrogenase
Cyclophosphamide
• Powerful immunosuppressant (also anti-tumor)
• Used in vasculitis, glomerulonephritis (oral)
• Prodrug: Requires bioactivation by liver
• Converted to phosphoramide mustard
• Metabolized by P450 system
• “Alkylating agent”
• Adds an alkyl group to the N7 position
• DNA strands will cross link
• Inhibits DNA replication → cell death
Cyclophosphamide
Side Effects
• Myelosuppression
• ↓WBC, ↓Hct, ↓Plt
• Hemorrhagic cystitis
• Acrolein metabolite toxic to bladder
• Hematuria +/- dysuria
• Lower risk with hydration and mesna
• Mesna: sodium 2-mercaptoethane sulfonate
• Mesna binds and inactivates acrolein in the urine
Cyclophosphamide
Side Effects
• SIADH
• Usually IV dosing for chemotherapy
• Hyponatremia; possible seizures
• Compounded by IVF
• Complex mechanism: More ADH release, less renal response
Azathioprine
• Transplants, autoimmune diseases
• Prodrug converted to 6-Mercaptopurine (6-MP)
• Analog to hypoxanthine (purine like adenine, guanine)
• 6-MP competes for binding to HGPRT
• Hypoxanthine guanine phosphoribosyltransferase
• Converts hypoxanthine to inosine monophosphate
• Also guanine to guanosine monophosphate
Hypoxanthine Guanine 6-MP

Azathioprine
GMP
IMP GMP
AMP
HGPRT
Hypoxanthine Guanine
Guanine
Azathioprine
↓Purines
HGPRT (A, G)
6-MP Thioinosinic acid

monophosphate
Azathioprine
Adverse Effects
• Bone marrow suppression
• GI: Anorexia, nausea, and vomiting
• Caution with allopurinol
• Xanthine oxidase inhibitor
• Metabolizes purines → uric acid
• Blunts metabolism of 6-MP/azathioprine
• ↑ risk of adverse effects
Xanthine
Oxidase
6-thiouric acid
6-MP (inactive)
Muromonab-CD3
OKT3
• Monoclonal antibody
• Used in organ transplantation
• Binds to epsilon chain of CD3 (T cells)
• Blocks T-cell activation
• Leads to T-cell depletion from circulation
Muromonab-CD3
OKT3
• Key side effect: Cytokine release syndrome

• Occurs after first or second dose
• Fevers, rigors, nausea, vomiting, diarrhea, hypotension
• Sometimes chest pain, dyspnea or wheezing
• Arthralgias and myalgias
• Caused by initial activation of T cells → release of cytokines
• Minimized by pre-medication with steroids, antihistamines
Infliximab
• Antibody against TNF-α
• Used in rheumatoid arthritis, Crohn’s
• “Chimeric”
• Both mouse (murine) and human components
• Antigen-binding portion of molecule: murine
• Constant Fc domain: human
• Risk of reactivation TB
• PPD screening done prior to treatment
• Risk of other infections: bacterial, hepatitis, zoster
Other TNF-α Inhibitors
• Adalimumab (monoclonal antibody TNF-α)
• Golimumab (monoclonal antibody TNF-α)
• Etanercept
• Made by recombinant DNA
• Recombinant protein of TNF receptor
• “Decoy receptor”
• Binds TNF instead of TNF receptor
Malaria Drugs
• Chloroquine and hydroxychloroquine
• Malaria drugs with immunosuppressive actions
• Block TLRs in B-cells (↓activation)
• Weak bases: ↑pH in immune cells → ↓ activity
• Other actions
• Used in rheumatoid arthritis, SLE
Systemic Lupus
Erythematosus
Jason Ryan, MD, MPH
SLE
Systemic Lupus Erythematosus
• Autoimmune disease
• Most patients (90%) are women
• Usually develops age 15 to 45
Picpedia.org
SLE
Systemic Lupus Erythematosus
• Antibodies against nuclear material

• Key finding: anti-nuclear antibodies (ANA)
• Antibody-antigen complexes circulate in plasma
• Type III hypersensitivity reaction
• Deposit in MANY tissues (diffuse symptoms)
• Antibody-antigen complexes activated complement
• Low C3/C4 levels (hypocomplementemia)
• Low CH50
SLE
Cause
• Etiology unknown
• Likely genetic, immune, environmental factors
• Viruses and UV light may play a role
Lupus Antibodies
• Anti-nuclear antibodies (ANA)
• Present in serum of lupus patients
• Also present in 5% normal patients
• Also present in many other autoimmune disorders
• Sensitive but not specific
• Negative test = disease very unlikely
• Reported as titre: 1:20 or 1:200
• Often 1:160 considered positive
Lupus Antibodies
• Anti-double stranded DNA (anti-dsDNA)
• Specific for SLE
• Associated with disease activity (↑ in flares)
• Associated with renal involvement (glomerulonephritis)
• Anti-smith (anti-Sm)
• Specific for SLE
• Directed against small nuclear ribonucleoprotein (snRNPs)
snRNPs
Small nuclear ribonucleoprotein
• Combine with RNA transcripts

• Form a “spliceosome”
• Removes a portion of the RNA transcript
• Antibodies against RNP (anti-Sm) in lupus
Extractable Nuclear Antigens
ENA Panel
• Panel of blood tests against nuclear antigens

SLE
Symptoms
• Flares and remissions common

• Fever, weight loss, fatigue, lymphadenopathy
Malar Rash
• Classic lupus skin finding
• “Butterfly” rash
• Common on sunlight exposure
• Can also see “discoid” lesion
• Circular skin lesion
• Classically on forearm
Raynaud Phenomenon
• White/blue fingertips
• Painful on exposure to cold
• Vasospasm of the artery → ischemia
• Can lead to fingertip ulcers
• Seen in other conditions
• Isolated
• Other autoimmune disorders
Jamclaassen~commonswiki /Wikipedia
SLE
Symptoms
• Oral or nasal ulcers

• Arthritis (tender, swollen joints)
• Serositis de:Benutzer:Padawan/Wikipedia
• Inflammation of pleura (pain with inspiration)

• Inflammation of pericardium (pericarditis)
• “Penias”
• Anemia, thrombocytopenia, leukopenia
• Antibody attack of cells (Type II hypersensitivity)
Databese Center for Life Science (DBCLS)

Lupus Cerebritis
CNS Involvement
• Cognitive dysfunction
• Confusion
• Memory loss
• Stroke
• Seizures
Lupus Nephropathy
• Nephritic or nephrotic syndrome (or both)
• Common cause of death in lupus
• Diffuse proliferative glomerular nephritis
• Most common SLE renal syndrome
• Nephritic syndrome
• Membranous glomerular nephritis
• Nephrotic syndrome
Pixabay/Public Domain
Cardiac Manifestations
• Libman-Sacks (marantic) endocarditis
• Nonbacterial inflammation of valves
• Classically affects both sides of mitral valve
Anti-Phospholipid Antibodies
• Occur in association with lupus
• Can also occur as a primary problem
• Antibodies against proteins in phospholipids
• Three important clinical consequences
• “Antiphospholipid syndrome”
• Increased risk of venous and arterial thrombosis
• DVT, stroke, fetal loss
• Increased PTT
• False positive syphilis (RPR/VDRL)
Anti-Phospholipid Antibodies
• Anti-cardiolipin
• False positive RPR/VDRL
• Syphilis also produces these antibodies
• “Lupus anticoagulant”
• Interferes with PTT test
• False elevation
• Anti-β2 glycoprotein
SLE
Diagnosis
• Need four of 11 criteria

Drug-Induced Lupus
• Lupus-like syndrome after taking a drug
• Classic drugs: INH, hydralazine, procainamide
• Often rash, arthritis, penias, ANA+
• Kidney or CNS involvement rare
• Key features: anti-histone antibodies
• Resolves on stopping the drug
SLE
Treatment
• Steroids
• Other immunosuppressants
• Avoid sunlight
• Many patients photosensitive Pixabay/Public Domain
• Can trigger flares

• Causes of death
• Renal failure
• Infection (immunosuppression drugs)
• Coronary disease (SLE → increased risk)
Neonatal Lupus
• Maternal antibodies → fetus
• 1 to 2% babies born if maternal autoimmune disease
• Systemic lupus erythematosus
• Sjogren's syndrome
• +SSA/Ro or + SSB/La – either disease
Ernest F/Wikipedia
Neonatal Lupus
• At birth or first few weeks of life
• Rash
• Multiple red, circular lesions on face, scalp
• Congenital complete heart block
• Slow heart rate (50s)
• Often does not respond to steroids
Rheumatoid
Arthritis
Jason Ryan, MD, MPH
Rheumatoid Arthritis
• Autoimmune disorder
• Inflammation of joints especially hands, wrists
• More common in women
• Usual age of onset 40 - 60
• Synovium
• Thin layer of tissue (few cells thick)
• Lines joints and tendon sheaths
• Secretes hyaluronic acid to lubricate joint space
• Inflammation
• Unknown trigger
• Overproduction of TNF and IL-6
• Synovial hypertrophy
• Thickens into pannus
• Infiltrated with inflammatory cells, granulation tissue
• Increase in synovial fluid
• Erodes into cartilage, bone
• Antibody-mediated
• Type III hypersensitivity
Synovial Joint
Open Stax College/Wikipedia

• Symmetric joint inflammation
• Gradual onset
• Pain, stiffness, swelling
• Classically “morning stiffness”
• Joint stiffness >1 hour after rising
• Improves with use
• May have systemic symptoms (fever)
• Classically affects MCP and PIP joints of hands
• Often tender to touch
• DIP joints spared

davida__jones/Flikr
• Bones can erode/deviate
• Ulnar deviation
• Swelling of MCP joints → deviated wrist
• Swan neck deformity
• Hyperextended PIP joint
• Flexed DIP
Phoenix119/Wikipedia
• Other joints:
• Wrists
• Elbows
• Knees
• Hips
• Toes
• Baker's cyst (popliteal cyst)
• Synovium-lined sac at back of knee
• Continuous with the joint space
• If ruptures → symptoms similar to DVT
• Serositis
• Pleuritis, pleural effusion
• Pericarditis, pericardial effusion
Subcutaneous nodules
• Palpable nodules common (20 to 35% patients)
• Almost always occur in patients with RF+
• Common on elbow (can occur anywhere)
• Central necrosis surrounded by
macrophages/lymphocytes
• Usually no specific treatment
Nephron/Wikipedia
• Episcleritis
• Red, painful without discharge
• Scleritis
• Often bilateral
• Dark, red eyes
• Deep ocular pain on eye movement
• Uveitis Image courtesy of Kribz
• Anterior/posterior
• Floaters if posterior
Sjogren’s Syndrome
• Salivary and lacrimal glands
• Dry eyes, dry mouth (sicca symptoms)
• Commonly associated with rheumatoid arthritis
Lusb/Wikipedia Joyhill09
Osteoporosis
• Accelerated by RA
• Also often worsened by steroid treatment
• 30 percent ↑risk of major fracture
• 40 percent ↑risk hip fracture

• ~80% positive rheumatoid factor
• Antibodies against Fc portion of IgG antibody
• “Seropositive” rheumatoid arthritis
• Poor specificity
• Positive in endocarditis, Hep B, Hep C
• Positive in Sjogren’s, Lupus
• Antibodies to citrullinated peptides (ACPA)
• Specific marker of RA
Urea Cycle Aspartate
ATP
Carbamoyl
Phosphate
Citrulline
Ornithine Argininosuccinate
Urea
Arginine
Fumarate
Citrulline
• Non-standard amino acid - not encoded by genome
• Incorporated into proteins via post-translational
modification
• More incorporation in inflammation
• Anti-citrulline peptide antibodies used in RA
• Up to 80% of patients with RA
• Elevated CRP and ESR
• Strong association with HLA-DR4
Treatment
• NSAIDs
• Steroids
• Disease-modifying antirheumatic drugs (DMARDs)
• Protect joints from destruction
• Methotrexate
• Azathioprine
• Cyclosporine
• Hydroxychloroquine
• Sulfasalazine
• Leflunomide
• TNF-a inhibitors (antibodies against TNF-α)
Sulfasalazine
Acetylsalicylic acid
(aspirin)
Sulfasalazine
Colonic
Bacteria
Sulfapyridine 5-aminosalicylic acid

(5-ASA)
Leflunomide
• Inhibits dihydroorotate dehydrogenase
• Inhibits pyrimidine synthesis
• Side effects: diarrhea, abnormal LFTs, ↓WBCs
• Also used in psoriatic arthritis
CMP
Dihydroorotate
Dehydrogenase UMP
TMP
Dihydroorotic acid Orotic Acid
Infliximab
• Antibody against TNF-α
• Used in rheumatoid arthritis, Crohn’s
• Risk of reactivation TB
• PPD screening done prior to treatment
• Risk of other infections: bacterial, zoster
Other TNF-α Inhibitors
• Adalimumab (monoclonal antibody TNF-α)
• Golimumab (monoclonal antibody TNF-α)
• Etanercept
• Recombinant protein of TNF receptor
• “Decoy receptor”
• Binds TNF instead of TNF receptor
Long Term Complications
• Increased risk of coronary disease
• Leading cause of mortality
• Amyloidosis
• Secondary (AA) amyloidosis
Ed Uthman, MD/Wikipedia
Felty Syndrome
• Syndrome of splenomegaly, neutropenia in RA
• Classically occurs many years after onset RA
• Usually in patient with severe RA
• Joint deformity
• Extra-articular disease
• Improves with RA therapy
Bob Blaylock/Wikipedia
Scleroderma
Jason Ryan, MD, MPH
Scleroderma
Systemic Sclerosis
• Stiff, hardened tissue (sclerosis)
• Skin, other organ systems involved
Scleroderma
Systemic Sclerosis
• Endothelial cell damage

• Trigger unclear
• Antibodies, cytokines → damage
• Result is fibroblast activation
• Excess collagen deposition
Scleroderma
Systemic Sclerosis
• Most common demographic is women

• Peak onset 30-50 years old
• Presents in two clinical syndromes
• Diffuse
• Limited (CREST)
Diffuse Scleroderma
• Diffuse skin thickening
• Raynaud’s phenomenon
• Often initial sign
• Followed ~ 1 year with other signs/symptoms
• Early involvement of visceral organs
• Renal disease – renal failure
• GI tract – dysmotility, heartburn
• Heart: pericarditis, myocarditis, conduction disease
• Joints/muscles: Arthralgia, myalgias
Pulmonary Disease
• Pulmonary hypertension
• Can progress to right heart failure
• RV heave
• Elevated jugular veins
• Pitting edema
• Routine monitoring: echocardiography
• Interstitial lung disease
Scleroderma Renal Crisis
• Life-threatening complication of diffuse scleroderma
• Acute worsening of renal function
• Marked hypertension
• Responds to ACE inhibitors
Limited Scleroderma
CREST
• “Limited” skin involvement

• Skin sclerosis restricted to hands
• Sometimes distal forearm, face or neck
• CREST
• Calcinosis
• Raynaud’s phenomenon
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasias
Calcinosis
CREST
• Calcium deposits in subcutaneous tissue

• Bumps on elbows, knees and fingers
• Can break skin, leak white liquid
• X-rays of hands may show soft tissue calcifications
Raynaud’s Phenomenon
CREST
• White/blue fingertips
• Painful on exposure to cold
• Vasospasm of the artery → ischemia
• Can lead to fingertip ulcers
• Often 1st sign for years/decades
• Seen in other conditions
• Isolated
• Other autoimmune disorders
Jamclaassen~commonswiki /Wikipedia
Esophageal Dysmotility
CREST
• Difficulty swallowing
• Dysmotility
• Reflux/heartburn
• LES hypotonia
• “Incompetent LES”
Olek Remesz/Wikipedia
Sclerodactyly
CREST
• Fibrosis of skin of hands
• Can begin as fingers puffy, hard to bend
• Later, skin often be becomes shiny skin
• Thickened skin (can’t pinch the skin)
• Loss of wrinkles
• Severe form: hands like claws
• Also seen in diffuse type
James Heilman /Wikipedia

Telangiectasias
CREST
• Skin lesions
• Dilated capillaries
• Face, hands, mucous membranes
Herbert L. Fred, MD and Hendrik A. van Dijk

Limited Scleroderma
CREST
• Generally more benign course than diffuse

• Rarely involves heart, kidneys
• Main risk is pulmonary disease
• Leading cause of death
• Pulmonary hypertension
• Interstitial lung disease
• Similar features to diffuse scleroderma
Scleroderma
Systemic Sclerosis
• Antinuclear antibody (ANA) – Not specific

• Anti-topoisomerase I (anti-Scl-70) antibody
• Diffuse disease
• Anti-centromere antibody (ACA)
• Limited disease
• CREST = centromere
• Anti-RNA polymerase III antibody
• Diffuse disease
• Associated with rapidly progressive skin involvement
• Also increased risk for renal crisis
Scleroderma
Systemic Sclerosis
• Treatment usually aimed at organ system

• GI tract: proton pump inhibitors
• Raynaud’s: Calcium channel blockers
• Pulmonary: Pulmonary hypertension drugs
• Immunosuppressants have limited role
• Little proven benefit
• Used in rare, special cases
Primary Biliary Cirrhosis
• T-cell destruction small bile ducts
• Often presents jaundice, fatigue, itching
• Can lead to cirrhosis and liver failure
• Elevated conjugated bilirubin, alkaline phosphatase
• Associated with scleroderma
• 5 to 15% PBC patients have limited scleroderma
• Also associated with Sjogren’s, Lupus, RA
• Also Hashimoto’s thyroiditis
Jason Ryan, MD, MPH
• Destruction of salivary and lacrimal glands
Lusb/Wikipedia Joyhill09
• Dry eyes (keratoconjunctivitis sicca)
• May present as feeling of dirt/debris in eyes
• Dry mouth (xerostomia)
• Difficulty chewing dry foods (i.e. crackers)
• Cavities
• Bad breath
Jamesbrdfl/Deviant Art
“Extraglandular” disease symptoms
• Xerosis
• Dry, scaly skin
• Often lower extremities and axilla
• Joints: arthralgias or arthritis
• Raynaud’s phenomena
• Many, many other potential symptoms
• More common among women
• Age of onset usually in 40s
• Many elderly patients have “sicca symptoms”
• Dry mouth, dry eyes
• Not due to Sjogren’s
• Antibody tests and/or biopsy = normal
• Lymphocyte mediated
• Type IV hypersensitivity disorder
• Biopsy of salivary gland: Lymphocytic sialadenitis
KGH/Wikipedia
• Primary or secondary
• Often associated with rheumatoid arthritis and lupus
• 40-65% of primary biliary cirrhosis patients have Sjögren's
Antibodies
• Four relevant antibody tests
Schirmer Test
• Tests reflex tear production
• Filter paper placed near lower eyelid
• Patient closes eyes
• Amount of wetting (mm) measured over 5 minutes
Jmarchn/Wikipedia
Salivary Testing
• Salivary gland scintigraphy
• Nuclear test
• Low uptake of radionuclide in patients with SS
• Whole sialometry
• Measurement of saliva production
• Patient collects all saliva over 15 minutes
• Sample weighed
Diagnosis
• Any 4 of 6 criteria
• Must include either histopathology or autoantibodies
Treatment
• Good oral hygiene
• Artificial saliva
• Muscarinic agonists: pilocarpine
• Sometimes steroids for extraglandular disease
Bill Branson/Public Domain

B cell Lymphoma
• Increased risk among Sjogren’s patients
• 5-10% of patients
• May present as persistent unilateral swollen gland
• May mimic past swelling
KGH/Wikipedia
Neonatal Lupus
• Maternal antibodies → fetus
• 1 to 2% babies born if maternal autoimmune disease
• Systemic lupus erythematosus
• Sjögren's syndrome
• +SSA/Ro or + SSB/La – either disease
Ernest F/Wikipedia
Neonatal Lupus
• At birth or first few weeks of life
• Rash
• Multiple red, circular lesions on face, scalp
• Congenital complete heart block
• Slow heart rate (50s)
• Often does not respond to steroids
Vasculitis
Jason Ryan, MD, MPH
Vasculitis
• Inflammation of blood vessels
• Leukocytes in blood vessel walls
• Typical inflammation symptoms
• Fever
• Myalgias
• Arthralgias
• Fatigue
• Organ/disease specific symptoms
• Vessel lumen narrows or occludes from inflammation
Classification
Palpable Purpura
• Purpura: red-purple skin lesions
• Extravagation of blood into the skin
• Does not blanch when pressed
* Images courtesy Dr. James Heilman and Wikipedia; used with permission
Palpable Purpura
• Non-palpable purpura
• Usually non-inflammatory
• Petechiae (small), Ecchymosis (large)
• Palpable purpura
• Occurs in vasculitis
• Raised
• Small vessel inflammation
• Leukocytoclastic vasculitis
* Images courtesy Dr. James Heilman and Wikipedia; used with permission
Vasculitis Treatment
• Most treated with steroids or cyclophosphamide
Classification
Large Vessel Vasculitis
• Temporal arteritis
• Takayasu’s arteritis
• Granulomatous inflammation
• Narrowing of large arteries
Temporal Arteritis
Giant Cell Arteritis
• Narrowing of temporal artery system

• Headache, jaw claudication (pain on chewing)
• If not treated → blindness
• Ophthalmic artery occlusion
Temporal Arteritis
Giant Cell Arteritis
• High ESR
• Diagnosis: Biopsy temporal artery (granulomas)
• Treat with high dose steroids (don’t wait for biopsy)
• Classic case:
• Elderly female with headache
• Pain on chewing
• High ESR
Dr. Ryan’s Grandmother

Takayasu’s Arteritis
• Granulomatous thickening of aortic arch and branches
• Up to 90% of cases occur in women
• Greatest prevalence in Asia
Public Domain
Takayasu’s Arteritis
• Classic symptoms: Weak pulses one arm
• "Pulseless disease"
• Proximal great vessels
• BP difference between arms/legs
• Bruits over arteries
• ↑ESR
• Treat with steroids
Kawasaki Disease
• Autoimmune attack of medium vessels
• Most cases occur in children
• Classic involvement: skin, lips, tongue
• Diffuse, red rash
• Palms, soles → later desquamates
• Changes in lips/oral mucosa: "strawberry tongue”
• Feared complication: coronary aneurysms
• Rupture → myocardial infarction
• Treatment: IV immunoglobulin and aspirin
AHA Scientific Statement: Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease.
Circulation 2004:110:2747-2771
Kawasaki Disease
Wikipedia/Dong Soo Kim Wikipedia/mprice18

Kawasaki Disease
Wikipedia/ Maen K Househ

Scarlet Fever
• Fever, sore throat, diffuse red rash
• Many small papules ("sandpaper" skin)
• Classic finding: Strawberry tongue
• Eventually skin desquamates
Image courtesy of Wikipedia/Public Domain
Image courtesy of Afag Azizova/Wikipedia

Reye’s Syndrome
• Encephalopathy, liver failure, fatty infiltration
• Symptoms: vomiting, confusion, seizures, coma
• Often follows viral illness
• Influenza, varicella
• Caused by diffuse mitochondrial insult
• Associated with aspirin use in children
• Generally, aspirin not used for kids
• Only exception is Kawasaki
Buerger’s Disease
thromboangiitis obliterans
• Male smokers
• Poor blood flow to hands/feet
• Gangrene
• Autoamputation of digits
• Superficial nodular phlebitis
• Tender nodules over course of a vein
• Raynaud's phenomenon
• Segmental thrombosing vasculitis Dr. James Heilman/Wikipedia
• Treatment: Smoking cessation

Polyarteritis Nodosa
• Immune complex mediated disease: medium vessels
• Type III hypersensitivity reactions
• Classic demographic: Hep B+
• Nerves: Motor/sensory deficits
• Skin: Nodules, purpura
• Kidneys: Renal failure

• Many aneurysms and constrictions on arteriogram
• Kidney, liver, and mesenteric arteries
• Rosary sign
• Transmural inflammation of medium vessel wall
• Fibrinoid necrosis
• Classic case:
• Hep B+, nerve defects, skin nodules, purpura, renal failure
• Diagnosis:
• Angiogram (aneurysms)
• Tissue biopsy of affected system
• Treatment: Corticosteroids, cyclophosphamide
Wikipedia/mprice18
Henoch-Schonlein purpura
• Most common childhood systemic vasculitis
• Often follows URI
• Associated with IgA
• Vasculitis from IgA complex deposition
• IgA nephropathy
• Also C3 deposition
IgA Antibody

• Skin: palpable purpura on buttocks/legs
• GI: abdominal pain, melena
• Kidney: Nephritis
• Classic case:
• Child with recent URI
• Melena
• Tissue biopsy is best test
• Usually self-limited
Emmanuelm/Wikipedia
• Feared result: renal failure
• More common adults
• Severe cases: steroids/cyclophosphamide (rarely
done)
ANCA Diseases
Anti-neutrophil cytoplasmic antibodies
• Churg-Strauss syndrome
• Wegener's Granulomatosis
• Microscopic Polyangiitis
Daisuke Koya, Kazuyuki Shibuya,
• All have pulmonary involvement Ryuichi Kikkawa and Masakazu Haneda.
• All have renal involvement

• Crescentic RPGN
• “Pauci-immune”
• Paucity of Ig (negative IF)
• Nephritic syndrome
• Proteinuria, hematuria
Images courtesy of bilalbanday

ANCA Diseases
Anti-neutrophil cytoplasmic antibodies
• ANCA
• Autoantibodies
• Attack neutrophil proteins
• Two patterns distinguish diseases
• c-ANCA (cytoplasmic)
• Usually proteinase 3 (PR3) antibodies
• Wegener’s only
• p-ANCA (perinuclear)
• Usually myeloperoxidase (MPO) antibodies
• Churg-Strauss and Microscopic Polyangiitis
Churg-Strauss syndrome
• Asthma, sinusitis, neuropathy
• Eosinophilia
• p-ANCA, elevated IgE level
• Granulomatous, necrotizing vasculitis
• Can also involve heart, GI, kidneys
• Treatment: steroids, cyclophosphamide
Wegener's Granulomatosis
(granulomatosis with polyangiitis)
• Sinusitis, otitis media, hemoptysis

• Upper and lower airway disease
• Renal: hematuria, red cell casts
• Purpura
• Granulomas on biopsy BruceBlaus/Wikipedia
• c-ANCA
• Treatment: steroids, cyclophosphamide
Microscopic Polyangiitis
• Hemoptysis, kidney failure, purpura
• Just like Wegner’s except
• No upper airway disease (sinusitis)
• p-ANCA not c-ANCA
• No granulomas on biopsy
• Treatment: steroids and cyclophosphamide
Goodpasture’s Syndrome
• Antibody to collagen (type II hypersensitivity)
• Antibodies to alpha-3 chain of type IV collagen
• Anti-GBM
• Anti-alveoli
• Hemoptysis and nephritic syndrome
• Linear IF (IgG, C3)
• Classic case
• Young adult
• Male
• Hemoptysis
• Hematuria
Images courtesy of bilalbanday

Treatment Summary
Diseases Treatment
Temporal Arteritis Steroids
Takayasu’s Arteritis Steroids
Polyarteritis Nodosa Steroids/CycP

Kawasaki Disease IVIG/Aspirin
Buerger's disease Smoking Cessation
Churg-Strauss Steroids/CycP
Wegener’s granulomatosis Steroids/CycP
Microscopic polyangiitis Steroids/CycP
Henoch-Schönlein purpura Steroids/CycP
Blood Test Summary

Immunology

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Innate Immunity

Jason Ryan, MD, MPH

Skin/ Innate Adaptive

• Recognize molecules that are “foreign”

• Mannose (polysaccharide on bacteria/yeast)

• Key cytokines are IL-1 and TNF-α

• Antibodies coat pathogen or cell

• Natural Killer Cells

• Skin and mucosal membranes

Natural Killer T-cells B-cells Macrophage

Martin Brändli /Wikipedia

Sources: Cavalcanti et al, Pulmonary Medicine, Volume 2012 (2012)

• Injection tuberculin protein under skin

Normal Antigen Super Antigen

Martin Brändli /Wikipedia

Heavy Heavy Fvasconcellos /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Public Domain /Wikipedia

Martin Brändli /Wikipedia

Martin Brändli /Wikipedia

Bcell Bcell Bcell

Bcell Bcell Bcell

Bcell Somatic Hypermutation

Primary response: slower, weaker

7-10days Second antigen exposure

Erectile Dysphagia Abdominal

• Classically causes sudden hemolysis at night

• Like C3, impaired defense against encapsulated bugs

NEVER give ACE-inhibitors to patients

Paulo Henrique Orlandi Mourao /Mikael Häggström Dr Graham Beards

James Heilman, MD/Wikipedia

Ricciotti E, FitzGerald G; Prostaglandins and Inflammation

Martin Brändli /Wikipedia

• IC in plasma → systemic disease

• Urticaria or palpable purpura

• Classic serum sickness

• Local tissue reaction, usually in the skin

• Local immune complexes form

• Reported with skin injections:

• Classic example: PPD test (tuberculosis)

Usually indicated when organ has failed

• Antigens that make up MHC class I and II molecules

Source: American Society for Histocompatibility and Immunogenetics (ASHI)

MULLEY W, KANELLIS J. Understanding crossmatch testing in organ transplantation:

• Loss of T-cells, B-cells, Granulocytes, Complement

• Recurrent respiratory bacterial infections

• Defective B cell maturation

• Similar to X-linked Agammaglobulinemia

• Failure of 3rd/4th pharyngeal pouch to form

• Most cases: 22q11 chromosomal deletion

• No thymus shadow on CXR

• Rare syndrome, poorly understood

D Lilic. New perspectives on the immunology of chronic mucocutaneous candidiasis.

• Loss of cell-mediated and humoral immunity

• T-cell/B cell areas absent/diminished: