INTRODUCTION TO

BASIC IMMUNOLOGY
(MBS400)

1
IMMUNOLOGY
QUICK
OVERVIEW
Objectives
▪ Trace the study of immunology
▪ Examine and question prior assumptions related to
immunology
▪ Practice and apply some immunology-specific
vocabulary and concepts important to the field of
immunology.
▪ Recognize the need for balance and regulation of
immune processes.
▪ Begin to integrate concepts from immunity into
real-world issues and medical applications.
1
Immunity
Virus
Parasites

Fungi

Bacteria

Immunity is the body’s

response to what it recognizes
as harmful foreign materials
or abnormal cells 4
 Importance of Immunology
- Biosimilars
▪ Biosimilars (biopharmaceutical products of
immunology) are growing and immensely
contributing to revenue in the pharmaceutical
industry.

3
The Top Selling Prescription
Drugs By Revenue (small
molecule drugs and biosimilars)
7 of the 10 top selling drugs in the developed markets are biosimilars

10. Xarelto (rivaroxaban) - Cardiovascular

diseases
9. Opdivo (nivolumab) – anti-PD-1
8. Eylea (aflibercept) - wet macular
degeneration, macular oedema secondary to
retinal vein occlusion
7. Avastin (bevacizumab) - lung, colorectal,
kidney, cervical, ovarian cancer and relapsed
glioblastoma
6. Herceptin (trastuzumab) - HER2-positive
breast cancer 4
The Top Selling Prescription
Drugs By Revenue
5. Enbrel (etanercept) - rheumatoid arthritis, plaque
psoriasis, and psoriatic arthritis

4. Keytruda (pembrolizumab) - anti-PD-1 therapy

3. Revlimid (lenalidomide) - multiple myeloma,

relapsed/refractory non-Hodgkin lymphoma, and diffuse large B-
cell lymphoma

2. Eliquis (apixaban) - reduce stroke and systemic

embolism risk

1. Humira (adalimumab) - autoimmune diseases,

including rheumatoid arthritis, psoriatic arthritis, Crohn’s disease,
ankylosing spondylitis, and plaque psoriasis
5
Immunity – Types of
pathogens
Pathogens
PARASITES vary in size

Worms and
protozoa are
classified as
parasites.

6
Immunity
Consists of following activities:
1. Defense against invading pathogens
(viruses, bacteria, etc)
2. Removal of 'worn-out' cells (e.g.,
old RBCs) & tissue debris (e.g., from
injury or disease)
3. Identification & destruction of
abnormal or mutant cells (primary
defense against cancer)
4. Rejection of 'foreign' cells (e.g.,
organ transplant)
5. Inappropriate responses:
i. Allergies
ii. Autoimmune diseases

7
Immunity
• Skin
• Lining of mucus membranes
• Secretions
• Blood cells and vasculature

• Liver
• Bone marrow

• Lymphatic system and lymphoid

organs
• Most tissues – have resident immune10
cells
Overview of the Immune System
Cells and Organs of the
immune system
Cells of the immune system are generated in
the Primary Lymphoid Tissues.
1. Thymus – where T lymphocyte immune
system cells develop functionality.

2. Bone marrow – where all the cells of

immune response generate.

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12
Overview of the Immune System
Cells and Organs of the
immune system
The adaptive immune responses are induced in
the Secondary Lymphoid Tissues.
1. Mucosa Associated Lymphoid Tissue
(MALT): Pathogens at mucosal surfaces.
i.e. Respiratory, Gastrointestinal, Urogenital tracts
2. Lymph nodes: Pathogens in body tissues
3. Spleen: Pathogens in blood circulation

16
Overview of the Immune System

Immune
System

Innate Adaptive
(Nonspecific) (Specific)
1o line of defense 2o line of defense

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 Where do immune cells
come from?
Stem cells
A stem cell is an
unspecialized cell that is
capable of self
renewing itself and
developing into
specialized cells of a
variety of cell types.
15
 Where do immune cells
come from?
Stem cells
Classes of stem cells;
1.Totipotent:

2.Pluripotent:

3.Multipotent:

4.Unipotent:
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 Where do immune cells
come from?
Stem cells
Classes of stem cells;
1.Totipotent: Hematopoietic
Stem Cell (HSC)
2.Pluripotent:

3.Multipotent:

4.Unipotent:
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HEMATOPOIESIS the
process by which HSCs HSC
differentiate into mature Self -
blood cells Myeloid
renewal Lymphoid Dendritic
Dendritic progenitor
progenitor cell
cell
pAPC
Macrophage Monocyte THYMUS
TH cell
Granulocyte
Neutrophil monocyte T-cell
TC cytotoxic
progenitor progenitor
cell
T Suppressor
cell
Granul- Eosinophil Eosinophil
progenitor
ocytes B-cell
B-cell
Basophil progenitor
Basophil progenitor
Plasma
cell
Mast cell Innate Lymphoid
cell
Platelets Megakaryocyte

Erythrocyte pAPC – professional antigen

Erythrocyte 18
progenitor presenting cell
 INNATE IMMUNE CELLS –
Phagocytic cells
Monocytes present in Monocyte
the blood are short
lived, but they leave
the blood to develop
into long lived
macrophages

27
 INNATE IMMUNE CELLS –
Phagocytic cells
The phagocytic cells use
PRRs to recognise PAMPs.

The pathogen can also

become coated with
substances called opsonins
that are recognised by the
opsonin receptors on the Opsonin
phagocytic cells. receptor
Opsonin
28
Phagocytosis

Once engulfed by the

phagocyte, the pathogen is
destroyed using reactive
oxygen intermediates
generated by a respiratory
burst and by several non-
oxygen-dependent killing
mechanisms 30
 Relationship between particle size and
recognition by phagocytic cells

Phagocytic cells recognize particles with increasing

affinity as the size of the particle increases.
22
Innate immune cells

31
 Innate immunity vs Adaptive
Immunity
Innate Immunity Adaptive
(first line of defense) Immunity
(second line of defense)

▪ No time lag ▪A lag period

▪ Broad specificity for
Pathogen associated ▪ Antigen specific
molecular patterns (PAMPS)

▪ Development of
▪ No memory
memory
▪ Same intensity every ▪ Strongerand faster
time upon re-infection
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INNATE IMMUNITY VS
ADAPTIVE IMMUNITY

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How pathogens are
eliminated? Immune cells move
through both the blood
and lymphatic
circulation to access all
sites of infection. They
eliminate pathogen by;
1. Phagocytosis e.g.
macrophages
2. Release molecule to
kill the pathogen e.g.
Natural Killer cells
3. Kill infected cell e.g.
cytotoxic T cells

22
 Immune disorders and
deficiencies Janeway’s Immunology p32

Tolerance is the strategy by which the immune system is able to discriminate

between self and nonself, thereby, avoiding accidently destroying host tissues 27
Immune disorders and
deficiencies
▪ Immune deficiency(Recurrent infection) :
Insufficiency of the immune response to protect
against infectious agents
▪ Hypersensitivity (allergy): Overly zealous attacks
on common benign but foreign antigens
▪ Autoimmune disease: Erroneous targeting of self-
proteins or tissues by immune cells
▪ Immune imbalance: Dysregulation in the immune
system that leads to aberrant activity of immune
cells, especially enhanced inflammation and/or
and reduced immune inhibition

28
 Innate
2 Immunity
Innate immunity
EXTERNAL DEFENSES
1. Skin forms a physical barrier
2. Mucus prevents colonisation
3. Commensal microorganisms occupy niche
(competes with pathogens for nutrients and
space)
4. Acid pH (stomach) resists pathogens
5. Enzymes (in tears/ saliva) attack pathogens

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Innate immunity
INTERNAL DEFENSES
1. Phagocytic cells
2. Complement cells
3. Natural killer cells
4. Inflammatory response
5. Antimicrobial proteins

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Haematopoiesis

25
Innate immune response;
Recognition of threat

Activation of innate immune cells and complement system

Production of cytokines, chemokines, acute phase proteins

and defensins

Upregulation of cell adhesion molecules

Recruitment of cells to the site of infection or tissue

damage

Elimination of the stimulus

Resolution of the response

Tissue repair 33
Recognition of threat

PRRs found on
innate immune
have broad
specificity for
PAMPS on the
pathogen and
DAMPS on
damaged host
cells
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Recognition of threat

Soluble
PRR

Cell surface
PRR Intracellular
PRR
PRRs can be on the cell surface, soluble or
intracellar 35
Cell surface
PRRs

Intracellular
PRRs

36
Recognition of threat

Recognition is structurally-
specific but what is recognized
is common to whole groups of
organisms or host cells.

37
Acute phase response
This is an immediate response following
infection or tissue damage and involves
a change in concentration of certain
molecules. It involves;

1. Enhancing host resistance

2. Minimizing tissue injury
3. Promoting resolution and repair of
inflammatory lesion
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Signs of inflammation

39
Acute vs Chronic
inflammation

40
Acute inflammation

Cell types and molecules involved in acute inflammation

41
Acute inflammation stimuli

▪Infection
▪Tissue damage
▪Toxins
▪Foreign substances

42
Acute inflammation
consequences
▪ Proinflammatory cytokine production
▪ Complement activation
▪ Mediator release from mast cells
▪ Neutrophil adhesion to endothelium
▪ Vasodilation
▪ Increased vascular permeability
▪ Recruitment of neutrophils into tissues

43
Chronic inflammation
▪ Failure to eliminate the stimulus results in an ongoing
inflammatory immune response with a shift away
from neutrophil dominance
▪ Chronic inflammation can also arise insidiously
▪ T-cells and macrophages are dominant
▪ T-cells and NK cells release pro-inflammatory
cytokines such as IL-17, TNF𝜶 and IFN
▪ Pro-inflammatory cytokines recruit and activate
macrophages

44
Chronic inflammation

M

M1 M2

45
Chronic inflammation and
tissue damage

46
Diseases involving chronic
inflammation
▪ Rheumatoid arthritis
▪ Atherosclerosis
▪ Tuberculosis
▪ Pulmonary fibrosis
▪ Cancer
▪ Alzheimer disease

47
The complement system

48
Cont…

49
Cont…

(MAC)

50
Acute inflammatory
response

51
NK cell Activating
and inhibitory
receptors

An infected cell
loses expression of
MHC class I resulting
in NK cell activated
killing of the
infected cell.

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Pathogen evasion of innate
immunity
▪ Avoid detection by PRRs e.g. Helicobacter,
Coxiella, and Legionella bacteria
▪ Block PRR signaling pathways, preventing
activation of responses e.g. Vaccinia virus,
Yersinia bacteria
▪ Prevent killing or replication inhibition e.g.
M. tuberculosis and Staphylococcus aureus

53
cytokines
Small (~8 – 80 kDa) secreted proteins that act as
messengers between cells.

Main groups of cytokines are;

1. Interferons (IFN)
2. Interleukins (IL)
3. Colony Stimulating Factors (CSF)
4. Chemokine
5. Tumuour Necrosis Factor (TNF)
6. Transforming Growth Factors (TGF)

54
cytokines
Cytokines have multiple functions including control of
hematopoiesis and immune responses. They bind to
specific cytokine receptors which initiate intracellular
signalling

55
1. interferons

56
2. interleukin

57
3. Colony stimulating
factors

58
4. chemokine

IL-8 is both an interleukin and a chemokine

59
5. Tumour necrosis factor

60
6. Transforming growth
factors

61
How do cytokines
function?
Autocrine
Cytokines can act
on the same cell
that released
them (Autocrine)
or on another
cell (paracrine)

Paracrine
62
Cytokine network
interactions

Cytokine action can act in form of a

cascade forming some form of pathway
63
Cytokine network interactions
Other characteristics of cytokines;

64
Therapeutic blocking of
pathological cytokines
Antibodies could
be used to block
cytokine – cytokine
receptor
interaction to
control any
pathological state.

65
 Adaptive
3 Immunity
67
 Recognition of antigen by the
immune system

4 types of receptors are involved in the recognition of antigen by

the immune system. 68
Recognition of antigen by the
immune system
•PRR were the main focus of the
innate immunity. However, they are
present in both innate and adaptive
immunity.
•In this this session we look at
interactions involving the B-cells and
T-cells.

69
B-cell and T-cell development

B-cells are produced and mature in the bone marrow while

T-cells mature in the Thymus. 70
B-cell and T-cell development

B-cells and T-cells then move from the primary organs to the
secondary lymphoid tissues where they interact with the
antigens. 71
Humoral immunity;
-is immunity provided by the
antibodies present in bodily
fluids.
-is the major function of the B-
cell component of the adaptive
immune response.

72
Humoral immunity
T-cells and B-cells work together:
•B-cells function as professional antigen-
presenting cells using MHC class II to
present professional MHC to CD4+ T cells.
•Helper T-cells help B-cells to class switch
and differentiate into antibody-secreting
plasma cells.

73
What is MHC?
Stands for Major Histocompatibility Complex
• This is a complex of genes that are the major
determinants of tissue compatibility during
transplantation.
• MHCs are used to show protein antigens to T-
cells
• Human: HLA
• Mouse: H-2

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Two classes of MHC

75
TCR Recognition of Peptide-MHC

MHC class I presents peptides to CD8+ cytotoxic cells.

This will result in the activation of the T-cell and kill the
infected cell by the fas-fasL or the perforin-granzyme
apoptotic pathways
76
TCR Recognition of Peptide-MHC

MHC class II presents antigens to CD4+ helper or

regulatory T-cells. This results in the activation of the T-
cell to release cytokines for particular functions
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TCR Recognition of Peptide-MHC

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Superantigen

79
The MHC gene locus

Class I MHCs are coded by the B,C,A genes while

class II are coded for by the DP, DQ and DR
genes located on chromosome 6 of humans.
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The MHC gene
locus

81
The MHC gene
locus
Structure of antibody

83
 Structure of antibody
• 2 identical heavy chains (~50 kDa) and 2 identical light
chains (~25 kDa) totalling to ~150 kDa.
• Composed of variable region for antigen binding and
constant region for effector functions.
• Light chain constant region can be a kappa or lamba
light chain.
• Heavy chain constant region determines the class of
the antibody i.e.
1. Mu (, IgM)
2. Delta (, IgD),
3. Gamma (, IgG): IgG1-IgG4
4. Alpha (𝜶, IgA): IgA1, IgA2
5. Epsilon (, IgE)
84
Antibody concentration in the blood

85
 Antibodies bind to epitopes on the
antigen

Antibodies recognise particular amino acid sequence on the

antigen on areas called epitopes. A single antigen can have
several epitopes bound by different antibodies
86
Antibody binds non-convalently to
epitopes
Amino acids in the antigen binding region interact with
the epitope using non-convalent (reversible) forces;

1. Hydrogen bonding
2. Electrostatic interactions
3. Van der Waals interactions
4. Hydrophobic interactions

Overall binding strength is called the Affinity of the

interaction. Compare with Avidity.

87
What is Class switching?

B-cells are initially made of IgM. With the help

of T helper cells in a process called class
switching, the IgM is converted to the rest of
the IgGs eg IgG.
88
Cell-mediated immunity
•Is immunity provided by cytotoxic T-
cells and by T helper cell-mediated
activation of macrophages
•Is required to defeat intracellular
pathogens which are hidden from the
effects of antibody and complement

89
 Cell-mediated immunity

Th-cells are at the core of this immunity and they act by

producing cytokines which activate Tc cells and
macrophages. 90
 Cell-mediated immunity
Digested into
T-cells recognize protein peptides
protein antigens
that are
processed into
peptides then
presented to the
T-cell receptor

91
 Structure of TCR
Variable domain
involved in binding

TCR are
composed of
two chains
Constant stabilised by
domain disulphide
bond

92
T-cells are classified based on TCR
structure;

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𝜶 T-cells

94
Th0

• The cytokines secreted by the dendritic cell depend on which cell

surface, cytoplasmic or endosomal PRRs are activated. Therefore,
what Th0 becomes depends on the pathogens that are present
determined by the PAMPs.
• Also influenced by activation of other cell types

95
Th1

Th1 produces cytokines which activate cytotoxic T

cells, macrophages and B cells but inhibits Th2,
respectively. 96
Th1 activation of cytotoxic t-cells

Dendritic cells have both MCH I and II. Presentation

of peptides to Th1 cell leads to production of IL-2
which activates the Tc 97
 Th1 activation of macrophages

Macrophage also have MCH I and II. Presentation of

peptides to Th1 cell leads to production of IFN
which activates macrophage microbial mechanism 98
 Th2

Th2 activates B-cells and eosinophils and inhibits

Th1 (Th1 and Th2 are antagonistic)
99
Regulatory T-cells

Mainly suppress immune response by the release of

cytokines which down-regulate the activate of a
variety of cells or by cell – cell contact with the cell
that is to be suppressed.
100
Cytotoxic T-cells

1.Kill infected or tumour

cells
2.Secrete cytokines
• Tc1: IFN, etc
• Tc2: IL-4, etc

101
 Killing by the cytotoxic T-cells

The killing by Tc depends on the antigens presented on the MHC I cell.

This results in the triggering of either the FasL-Fas or Granzymes-perforin
which activate the Caspase enzyme responsible for apoptosis.

102
Removal of killed cells by
macrophages

After the apoptotic signals are sent into the cell, some
membrane portions are externalized hence being
exposed phagocytic cells such as macrophages. 103
Adaptive Immunity Deficiencies

•Sometimes the Adaptive Immunity can have

defects that are;
1. Primary Immunodeficiency diseases are due
to intrinsic defects in cells of the immune
system and are for the most part, genetically
determined.
2. Secondary Immunodeficiency diseases are
usually not genetically determined. May be
acquired.
104
B cell primary deficiencies

1. X-Linked agammaglobulinemia (X-LA)

2. IgA deficiency
3. IgG subclass deficiency
4. Common Variable Immunodeficiency (CVID)
5. Immunodeficiency with increases IgM (HIgM)
6. Transient Hypogammaglobulinemia of infancy
Read more

105
T cell primary deficiencies

1. Severe combined immunodeficiency

2. Adenosine deaminase deficiency
3. DiGeorge anomaly
4. Hereditary ataxia telangiectasia (AT)
5. MHC Class II deficiency
6. Purine nucleoside phosphorylase deficiency
7. Wiskott-Aldrich syndrome (WAS)
Read more

106
AIDS and Secondary Immunodeficiency
• Secondary Immunodefiencies may be caused by:
•Some drugs: they can alter the immune
function, like steroids
•Nutrient deficiencies can lead to impaired
immune responses, like malnutrition
•HIV infection which leads to the most
significant global cause of immunodeficiency
•AIDS is caused by HIV

107
 INTRODUCTION TO
CLINICAL IMMUNOLOGY
(MBS600)

108
Immune disorders and
deficiencies
▪ Immune deficiency(Recurrent infection) :
Insufficiency of the immune response to protect
against infectious agents
▪ Hypersensitivity (allergy): Overly zealous attacks
on common benign but foreign antigens
▪ Autoimmune disease: Erroneous targeting of self-
proteins or tissues by immune cells
▪ Immune imbalance: Dysregulation in the immune
system that leads to aberrant activity of immune
cells, especially enhanced inflammation and/or
and reduced immune inhibition

109
 Transplant immunology

Tumour Immunology

Hypersensitivity

Outline Autoimmunity

Infection and Immunity

Vaccinology
11
0
Transplant
immunology

11
1
Transplantation
Transfer of cells, tissue or an organ between different
parts of the body or between different individuals

• Solid-organ transplant has risk of immunological rejection. Bone marrow

transplant can result in either graft rejection or graft-versus-host rejection.
• Xenotransplant, from sources such as a pig, increases the availability of
organs for transplantation 112
 The growing allogeneic organ supply/demand imbalance has resulted in an expanding
transplant waiting list.

Megan Sykes, and David H. Sachs Sci. Immunol.

2019;4:eaau6298
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association 113
for the Advancement of Science. No claim to original U.S. Government Works
Classification

114
Rules of transplantation

Identical strains can accept skin grafts. Unidentical strains reject

skin grafts. Hybrid accepts skin grafts but cannot donate 115
 1st and 2nd allograft rejection

Results of the experiments shown indicate that graft

rejection displays the features of adaptive immune
responses. First set rejection takes longer than second
set rejection 116
 Rejection response

Looking at the time course of rejection in recipient

patients we can identify 4 different phases of rejection.
117
Some common transplants

118
Graft survival rates

119
Blood transfusion

120
 Direct alloantigen recognition
(foreign) (foreign)

(self)

T-cells recognizes unprocessed allogeneic MHC molecule

on graft APC. A professional APC for MHC class II or any
allogeneic cell for MHC class resulting in rejection
121
 Indirect alloantigen recognition
(foreign) (self) (self)

Presentation of processed peptide of allogeneic

MHC molecule bound to self MHC molecule 122
The immune response e.g. a liver graft

Recipient and donor APCs are present. In the presence of co-stimuli

Th0 differentiates into the different subclasses. Tregs contribute to
graft acceptance while Th1 (upregulates MHCs on donor cells) and Th2
(activate B-cells to secrete antibodies) contribute to graft rejection.
123
Major Histocompatibility Complex

Children inherit one set of the HLAs from the mother

and one from the father. 124
 Major Histocompatibility Complex

Variability of MHCs is
contributed by the α-chain
and β-chain. The β-chain does
not form part of the peptide
binding groove of the MHC I. 125
MHC Disparity between individuals

At the DR, A2 and B loci the two individuals

share some similarity. So how do the rest of the
mismatches contribute to survival?
126
Influence of MHC Matching on
Graft Survival

The closer the match the better the chance for

longer survival in the recipient. 127
Tissue Typing

• This patient has

developed renal failure
and needs a kidney
transplant.
• He has been HLA typed
for all the A, B, and DR
loci
128
 Tissue Typing

Patients awaiting
transplants are
placed on a register
with many others,
each of whom are
likely to have
different HLA types.

129
Tissue Typing
1. A potential donor is HLA typed and each kidney is
sent to a hospital where a good HLA match is
registered.
2. A blood sample from the donor is also sent to the
hospital.

130
 Tissue Typing
3. In the cross-match, donor
B cells are mixed with
recipient serum. In this
case, preformed
antibodies are binding the
donor cells; this
transplantation cannot
take place.
4. In this case, the recipient
has no antibodies against
donor cells, and the
transplant can go ahead.
131
Mechanism of immunosuppressive
drugs Its usually impossible to
match all transplant
candidates unless they are
identical twins. Therefore,
immunosuppressive drugs
are used.
• Anti-TCR
• CTLA4-Ig
• Cyclosporine
• Anti-IL-2R
• Rapamycin
• Azathioprine
• Mycophenolate 132
Graft versus Host Reaction

The immunocompromise recipient’s cells are killed by

radiation before introduction of stem cells from bone
marrow. Donor immune cells can recognise recipient cells
leading to the death of those cells resulting in GVHD.133
Tumour
Immunology
135
Introduction
Tumour immunology involves;
1. Immune system cells becoming
malignant
2. How the immune responds to these
tumours
3. How the immune system can be
harnessed to attack tumours.

136
Cancer Prevalence (WHO, 2018)
The most common cancers are:
1. Lung (2.09 million cases)
2. Breast (2.09 million cases)
3. Colorectal (1.80 million cases)
4. Prostate (1.28 million cases)
5. Skin cancer (non-melanoma) (1.04 million cases)
6. Stomach (1.03 million cases)
The most common causes of cancer death are cancers of:
1. Lung (1.76 million deaths)
2. Colorectal (862 000 deaths)
3. Stomach (783 000 deaths)
4. Liver (782 000 deaths)
5. Breast (627 000 deaths)
137
Introduction
Cancer types;
1. Carcinoma: organs and glands
2. Sarcoma: connective tissue
3. Melanoma: skin
4. Lymphoma: Lymphocytes
5. Leukaemia: Blood

138
Introduction
Leukaemia: Develops in the bone
marrow
• Acute lymphoblastic leukaemia (ALL)
• Acute myeloid leukaemia (AML)
• Chronic lymphocytic leukaemia (CLL)
• Chronic myeloid leukaemia (CML)

139
Introduction
Lymphoma: Develops in the lymphatic system
• Hodgkin lymphoma
• Non-Hodgkin lymphoma

Myeloma: Plasma cell tumour

140
 Tumours of the immune system

ALL is usually In myeloma, the clone of

derived from malignant plasma cells
immature pre-B produces monoclonal
cells. Blasts are immunoglobulin.
present in bone
marrow and In CLL and lymphoma, malignant
blood population is mature B-cells. In CLL
malignant cells are present in
blood while in lymphoma they are
141
present in lymph node
 Chronic lymphocytic leukaemia
A1 A2

Normally
• CD19 is found CD19
on B-cells

• CD5 is found A3 A4
on T-cells

CD5 143
 Chronic lymphocytic leukaemia

In most
cases of CD19
CLL, CD5
is present
on the
surface of
B-cells
CD5 144
Post-transplant Lymphoma

145
Does the immune system naturally
prevent or attack cancers?

146
 Immune system can prevent tumours
linked to oncogenic pathogens

HTLV1: Human T-cell Leukaemia virus-1, EBV: Epstein Barr virus,

HPV: Human Papilloma virus, HBV: Hepatitis B virus, Hepatitis C virus
147
Tumour antigens

148
 Tumour antigens

149
 Tumour antigens
5

150
Anti-tumour responses
• Antibody + complement
• Antibody-dependent cellular cytotoxicity
(ADCC)
• Direct NK cell cytotoxicity
• Cytotoxic t-cells recognizing tumour-derived
peptides presented by MHC class I

151
Immune cells are naturally present
in tumours
- T-cells -Tregs
- NK cells -Myeloid-derived
- Macrophages -suppressor cells (MDSC)

Anti-tumour Reduce anti-

response tumour
response

152
Why do tumours not succumb to
the immune response?
Tumours;
1. Share most antigens with the normal cell type
from which they arose. Lymphocytes therefore
tolerant.
2. Exhibit Darwinian selection of tumour antigen
loss mutants.
3. Fail to produce Damage Associated Molecular
Patterns
4. Can have reduced expression of MHC molecules

153
Why do tumours not succumb to
the immune response?
Tumours;
5. Inducing viruses interfere with antigen processing
and presentation pathways.
6. Have low levels of costimulatory molecules and
therefore induce T-cell anergy.
7. Can upregulate bcl-2 to resist killing by CTL
8. Produce immunosuppressive molecules

154
Intervening in vivo – checkpoint
inhibitor blockade

• Immune checkpoints prevent ongoing immune

response.
• Necessary to prevent excessive responses to
transient infection
• But checkpoint is undesirable when a response
required to permanent tumour

155
Intervening in vivo – checkpoint
inhibitor blockade

PD: Programmed Death

156
Harnessing immune system to
attack tumours

• Non-specific immunotherapy
• Monoclonal antibodies
• Cell transfer
• Gene therapy
• Vaccines
157
Non-specific immunotherapy

158
Monoclonal antibodies

159
Immunoconjugates

160
Bispecific antibodies for tumour
therapy

161
Adoptive cell transfer

CAR- Chimeric Antigen Receptor 162

Tumour vaccines

163
 Provenge (Sipuleucel-T)

On Day 1 leukapheresis to isolate precursors of dendritic cells. Prostatic acid phosphatase

linked to GM-CSF is incubated with the isolated cells. The precursors then differentiate
and the acid phosphatase tumour antigen gets delivered by the dendritic cells back into
the patient which are specific for this tumour antigen. 164
165
Hypersensitivity
Objectives
▪ Distinguish between the four different types of
hypersensitivities.
▪ recognize the beneficial functions of the underlying
hypersensitivity immune
▪ Discuss the roles of environmental factors and
genetics in the predisposition to allergies
▪ Describe how beneficial local inflammatory responses
may become harmful chronic inflammatory responses

167
Immune disorders and
deficiencies Janeway’s Immunology p32

HYPERSENSITIVITY

Hypersensitivity is a normal body response.

168
Hypersensitivity
▪ Is exaggerated or inappropriate immune response leading to
pathology. It is classified into 4 groups;
i. Type I: IgE mediated mast cell degranulation
ii. Type II: Cytotoxic antibodies against cell surface antigens
iii. Type III: Immune complex mediated hypersensitivity
iv. Type IV: Delayed typed hypersensitivity mediated by T cells

Types I – III are mediated by antibodies while Type IV is

mediated by T cells

169
Type I hypersensitivity
▪ Type I
hypersensitivity is
also referred to as
Atopy. Atopy
refers to the
genetic tendency
to develop allergic
diseases.
▪ Besides the
genetic factor,
other risk factors
are involved. 170
Type I hypersensitivity

▪ Binding of allergen to
the IgE found on the
surface of mast cells
causes degranulation
of the mast cell
resulting in the release
of pro-inflammatory
molecules.

171
172
Type I hypersensitivity

▪ Binding of allergen to
the IgE found on the
surface of mast cells
causes degranulation
of the mast cell
resulting in the release
of pro-inflammatory
molecules.

173
Type I hypersensitivity

Immediate IgE-
mediated response,
resolves within 1hour.

Frequently followed by
late phase reaction
occurring 4-12 hrs
later involving CD4+
helper T-cells,
monocytes and
eosinophils.
174
Atopic allergy prevalence
globally

175
Anaphylaxis
▪ This is a severe systemic hypersensitivity to allergen
in an injection, sting or by epithelial exposure (e.g. in
the gut mucosa)
▪ Rapid vasodilation leading to a substantial drop in
blood pressure
▪ Constriction of airways
▪ Oedema
▪ Anaphylactic shock often fatal
▪ Immediate administration of epinephrine reverse
bronchoconstriction and vasodilation

176
Mast cell mediators

177
Synthesis of leukotrienes
and prostaglandins

178
Allergens

179
IgE

180
Mast cell activation
A IgEs coat resting
mast cell without
any resulting
activity.

B However, as
soon as the
antigen binds and
activates the mast
cell pro-
inflammatory
molecules are
released. 181
Mediators produced by
the Mast cell

182
Allergic inflammation in
the bronchus

183
Diagnosis of atopic
allergy – skin prick test
Small amounts of the
suspected allergen are
injected under the skin
leading to release of
inflammatory mediators.

The results in the

vasodilation and edema
causing characteristic
‘wheal and flare’
response.

184
Diagnosis of atopic allergy –
Allergen specific IgE (RAST)

The amount of IgE

against a particular
allergen that is
present in a patient
is measured using
the Allergen specific
IgE Test (RAST)
185
Therapeutic options

186
 Treatment for asthma

Histamine does not play a significant role in bronchial constriction,

therefore antihistamines (H1 receptor antagonists) are not used to
treat asthma 187
Allergy immunotherapy

188
Type II hypersensitivity
Cytotoxic antibodies against cell
surface antigen e.g.
▪ Transfusion reactions
▪ Autoimmune haemolytic anaemia
▪ Pernicious anaemia
▪ Haemolytic disease of the foetus and
new-born
▪ Autoimmune thrombocytopenic
purpura
▪ Acute rheumatic fever
▪ Goodpasture syndrome
▪ Grave’s disease
▪ Myasthenia gravis

189
Antibody mediated effects
1. Complement and Fc receptor-mediated inflammation

Antibody binding to cell surfaces may result in antibody-

mediated responses such as the complement’s Classical
pathway which produces the complement products. 190
Antibody mediated effects
2. Abnormal physiologic responses without cell/tissue injury

191
Transfusion reactions

192
Transfusion reactions

193
Haemolytic disease of the foetus and
new-born (Rhesus D incompatibility)
First Second
Labour Post partum
pregnancy pregnancy

This rh- During labour The foetal The maternal

woman has foetal red red cells anti-D
conceived a cells leak into survive long antibodies cross
rh+ foetus the mother enough to the placenta
elicit an IgG and attack the
194
response fetal red cells.
Haemolytic disease of the foetus and
new-born (Rhesus D incompatibility)
First Second
Labour Post partum
pregnancy pregnancy

Prevention: Anti-RhD 28 weeks and within 72

hours of birth. Coombs' test is used to detect antibodies
195
that act against the surface of your red blood cells
Type III hypersensitivity
Immune complex mediated e.g.
Systemic lupus erythematosus: anti-nuclear
antibodies
Post-streptococcal glomerulonephritis:
streptococcal cell wall antigens.
Serum sickness: foreign antisera (e.g.
antivenom)
Polyarteritis nodosa: hepatitis B virus
surface antigen

196
 Immune complex
mediated tissue injury

Tissue injury occurs when circulating immune complexes activate complement- and
Fc receptor mediated inflammatory cells. Lysosomal enzymes released and
reactive oxygen species produced by neutrophils resulting in Vasculitis
197
Consequences of immune
complex

198
Type IV hypersensitivity
Delayed type T-cell mediated e.g.
▪ Tuberculin reaction
▪ Contact dermatitis
▪ Hashimoto’s thyroiditis
▪ Multiple sclerosis
▪ Type I diabetes
▪ Guillain-Barre syndrome
▪ Celiac disease
▪ Crohn’s disease

199
 Mechanism of tissue
injury and cell death
CYTOKINE MEDIATED INFLAMMATION

Antigen Presenting Cells in the tissues activate the CD4+ T cells which
release cytokines to activate Tc resulting in inflammation and tissue injury 200
T-cell activation stimulates
macrophages and
fibroblasts

T-cell activation
in Type IV HS
stimulates both
macrophages
and fibroblasts.

202
AUTOIMMUNITY
Autoimmune disease
A pathological reaction against a normal body component. Global
prevalence is about ~5%

204
Autoimmune disease
CHARACTERISTICS

205
Autoimmune disease
CHARACTERISTICS

206
Immunological Tolerance
During Central tolerance B and T
cells under tolerance tests where
cells that recognise self antigen
undergo
▪ apoptosis,
▪ receptor editing or
▪ development of regulatory cells

Peripheral tolerance is a backup

mechanism which involves
▪ anergy,
▪ apoptosis or
▪ suppression by the regulatory
cells. 207
AIRE The autoimmune regulator
(AIRE) protein is part of a
complex that regulates the
expression of tissue-
restricted antigens (TRAs) in
medullary thymic epithelial
cells (MTECs). Peptides
derived from these antigens
are displayed on the MTEC
and recognized by immature
antigen-specific T cells,
leading to the deletion of
many self-reactive T cells.

In the absence of functional

AIRE, these self-reactive T
cells are not eliminated; they
can enter tissues where the
antigens continue to be
produced and cause injury.

208
The development of AD

Several factors have to align to result

an immune disease
209
Some autoimmune disease
susceptibility genes

210
MHC association in ADs

211
Role of infection in AD A. Normally, encounter of a

development
mature self-reactive T cell
with a self antigen presented
by a co-stimulator-deficient
resting tissue APC results in
peripheral tolerance by
anergy.

B. Microbes may activate the

APCs to express co-
stimulators, and when these
APCs present self antigens,
the self-reactive T cells are
activated rather than
rendered tolerant.

C. Some microbial antigens

may cross-react with self
antigens (molecular mimicry).
Therefore, immune
responses initiated by the
microbes may activate T cells
specific for self antigens. 212
Dendritic cell – T cell interaction

CD80 = B7 213
Some target organs and tissues of
autoimmune disease

214
Some autoimmune disease
therapies
1. Replacement of missing component
▪ Hashimoto’s disease: thyroxine
▪ Type 1 diabetes: insulin, islet cell transplantation
▪ Pernicious anaemia: vitamin B12

2. Inhibition of hormone overproduction

▪ Grave’s disease: thyroid peroxidase inhibitors, etc

3. Thymectomy
▪ Myasthenia gravis

4. Anticholinesterase drugs
▪ Myasthenia gravis

5. Cytokines
▪ Multiple sclerosis: IFN

6. Cytokine inhibitors
▪ Rheumatoid arthritis, Anti-TNF 215
Some autoimmune disease
therapies
7. Adhesion molecule inhibition
▪ Multiple sclerosis: natalizumab (monoclonal anti-𝜶-integrin)

8. Disease-modifying anti-rheumatic drugs (DMARDs)

▪ Rheumatological conditions: methotrexate, sulfasalazine, gold salts,
leflunomide
9. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids
▪ SLE, RA, autoimmune hemolytic anemia, Goodpasture’s syndrome

10. Anti-B-cells:
▪ RA: anti-CD20

11. Anti-mitotic drugs (azathioprine, cyclophosphamide, methotrexate)

▪ Autoimmune thrombocytopenic purpura, SLE, myasthenia gravis,
autoimmune hemolytic anemia
12. Pooled normal immunoglobulin
▪ Gillain-Barré syndrome, myasthenia gravis
216
 SLE

Persistent high-level anti-nuclear IgG

antibody production 217
Clinical features of SLE

Immune complexes get trapped in areas of the

body which have very little space 218
Multiple sclerosis

219
MRI of MS patient
showing
Periventricular
demyelination
plaques

220
Pharmacology of inflammation

222
Pharmacology of inflammation

223
INFECTION
AND
IMMUNITY
CONTENTS
1. Overview of immune responses
to microbes
2. Bacteria
3. Fungi
4. Viruses
5. Parasites

225
1. Overview of immune responses to microbes
The development of an infectious disease in an individual involves complex
interactions between the microbe and the host.

The key events during infection include

i. entry of the microbe,
ii. invasion and colonization of host tissues, evasion of host immunity, and,
iii. tissue injury or functional impairment.

Microbes produce disease by

▪ killing the host cells they infect, or

▪ by liberating toxins that can cause tissue damage and functional derangements in
neighboring or distant cells and tissues that are not infected, or
▪ by stimulating immune responses that injure both the infected tissues and normal
tissues.
226
1. Overview of immune responses to microbes
▪ Defence against microbes is mediated by the effector mechanisms of innate
and adaptive immunity
▪ The initial reaction to pathogens that breach the external protective barriers
is usually an acute inflammatory response involving an influx of leukocytes,
complement, antibody, and other plasma proteins into a site of infection or
injury as discussed in previous lectures.
▪ The survival and pathogenicity of microbes in a host are critically influenced
by the ability of the microbes to evade or resist the effector mechanisms of
immunity.
▪ Some microbes establish latent, or persistent infections in which the
immune response controls but does not eliminate the microbe.
▪ In many infections, tissue injury and disease may be caused by the host
response to the microbe rather than by the microbe itself.
▪ Inherited and acquired defects in innate and adaptive immunity are
important causes of susceptibility to infections.

227
2. BACTERIA
Bacteria can be either extracellular or intracellular in their pathogenesis:
▪ Extracellular bacteria are capable of replicating outside host cells, for
example, in the blood, in connective tissues, and in tissue spaces such
as the lumens of the airways and gastrointestinal tract. They cause
disease by two principal mechanisms.
1. induce inflammation, which results in tissue destruction at the site of
infection.
2. they produce toxins

▪ Intracellular bacteria can survive and even to replicate within

phagocytes. Because these microbes can find a niche where they are
inaccessible to circulating antibodies, their elimination requires the
mechanisms of cell-mediated immunity.

228
2. BACTERIA (CONT…)

Extracellular

Intracellular

229
 • The principal mechanisms of innate
2a) Extracellular immunity to extracellular bacteria are
complement activation, phagocytosis,
bacteria and the inflammatory response.

A. Humoral immunity is a major protective

immune response against extracellular
bacteria. Antibody responses are
directed against cell wall antigens and
secreted and cell-associated toxins,
which may be polysaccharides or
proteins. The polysaccharides are
prototypic T-independent antigens, and
humoral immunity is the principal
mechanism of defense against
polysaccharide-rich encapsulated
bacteria.

B. The protein antigens of extracellular

bacteria also activate CD4+ helper T
cells, which produce cytokines that
induce local inflammation, enhance the
phagocytic and microbicidal activities of
macrophages and neutrophils, and
stimulate antibody production.
230
2b) Intracellular bacteria

The innate immune response to intracellular bacteria consists of phagocytes and NK cells,
interactions among which are mediated by cytokines (IL-12 and IFN-γ). The typical adaptive
immune response to these microbes is cell-mediated immunity, in which T cells activate
phagocytes to eliminate the microbes. Innate immunity may control bacterial growth, but
elimination of the bacteria requires adaptive immunity 231
2c. Bacteria immune evasion
i) Phagocytosis avoidance strategies by extracellular bacteria.

Virulent bacteria escape phagocytosis is by:

a) Microbe attaches to surface component to enter Nonphagocytic cell;
b) surface inhibitor of phagocytosis;
c) exotoxin poisons phagocyte;
232
d) capsule gives poor phagocyte adherence
2c. Bacteria immune evasion
ii) Complement avoidance strategies by extracellular
bacteria
Virulent bacteria escape the
complement by;
a) Accelerated breakdown of
complement by action of microbial
products;
b) complement effectors are deviated
from the microbial cell wall;
c) capsule provides non-stabilizing
surface for alternative pathway
convertase;
d) capsule impervious to complement
membrane attack complex (MAC).
233
2c. Bacteria immune evasion
iii) Evasion of macrophage defences by enteric bacteria
▪ The IpaB (invasion plasmid antigen B) and SipB
(Salmonella invasion protein B) molecules secreted by
Shigella and Salmonella, respectively, can activate
caspase‐1 and thereby set off a train of events that will
lead to the death of the macrophage by apoptosis.
▪ The SpiC (Salmonella pathogenicity island C) protein
from Salmonella inhibits the trafficking of cellular
vesicles, and therefore is able to prevent lysosomes
fusing with phagocytic vesicles.
▪ Yersinia produces a number of Yop molecules (Yersinia
outer proteins) able to interfere with the normal
functioning of the phagocyte. For example,
▪ YopJ inhibits TNF production and downregulates
NFκB and MAP kinases, thereby facilitating
apoptosis by inhibiting anti‐apoptotic pathways.
▪ YopT prevents phagocytosis by modifying the
GTPase RhoA involved in regulating the actin
cytoskeleton.
234
ANTIBACTERIAL AGENTS

There is a very large spectrum of inhibitors. Some

examples are given above 235
 3. FUNGI
▪ Fungal infections (mycoses) are usually opportunistic infections being a major problem
in the immune-compromised (such as Pneumocystis jiroveci pneumonia in AIDS
patients). Neutrophil deficiency as a result of bone marrow suppression or damage is
frequently associated with such infections. Other examples are shown in the table.
▪ Immune response to mycoses is often combinations of the responses to extracellular
and intracellular bacteria.
▪ Phagocytosis, particularly following Th1‐cell mediated activation of macrophages by
IFNγ and TNF, plays a major role in dealing with fungal infections.

236
3. FUNGI - Classification

237
 3a. Activation of immunity to fungi
• A. fumigatus, Aspergillus
fumigatus;
• C. albicans,
Candida albicans;
• C. neoformans,
Cryptococcus
neoformans;
• F. pedrosoi,
Fonsecaea pedrosoi;
• H. capsulatum,
Histoplasma capsulatum;
• P. brasiliensis,
Paracoccidioides
brasiliensis;
• P. jirovecii,
Pneumocystis jirovecii

A number of different PAMPS present on fungal cell walls can activate both
the innate and adaptive immune response through the canonical MyD88
(or CARD9, Caspase recruitment domain‐containing protein 9) pathways
following their recognition by PRRs on the host cells. 238
3b. ANTIFUNGALS

▪ Examples of antifungals are given above. They mainly

focus on these 4 groups.

239
 4. VIRUSES
▪ Viruses are obligatory intracellular microorganisms that use components of the nucleic
acid and protein synthetic machinery of the host to replicate and spread.
▪ Viruses typically infect various cell types by using normal cell surface molecules as
receptors to enter the cells. After entering cells, viruses can cause tissue injury and
disease by any of several mechanisms as listed below.

240
4a. Control of infection by ▪ Free virus released by budding from
enveloped (“budding”) the cell surface is neutralized by
antibody.
viruses
▪ Innate and adaptive immune
responses to viruses are aimed at
blocking infection and eliminating
infected cells. Infection is prevented
by type I interferons as part of innate
immunity and neutralizing antibodies
contributing to adaptive immunity.
Once infection is established, infected
cells are eliminated by NK cells in the
innate response and cytotoxic T-cells
in the adaptive response.
▪ In latent infections, viral DNA persists
in host cells, but the virus does not
replicate or kill infected cells.
▪ In some viral infections, tissue injury
may be caused by CTLs. 241
 4a. i) EXAMPLES OF ‘BUDDING’ VIRUSES
▪ oncornaviruses (= oncogenic RNA virus, e.g., murine leukemogenic),
▪ orthomyxoviruses (influenza),
▪ paramyxoviruses (mumps, measles),
▪ togaviruses (dengue),
▪ rhabdoviruses (rabies),
▪ arenaviruses (lymphocytic choriomeningitis),
▪ adenoviruses,
▪ Herpes viruses (simplex, varicella zoster, cytomegaloviruse, Epstein–
Barr, Marek’s disease),
▪ poxviruses (vaccinia),
▪ papovaviruses (SV40, polyoma), and
▪ rubella viruses 242
4b. Virus Immune evasion
▪ Viruses can alter their antigens and are thus
no longer targets of immune responses. The
principal mechanisms of antigenic variation
are point mutations (antigenic drift) and
reassortment of RNA genomes [in RNA
viruses, (antigenic shift)].
▪ Some viruses inhibit class I MHC–associated
presentation of cytosolic protein antigens.
▪ Some viruses produce molecules that
inhibit the immune response.
▪ Some chronic viral infections are associated
with failure of CTL responses
▪ Viruses may infect and either kill or
inactivate immunocompetent cells

243
CTL: Cytotoxic T Lymphocytes
4c. ANTIVIRALS

Antiviral agents attack the viruses at different

stages of infection as shown.
244
5. PARASITES
Classification

245
5. PARASITES
Classification
Parasites can be classified according to:
A. According to their habitat
I. Endoparasites:
▪ parasites of humans live within the host e.g Giardia,
Malaria etc.
▪ internal, infection
II. Ectoparasites:
▪ parasites of humans live on the surface or within the
superficial tissue of the host e.g fleas, lice, bugs, mites,
ticks etc.
▪ external, attached to the skin or superficial tissues ,
infestation
5. PARASITES
Classification
B. According to their dependence on the host:
I.Obligatory or permanent parasite: Completely dependent
on its host and can’t survive without it e.g. plasmodium.
II. Intermittent or temporary parasite: visits the host only for
feeding and then leaves it e.g bed bugs.
III. Facultative parasite: can exist in free living or parasitic
state under unfavourable environment e.g Strongyloides
stercoralis.
IV. Accidental parasite: normally free living organisms that
affects the human body by mistake e.g. Toxocara canis (a dog
parasite) in man.
 5. PARASITES
▪ Parasitic infection refers to infection
with animal parasites such as
protozoa, helminths, and
ectoparasites (e.g., ticks and mites).
▪ Such parasites currently account for
greater morbidity and mortality than
any other class of infectious
organisms, particularly in developing
countries.
▪ The consequences of parasitic
infection could be, at one extreme, a
lack of immune response leading to
overwhelming superinfection, and, at
the other, an exaggerated
life‐threatening immunopathological
response.

248
 5. Immunity to Parasites
▪ Most parasitic infections are chronic because of weak innate immunity and the ability of
parasites to evade or resist elimination by adaptive immune responses.

249
5a. Importance of antibody and cell‐mediated
responses in protozoal infections
• A humoral response
develops when the
parasites invade the
bloodstream (e.g.
malaria,
trypanosomiasis),
whereas parasites that
grow within the tissues
(e.g., cutaneous
leishmaniasis) usually
elicit CM.
• Often, a chronically
infected host will be
resistant to reinfection
with fresh organisms, a
situation termed
concomitant immunity.
CM: Cell Mediated immunity 250
5b. Expulsion of nematode worms
from the gut
The parasite is first damaged by IgG
antibody passing into the gut lumen,
perhaps as a consequence of
IgE‐mediated inflammation and possibly
aided by accessory ADCC cells.
Cytokines such as IL‐4, IL‐13, and TNF
released by antigen ‐ specific triggering
of T‐cells stimulate proliferation of
goblet cells and secretion of mucus,
which coat the damaged worm and
facilitate its expulsion from the body by
increased gut motility induced by mast
cell mediators, such as leukotriene‐D4,
and diarrhoea resulting from inhibition
of glucose‐dependent sodium
absorption by mast cell‐derived
histamine and PGE2
251
5c. Parasite immune evasion

▪ Parasites evade protective immunity by reducing their immunogenicity

and by inhibiting host immune responses.
252
5d. ANTIPARASITIC AGENTS

This is made up of;

1. Antiprotozoal agents
2. Antimalarial agents
3. Amebicides
4. Antihelminthic agents 253
4 VACCINE IMMUNOLOGY
 OBJECTIVES
▪ Define Herd immunity and understand how it is
achieved

▪ Differentiate Active and passive immunity

▪ Be introduced to the vaccination schedule for

children

▪ Know the main types of vaccines

▪ Define antigenic shift and antigenic drift

255
INTRODUCTION
▪ Vaccines alone are credited with increasing life expectancy by
30 years.
▪ This has been achieved by the eradication of smallpox and
further application to other diseases like measles, mumps and
rubella and polio, etc.
▪ For a list of FDA approved vaccines visit
(https://www.fda.gov/vaccines-blood-
biologics/vaccines/vaccines-licensed-use-united-states)
▪ Vaccines aid in the establishment of herd immunity which is
required to keep infectious diseases under control in the
population.
▪ Herd immunity occurs when a large portion of a community
(the herd) becomes immune to a disease, making the spread of
disease from person to person unlikely. As a result, the whole
community becomes protected — not just those who are
immune.
256
HERD IMMUNITY
▪ A percentage of the population must be capable of getting a
disease in order for it to spread. This is called a threshold
proportion. If the proportion of the population that is immune
to the disease is greater than this threshold, the spread of the
disease will decline. This is known as the herd immunity
threshold.

▪ What percentage of a community needs to be immune in order

to achieve herd immunity? It varies from disease to disease.
The more contagious a disease is, the greater the proportion of
the population that needs to be immune to the disease to stop
its spread. For example, the measles is a highly contagious
illness. It’s estimated that 94% of the population must be
immune to interrupt the chain of transmission.

257
V S

258
HOW IS HERD IMMUNITY ACHIEVED?
1. VACCINES
▪ A vaccine is an ideal approach to achieving herd immunity. Vaccines
create immunity without causing illness or resulting complications.
Herd immunity makes it possible to protect the population from a
disease, including those who can’t be vaccinated, such as newborns or
those who have compromised immune systems. Using the concept of
herd immunity, vaccines have successfully controlled deadly
contagious diseases such as smallpox, polio, diphtheria, rubella and
many others.

▪ Reaching herd immunity through vaccination sometimes has

drawbacks, though. Protection from some vaccines can wane over time,
requiring revaccination. Sometimes people don’t get all of the shots
that they need to be completely protected from a disease.

▪ In addition, some people may object to vaccines because of religious

objections, fears about the possible risks or scepticism about the
benefits.
259
HOW IS HERD IMMUNITY ACHIEVED?
2. Natural infection
▪ Herd immunity can also be reached when a sufficient number of
people in the population have recovered from a disease and
have developed antibodies against future infection.

▪ However, there are some major problems with relying on

community infection to create herd immunity to the virus that
causes COVID-19. First, it isn’t yet clear if infection with the
COVID-19 virus makes a person immune to future infection.

▪ Research suggests that after infection with some coronaviruses,

reinfection with the same virus — though usually mild and only
happening in a fraction of people — is possible after a period of
months or years

260
 Timeline of select human vaccine development
Attenuated • Polio (IPV, OPV)
Whole killed • Measles; Mumps
Protein • Rubella: Adenovirus
Recombinant DNA • Rabies; Rotavirus
Recombinant RNA • Varicella; Japanese
• Yellow fever encephalitis; • Influenza (cold adapted)
• Influenza Tickborne • Rotavirus
Smallpox encephalitis; Hepatitis • Varicella Zoster
A; Hepatitis B • Human papillomavirus
(plasma)
Rabies
Variolation • COVID-19

1700 1800 1900 1950 2000 2013 2021

• Typhoid • Typhoid; Pneumococcus • Pneumococcal

• TB; Typhus
• Cholera • Meningococcus polyCHO conjugates
• Pertussis
• Plague • Meningococcal conjugate • Meningococcal
• Diptheria
• H influenzae b conjugate quadrivalent
• Tetanus
• Typhoid polyCHO conjugates
toxoid
• Acellular pertussis;
• Anthrax

261
Timeline of select human vaccine development
▪ The story of vaccines began with the long history of infectious disease in humans,

and in particular, with early uses of smallpox material to provide immunity to that
disease.

▪ Evidence exists that the Chinese employed smallpox inoculation (or variolation, as

such use of smallpox material was called) as early as 1000 CE. It was practiced in
Africa and Turkey as well, before it spread to Europe and the Americas.

▪ Edward Jenner’s innovations, begun with his successful 1796 use of cowpox material

to create immunity to smallpox, quickly made the practice widespread.

▪ Louis Pasteur’s 1885 rabies vaccine was the next to make an impact on human

disease. And then, at the dawn of bacteriology, developments rapidly followed.

Antitoxins and vaccines against diphtheria, tetanus, anthrax, cholera, plague, typhoid,
tuberculosis, and more were developed through the 1930s. 262
 ACTIVE AND PASSIVE IMMUNITY
Immunity to a disease is achieved
Adaptive through the presence of antibodies to
immunity
that disease in a person’s system
which neutralize or destroy toxins or
Naturally Artificially
acquired acquired disease-carrying organisms.
Antibodies are disease-specific. For
Active Passive Active Passive example, measles antibody will
Antigens Antibodies
enter the pass from
Antigens are Preformed protect a person who is exposed to
introduced antibodies in
body mother to immune
in vaccines;
naturally. fetus via
body serum are measles disease. But they may be also
Body placenta introduced
produces
induces
antibodies
or to infant
via the
antibodies by injection cross-reactive such as protection from
and
and mother’s
specialized mild
specialized
lymphocytes
smallpox by cowpox infection.
lymphocytes
There are two types of immunity:
active and passive. 263
ACTIVE VS PASSIVE IMMUNIZATION

264
Passive Immunization
Horse antisera against:
1. Snake venom
2. Botulism toxin
3. Diphtheria toxin

265
Passive Immunization
Pooled human Ig against:
1. Hepatitis A or B
2. Measles
3. Rabies
4. Tetanus
5. Varicella zoster
Humanized monoclonal against:
▪ Respiratory syncytial virus
266
VACCINES CAN ELICIT NEUTRALIZING
ANTIBODIES

Antibodies control infection by inhibiting virus

binding to receptor or toxin and can also prevent
the pathogen from colonizing the host surface. 267
IMMUNOLOGICAL BASIS OF ACTIVE VACCINATION

Pathogen

Vaccine

Because memory cells are already present as a result of

vaccination, a secondary immune response occurs on a
first encounter with the pathogen 19
Vaccination schedules for children;
•Tuberculosis (BCG) - at birth
•Diphtheria, tetanus, and pertussis (DPT vaccine) -
6, 10, and 14 weeks
•Measles – 9- 12 months
•Poliomyelitis - 6, 10, and 14 weeks

Other vaccines used in Zambia include rotavirus,

hepatitis B, pneumonia vaccines

269
VACCINE COMPONENTS

270
ADJUVANTS
Examples of adjuvants include;

▪ Aluminium salts: Al(OH)3, AlPO4, mixed Al-salts

▪ AS03: oil-in-water emulsion containing D-, L-alpha-tocopherol and

squalene

▪ AS04: Al(OH)3 and monophoshoryl lipid A (a low-toxicity derivative

of LPS which stimulates TLR4

▪ MF59: oil-in-water emulsion of squalene

▪ Virosomes: double membrane lecithin-phospholipid liposomes

(incorporating viral proteins)

271
USES OF VACCINES

1. Prevent infection Polio (OPV)

2. Control existing infection Zoster

3. Prevent disease development Rabies

post-exposure

4. Prevent foetal infection Rubella

5. Prevent/control cancer HBV/HPV

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TYPES OF VACCINES
▪ There are several different types of vaccines. Each type is designed to teach the

immune system how to fight off certain kinds of germs — and the serious
diseases they cause. When scientists create vaccines, they consider: How the
immune system responds to the germ, who needs to be vaccinated against the
germ and the best technology or approach to create the vaccine.

▪ Based on a number of these factors, scientists decide which type of vaccine they

will make. There are 4 main types of vaccines:

1. Live-attenuated vaccines

2. Inactivated vaccines

3. Subunit, recombinant, polysaccharide and conjugate vaccines

4. Toxoid vaccines
273
1. LIVE ATTENUATED VACCINES
Live vaccines use a weakened (or attenuated) form of the pathogen that
causes a disease

Advantages
1. Mimic natural infection hence providing appropriate
response
2. Stimulate both humoral and cell mediated responses.
3. Typically generate long-term immunity with reduced need
for booster immunization.
Disadvantages
1. Slight potential to revert back to virulent form
2. Often require refrigeration
3. Potential for spread from ‘vaccinee’
4. Not recommended for the immunocompromised due to risk
of significant pathology 274
1. LIVE ATTENUATED VACCINES
Examples include;
▪ Influenza (intranasal)
▪ Measles-Mumps-Rubella (MMR)
▪ Polio (OPV)
▪ Rotavirus
▪ Varicella zoster virus (chickenpox)
▪ Yellow fever

▪ Oral live typhoid vaccine (Ty21a)

▪ Bacille Calmette Guérin (BCG)

275
2. INACTIVATED VACCINE
Inactivated vaccines use the killed version of the pathogen that causes
a disease

Advantages
▪ Relatively easy to manufacture
▪ No possibility of reversion to virulent pathogen
▪ Safe for use in the immunocompromised

Disadvantages
▪ Adjuvants required
▪ Typically requires initial 2-3 immunizations and then relatively
frequent boosts
▪ Immunity can be short-lived and predominantly humoral with
poor cell-mediated immunity
276
2. INACTIVATED VACCINE
Examples include;
▪ Hepatitis A virus
▪ Influenza virus
▪ Japanese encephalitis virus
▪ Poliovirus (IPV)
▪ Rabies
▪ Tick borne encephalitis

277
3. SUBUNIT VACCINE
Subunit, recombinant, and polysaccharide vaccines use specific pieces of the
pathogen — like its protein, sugar, or capsid (a casing around the pathogen).

278
3. SUBUNIT , RECOMBINANT, POLYSACCHARIDE
AND CONJUGATE VACCINES
▪ Because these vaccines use only specific pieces of

the pathogen, they give a very strong immune

response that’s targeted to key parts of the pathogen.
They can also be used on almost everyone who
needs them, including people with weakened
immune systems and long-term health problems.

▪ One limitation of these vaccines is that you may need

booster shots to get ongoing protection against

diseases. 279
3. SUBUNIT , RECOMBINANT, POLYSACCHARIDE
AND CONJUGATE VACCINES
These vaccines are used to protect against:

• Hib (Haemophilus influenzae type b) disease

• Hepatitis B

• HPV (Human papillomavirus)

• Whooping cough (part of the DTaP combined vaccine)

• Pneumococcal disease

• Meningococcal disease

• Shingles
280
4. TOXOID VACCINES
▪ Chemically inactivated bacterial exotoxins

▪ Protect from disease but not from infection e.g.

tetanus toxoid and diphtheria toxoid.

▪ The bacterial toxin is chemically inactivated in the

lab making it harmless. The toxoid maintains some

B-cell epitopes thereby able to elicit memory B-
cells.

281
FUTURE OF VACCINES
There is need for better and improved vaccines
for;

▪ Influenza

▪ Malaria

▪ TB

▪ HIV

▪ COVID-19
282
Antigenic drift and shift in influenza virus
Influenza viruses are constantly changing. They can change in
two different ways.

▪ One way influenza viruses change is called antigenic drift.

These are small changes (or mutations) in the genes of

influenza viruses that can lead to changes in the surface
proteins of the virus: HA (hemagglutinin) and NA
(neuraminidase). The HA and NA surface proteins of influenza
viruses are antigens, which means they are recognized by the
immune system and are capable of triggering an immune
response.
283
Antigenic drift and shift in influenza virus
▪ The other type of change is called antigenic shift.

Antigenic shift is an abrupt, major change in an

influenza A virus, resulting in new HA and/or new HA
and NA proteins in influenza viruses that infect
humans. Shift can result in a new influenza A subtype
in humans. One way shift can happen is when an
influenza virus from an animal population gains the
ability to infect humans.

284
Antigenic drift and shift in influenza virus

285
HOW INFLUENZA (FLU) VACCINES
ARE MADE
There are three different influenza vaccine production technologies;

1. Egg-based flu vaccine: most common way that flu vaccines are for
more than 70 years. Egg-based vaccine manufacturing is used to
make both inactivated vaccine (usually called the “flu shot”) and live
attenuated vaccine (usually called the “nasal spray flu vaccine”).

2. Cell-based flu vaccine: this replaces the use of chicken eggs with
animal cells.

3. Recombinant flu vaccine: Recombinant flu vaccines do not require

having a candidate vaccine virus (CVV) sample to produce. Instead,
recombinant vaccines are created synthetically.

286
MALARIA VACCINE
▪ RTS,S/AS01 (Mosquirix) in Sub-Saharan
Africa is only approved malaria vaccine.
▪ This is composed of a portion of
circumsporozoite protein of Plasmodium
falciparum fused to hepatitis B surface
antigen
▪ Targets pre-erythrocytic stage of parasite
287
BCG VACCINE FOR TB
▪ BCG is an attenuated live Bacille Calmette Guérin strain
of Mycobacterium bovis
▪ Used to prevent childhood tuberculous meningitis and
military disease

Considered only for:

▪ Children who have a negative tuberculin skin test and
at high risk, e.g. continually exposed to isoniazid and
rifapin resistant M. tuberculosis.
▪ Health care workers routinely exposed to drug-
resistant M. tuberculosis
288
HIV VACCINE
▪ Success requires identification of immunogens and immunization
strategy that induces broad and long-lasting CTL immunity
together with broadly neutralizing antibodies.
▪ Broadly neutralizing antibodies identified in very small number of
people living with HIV and intravenous infusion of such
antibodies has been used in clinical trials.
▪ No vaccine tested in clinical trials so far has been sufficiently
successful.
▪ Thailand trial in 2009: 4 priming injections of recombinant
canarypox vector containing HIV gag, pol and env genes, 2
booster injections with recombinant gp120; limited protective
effect with efficacy of 25-30%.
▪ A trial in South Africa using similar vaccine failed.

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 COVID-19 VACCINES
▪ Protein Submit (PS) vaccines
▪ Non-replicating viral vector (VVnr) vaccines
▪ Replicating viral vector (VVr) vaccines,
▪ DNA vaccines
▪ Inactivated vaccines (IV)
▪ RNA vaccines
▪ Virus like particle (VLP) vaccines
▪ VVr plus antigen presenting cell (APC) vaccines
▪ VVnr plus APC vaccine
▪ Live attenuated virus (LAV) vaccine
COVID-19 VACCINES
FUTURE NEEDS

▪ Eradication of polio

▪ Effective vaccines for HIV, TB, malaria

▪ Broadly-specific influenza vaccine

▪ Therapeutic vaccines – hepatitis, HIV, cancer

▪ Vaccines against parasites

292