IMMUNITY TO MICROBES

General Facts
General Facts
Immunity to the following will be studied:
• Extracellular bacteria
• Intracellular bacteria
• Viruses
• Fungi

In each case the role of each of the following will be

addressed:
• Innate Immunity
• Specific Immunity
– Humoral immune response
– T cell response
 Immunity to Extracellular Bacteria
Example: pus-forming cocci, enteric organisms

• Innate Immunity:
1. Phagocytosis
by neutrophils, monocytes,
macrophages

effective
intracellular killing
 Immunity to
Extracellular Bacteria
2. Complement activation
by alternative pathway → cell lysis
• Specific Immunity:
Humoral Immune Response:

The main protective specific IR against

extracellular bacteria
• Specific Immunity:
Humoral Immune Response:
What do antibodies do?

1. Opsonization
• Specific Immunity:
Humoral Immune Response:

2. Agglutination: → prevention of spread

→ helping phagocytosis
• Specific Immunity:
Humoral Immune Response:
3. Neutralization of bacterial toxins
Inhibition of adhesion of bacteria to host cells
• Specific Immunity:
Humoral Immune Response:
4. Activation of complement
by classical pathway → cell lysis
• Specific Immunity:

T Cell response:
APCs internalize extracellular bacteria → presentation
of peptides on MHC II to Th cells which produce
cytokines:
– Activation of B cells (Ab production)
– Induction of local inflammation
– Activation of macrophages (for better phagocytosis &
intracellular killing)
Immunity to Intracellular Bacteria
Example: Mycobacteriae

• Innate Immunity:
1. Phagocytosis: Pathogenic intracellular bacteria
resist intracellular killing → chronic infections
and recurrences
Conclusion: Innate Immunity usually not efficient
in combating intracellular bacteria, unless
activated by IFN- γ

2. NK cells: produce IFN- γ → activation of

macrophages
Immunity to Intracellular Bacteria
Example: Mycobacteriae

IFN- γ
• Specific Immunity:
Humoral Immune Response: No role
WHY?

Antibodies
• Specific Immunity:
T-Cell Response:
Cell-mediated immunity (mainly activation of
macrophages by Th1 cells) is the main
protective immune response against
intracellular bacteria.
Question:
• What happens if a good Th1 response does
not occur in case of infection with intracellular
bacteria?

• Excellent Example:
– Leprosy caused by Mycobacterium leprae
 Comparison between Two Forms of Leprosy
Tuberculoid Leprosy Lepromatous Leprosy
• Predominantly Th1 • Predominantly Th2
• Macrophage activation → • Main response is humoral
good intracellular → useless
digestion → organism grows freely in
→ disease under control macrophages
→ localised infection → dissiminated infection
→ survival → death
(Good outcome) (Bad outcome)
• (some tissue damage may occur
due to inflammation &
macrophage activation)
 Immunity to Viruses

Facts about viruses:

• Obligate intracellular parasites
• Must replicate inside cells using host machinery
• Live in cytosol → peptides presented on MHC I
• After replication most viruses are liberated
(→ infection of other cells) but certain viruses
are not liberated
• Innate Immunity:
1. NK cells: very important early mechanism
• Innate Immunity:
2. Type I interferon:
• Inhibition of viral
replication

• Activation of NK cells
→ better killing of virally-
infected cells

• ↑Expression of MHC I on
infected cells → better
killing by cytotoxic T cells
• Specific Immuity:

Humoral Immune Response:

– Specific antibodies can play an important role in
combating viral infections.

Which antibodies are effective?

• Secretory IgA is important for neutralization of
viruses upon entrance through mucosa.
• Circulating IgG & IgM are important for viruses
passing through blood to target cell.
When are antibodies effective?

• Before viruses enter target cells

• After release from infected cells

T Cell Response:
• Cytotoxic T cell killing:
The main mechanism of specific immunity
against established viral infections
Tc cells are important before virus release from cells & most
important against viruses not released from cells.

• Helper T cells: Secrete cytokines:

➢ IL-2 → activation of Tc cells & NK cells
➢ IFN-γ → activation of NK cells
 Immunity to Fungi

• Innate Immunity:
1. The neutrophil is the most important cell of
the innate immune system in combating
fungi:
– Secretion of fungicidal substances
– Phagocytosis

2. Macrophages also effective

• Specific Immunity:
Fact: Most pathogenic fungi have same lifestyle
as intracellular bacteria
Similar lifestyle = similar specific immunity
Humoral Immune Response:
Antibodies produced but not effective
T cell Response:
• Cell mediated immunity is the main defense
mechanism
( Th1: Good, Th2: Bad )
Despite all these immune mechanisms…………
Infections DO occur !!!!!!!!!!!!
HOW?????????????

Pathogens have adapted strategies to EVADE the

immune system.

Examples of how - an extra-cellular organism,

- an intracellular one,
- a small RNA virus and
- a large DNA one
can evade immune system???
Examples:
• Extracellular bacteria e.g. S. pneumoniae:
Evasion of phagocytosis by capsule formation.
Intracellular bacteria e.g. M. tuberculosis:
Resistance of intraphagocytic destruction by
preventing fusion of phagosome with lysosomes.
Small RNA viruses e.g. influenza virus & HIV:
Evasion of immunological memory by
frequent mutation → continuous antigen change
 Large DNA viruses e.g. herpes viruses:
Down-regulation of MHC I expression on virally-
infected cell → NO recognition by Tc cells

Tc cell
 Active Acquired immunity

• Cells of immune system must be exposed to

antigen → specific stimulation of B/T cells
• Needs time to develop (Why?)
• Lasts after antigen is eliminated (Why?)
• May be acquired naturally or artificially (How?)
Natural Active Immunity

• Follows natural infections

• Infection may be clinical or subclinical.

• Immunity may be:

– Long-lasting (e.g. measles)
– Short-lived (e.g. influenza)
 Artificial Active Immunity
• By administration of
antigenic but harmless
material from pathogen :
VACCINATION
(ACTIVE IMMUNIZATION)
Forms:
• Whole killed organism
• Whole attenuated organism
• Parts of organism
• Products of organism
 Passive Acquired Immunity
• Ready-made antibodies/lymphocytes transferred
to a person
• Person’s immune system has no role
• Protection is immediate
• Protection is temporary
• May be acquired naturally (e.g., maternal Abs) or
artificially (e.g., Antitoxin)
 Natural Passive Immunity

• Transfer of maternal IgG

to foetus across placenta

• Passage of secretory IgA

to neoborn through colostrum

Very important for

protection of newborn
(first 6 months)
 Artificial Passive Immunity
Humoral Immunity:
By administration of antibodies:

PASSIVE IMMUNIZATION
Forms:
• Antitoxic serum
• Gamma globulin
• Convalescent serum
Artificial Passive Immunity
 Artificial Passive Immunity
Antitoxic serum:
Repeated injection of human volunteers or
animals
with toxoid (detoxified toxin)
→ production of large amounts of specific
antibody (= anti-toxin)
→ serum rich in that anti-toxin (= anti-toxic
serum)
→ administration to susceptible person
→ passive protection
 Artificial Passive
Immunity
Gamma Globulins:
• Pooled serum obtained
from many normal adults
(contains a mixture of protective
antibodies)

• Given to people with

immunodeficiency
 Artificial Passive Immunity
Convalescent serum:
• Obtained from a person recovering from
a certain infectious disease
→ rich in antibodies specific to causative
organism
(e.g hepatitis A)

• Given to exposed persons

 Artificial Passive Immunity
Cell-Mediated Immunity:
• By transfer of lymphocytes
Problem: rejection → not suitable clinically

• Can only be given to genetically identical

twins

• Used experimentally among genetically-

identical animals
Types of Acquired Immunity
 Comparison between Active & Passive Immunity
ACTIVE PASSIVE

Role of IS Yes No
Mechanism Stimulation of B/T Transfer of
cells Abs/lymphocytes
Onset of Delayed Immediate
protection
Duration Longer Shorter
Memory Yes No
Examples • Infections • Maternal Abs
• Vaccination • Antitoxin
 Vaccination

Definition:
Deliberate administration of microorganisms or
their products (in a harmless state) to produce
an immune response which is protective in the
future.
 Forms of Vaccination
• Whole killed organism
• Whole live attenuated organism
 Forms of Vaccination
• Parts of organism

• Products of organism
 The form of the vaccine determines
the kind of immune response

➢ Non-living vaccines: NOT presented on MHC I

→ NO activation of Tc cells
➢ Live vaccines: presented on BOTH MHC I & II
→ activation of BOTH Tc & Th cells

BUT: - Contraindicated in
Pregnant Women & Immuno-compromised Hosts
- needs Refrigeration
(more expensive & difficult in developing countries)
Classification of Vaccines
Tissue Injury In Immunological
Reactions

(Hypersensitivity Reactions)
Tissue Injury In Immunological Reactions

• This includes:

– Hypersensitivity reactions

– Autoimmune diseases

– Graft rejection
 Hypersensitivity Reactions

• Excessive or aberrant immune response to

foreign antigens leading to tissue damage.
Types of Hypersensitivity
 Type I Hypersensitivity
Atopy & anaphylaxis
First Exposure/Sensitization:
Exposure to the antigen IL-4 from Th2 cells
drives B cells to produce IgE
Specific IgE binds to mast cells (& basophils) via
Fc receptors

Subsequent Exposure/Degranulation:
Allergen cross-links IgE on mast cells
triggering of mast cells release of
mediators
Events in type I hypersensitivity
Effects of Mast cell activation on different tissues
Mast cell mediators & their actions
 Preformed
mediators: Enzymes
& toxic mediators are
released from the
preformed granules
(e.g., histamine, PAF).

 Newly formed
mediators:
Cytokines,
chemokines & lipid
mediators are
synthesized after
activation (e.g., PGs).
Immediate & late phases
 The immediate response is
caused by the direct effects on
blood vessels & smooth
muscle of rapidly metabolized
mediators such as histamine
released by mast cells.

 The late-phase response is

caused by the effects of an
influx of inflammatory
leukocytes attracted by
chemokines & other
mediators released by mast
cells during & after the
immediate response.
 Clinical forms

1. Systemic anaphylaxis (life threatening): severe

bronchospasm & shock. May be caused by
drugs (e.g., penicillin) or foreign serum.

2. Localized anaphylaxis (atopy): by inhalants,

contactants, ingestants.
 Diagnosis of type I hypersensitivity

• Skin testing (a wheal & flare

reaction may appear within 15-25
min).

• Measurement of total & allergen-

specific IgE.
Approaches to the treatment of type I
hypersensitivity
• Avoidance of the responsible allergen.

• Desensitization: by gradually injecting

increasing doses of the allergen in order to
shift the immune rersponse from Th2 to Th1
response to down regulate IgE production.

• Drugs: antihistaminics & corticosteroids.

 Type II Hypersensitivity
Cytolytic & cytotoxic reactions

• Caused by IgG or IgM antibodies reacting with

surface antigen.
Mechanism of type II hypersensitivity
Mechanism of type II hypersensitivity
Outcome:
1. Lysis by complement
activation
2. Attachment via Fc receptors
to neutrophils & macrophages
(IgG1 & IgG3):
 Opsonization
 Activation of these cells leading to
release of inflammatory mediators
3. ADCC
4. Altered signaling:
 Agonist (as in Grave’s disease)
 Antagonist (as in myasthenia gravis)
 Examples of diseases caused by type II
hypersensitivity
 ABO incompatibility
 Autoimmune hemolytic anemia
 Idiopathic (autoimmune) thrombocytopenic
purpura
 Acute rheumatic fever
 Myasthenia gravis
 Grave’s disease: stimulation of TSH receptors
 Graft rejection
 Type III hypersensitivity
(immune complex reactions)
Antibody (IgG or IgM) formed against soluble
antigen.

Immune complexes are formed.

Tend to deposit in blood vessels at sites of

turbulence (kidney glomeruli & synovium)
complement-mediated & Fc receptor-mediated
recruitment & activation of inflammatory cells
systemic disease with widespread
vasculitis, nephritis, arthritis.
Mechanism of damage in type-III
hypersensitivity
 Examples of diseases caused by type III
hypersensitivity
• Systemic lupus:
Ab to DNA & nucleoproteins nephritis,
vasculitis, arthritis.

• Polyarteritis nodosa: vasculitis.

• Post-streptococcal glomerulonephritis:
Ab against streptococcal cell wall antigens
nephritis.
 Examples of diseases caused by type III
hypersensitivity

• Viral infections: e.g., HBV.

• Hypersensitivity pneumonitis: immune

complexes are formed in the alveolar wall
pneumonitis.
Local form of Type III hypersensitivity
Arthus reaction
• In individuals who have already made IgG
antibody against an antigen & the same
antigen injected into the skin → immune
complexes.

• Because the dose of antigen is low, the

immune complexes are only formed close to
the site of injection, where they activate
mast cells.

• Mast cells can also be activated by C

activation → C5a

• As a result of mast-cell activation,

inflammatory cells invade the site & blood
vessel permeability & blood flow are
increased. Platelets also accumulate leading
to vessel occlusion resulting in local
erythema, edema & necrosis.
Serum sickness
Serum sickness is a classic example of
a transient immune complex-
mediated syndrome:

 Injection of a foreign protein leads

to an antibody response.
 These antibodies form immune
complexes with the circulating
foreign proteins.
 The complexes are deposited in
small vessels & activate complement
& phagocytes
→ fever & symptoms of vasculitis,
nephritis & arthritis.
 All these effects are transient &
resolve when the foreign protein is
cleared.
 Treatment of type II & III hypersensitivity

• Reduction of inflammation: by antihistaminics

& corticosteroids.

• Suppression of immune response: by

corticosteroids & immunosuppressive drugs.

• Plasmapheresis: to remove immune

complexes.
 Type IV hypersensitivity reactions
(T-cell mediated reactions)
Mechanism:
• Tissue damage is caused mainly by the
activation of macrophages by Th1 cells →
inflammatory response.

• Damage can also be caused directly by

cytotoxic T cells (CTL).

• Both mechanisms may be involved.

The delayed-type (type IV) hypersensitivity response is directed by
chemokines & cytokines released by TH1 cells stimulated by antigen
Delayed hypersensitivity reactions
(all take some time to develop)
Delayed type hypersensitivity reaction
Tuberculin skin test (TST)
(PPD antigen is injected ID)
Sequence of events in Contact hypersensitivity

(THE ANTIGEN is absorbed into the skin)

Poison Ivy
 Other diseases caused by Type IV
Hypersensitivity

• Insulin-dependent diabetes (Type I diabetes)

• Autoimmune diseases (e.g., rheumatoid arthritis)
• multiple sclerosis?
• Inflammatory bowel disease
• Graft rejection
 Treatment
• Corticosteroids.
• Antagonists to cytokines such as TNF.
• Inhibition of T cell responses by cyclosporine &
other immunosuppressants.

Under trial
• Antagonists against receptors of cytokines such as IL-2.
• Blocking co-stimulatory molecules such as B7.
• Inducing tolerance of specific T cells.
 TOLERANCE
&
AUTOIMMUNITY
Definition of Tolerance:
The absence of specific immune response
against some antigens in an immunocompetent
person.

Types of tolerance:
• Autotolerance (natural).

• Acquired (induced) tolerance to other antigens.

 Autotolerance
• Tolerance to self-antigens.
• Induced early, in utero.
• Failure → autoimmune disease.

Mechanisms:
• Central tolerance
• Peripheral tolerance
Central tolerance:
Negative Selection (Clonal Deletion):
Contact of immature B or T cells during
development with antigen (probably self-
antigen) → deletion or permanent
inactivation.

Where?

In primary lymphoid organs

 Opportunity to remove harmful
specificity at an early stage of
!!!!Cells specific for self antigen!!!! development
IMMUNOLOGICAL TOLERANCE

Antigen receptors recognising self antigens deleted early in lymphocyte

development
 Peripheral tolerance:
Sometimes:
• Self antigens are not expressed in primary
lymphoid organs:

→ immature lymphocytes do not meet them →

no chance for central tolerance to develop.

→ self-reactive lymphocytes allowed to

mature → autoimmunity !!
BUT:

→ Various regulatory mechanisms (peripheral

tolerance) make T helper cells unresponsive.

→ no immune response to self-antigens.

 Acquired (Induced Tolerance)
Definition:
Induction of tolerance to an antigen at any time
during life.

Question:
• When should we try to achieve this?
Answer:
To treat or prevent an unwanted immune response:

• Autoimmunity

• Allergic disease

• Graft rejection
How:
Antigen is given:
• In a certain form
&
• Under certain conditions → Tolerance

Antigen used is called TOLEROGEN

Factors Influencing Induction of Tolerance 1

• Dose:
– High dose → tolerance of B cells.
– Repeated minute doses → tolerance of T cells.
– Moderate dose → usually immunogenic.

• Form of antigen:
Soluble protein antigens more tolerogenic than
aggregated or particulate form.
Factors Influencing Induction of Tolerance 2

• Persistence of antigen or repeated

administration → maintenance of tolerance.

• Immunosuppressant + antigen →
↑development of tolerance (e.g., Cyclosporin).

• Age:
Best is prenatal or neonatal period because of
immaturity of immune system.
General rule:

T cell tolerance is easier to induce & lasts longer

compared to B cell tolerance

 AUTOIMMUNITY
Definition:

Adaptive immune response to self-antigens

due to breakdown in autotolerance →
production of autoantibodies and/or self
reactive T cells → autoimmune disease.
 Aetiology of autoimmune diseases:
1. Exposure to antigens that are normally sequestered:

Examples:
• Sperms: testicular trauma or infection → release of
sperm antigens → immune response → Ab formation →
↓ spermatogenesis.

• Lens: trauma → release of antigen → immune response

→ destruction of lens.
2. Structural modification of tissue proteins:

By drugs, chemicals or viruses → alteration of certain

tissue proteins

Example:
• Alpha-methyl dopa modifies RBC surface proteins
→ such protein no longer identified as self →immune
response → autoimmune hemolytic anemia.
3. Cross-reactivity:

Example:
Streptococcus pyogenes & heart tissue antigens

Infection → Abs produced against

Streptococcus pyogenes that react with heart
muscle antigens (due to antigenic similarity) →
damage → rheumatic fever & rheumatic heart
disease (RHD).
Ag 1 Ag 2
4. Breakdown of Immune Network:
• Interference with normal suppression of self-
reactive T cells that survived.
• Polyclonal activation of lymphocytes:
Certain microbes → non-specific activation of
many clones of lymphocytes (including self-
reactive clones) → autoimmune response.
• ↑ IL-2 by Th1 cells
→ overstimulation of immune system.
 Genetic Predisposition to Autoimmune Diseases

Facts:
• Genetics appear to play a role.
• Certain autoimmune diseases run in families.
Probable cause:
• MHC antigens:
Certain MHC antigens are good at presenting
certain self peptides → autoimmune response.
 Famous Examples
Systemic lupus erythematosus (SLE) ↔ DR3
Rheumatoid arthritis ↔ DR4
Ankylosing Spondylitis ↔ B27
Spectrum of Autoimmune Diseases

• Organ specific

• Non-organ specific

• In Between
Organ-specific:
Immune response directed against antigens of
a certain organ.

Examples:
• Grave’s disease
• Hashimoto’s disease
• Myxoedema
(All are autoimmune diseases directed against
thyroid gland).
• Excessive Stimulation
of Cells:

Example:
Grave’s disease:
Ab against thyroid cells
→ ↑ secretion of thyroxin
→ Thyrotoxicosis
Non-organ-specific:
Lesions not confined to one organ.

Examples:
• Systemic lupus erythematosus
• Rheumatoid arthritis
In Between:
Antibodies formed are not organ-specific but
lesions are localized to one organ.

Example:
Primary biliary cirrhosis (Antibody is against
mitochondria, but affection is mainly in the
liver).
Spectrum of Autoimmune diseases
 Mechanisms of Tissue Injury in Autoimmune Diseases

• Type II:
Cytotoxic reactions

Example:
Autoimmune haemolytic
anaemia
• Type III:
Immune-complex–mediated

Examples:
• SLE
• Rheumatoid arthritis
• Type IV:
Cell-mediated reaction

Example:
Ulcerative Colitis
 Laboratory diagnosis of Autoimmune Diseases

• ↑serum immunoglobulins

• Presence of autoantibodies:
e.g., Rheumatoid factor (IgM against own IgG), anti-
nuclear Ab (ANA), anti-DNA Ab, anti-mitochondrial Ab,
anti-smooth muscle Ab, anti-thyroid Ab.

• Detection of immune complexes in serum & in

tissues.

• ↓level of complement in serum.

 Management of Autoimmune Diseases

• Anti-inflammatory drugs

• Immunosuppressive drugs

• Plasmapheresis

• Interference with cytokine

network
TRANSPLANTATION
IMMUNOLOGY
 The Major Histocompatibility Complex
(MHC)

• A group of genes present on the short arm of

chromosome 6.
• They code for antigens expressed on cell
surface membranes (MHC antigens).
• MHC antigens also called HLA antigens.
• May cause immune response in genetically
distinct individuals → graft rejection.
 Structure of MHC

• Class I: A,B,C
• Class II: DP, DQ, DR
• Class III: Complement components
 MHC I molecules
Present on all nucleated cells
MHC II Molecules
Present only on APCs
 Characteristics of MHC

• Highly polymorphic (many possible alleles at each

genetic locus)

Example: HLA-A can be A1, A2, A3 or A4, etc.

HLA-B can be B1, B2, B3 or B4, etc.
 Inheritance of HLA

• One haplotype inherited from each of mother

& father.

• Co-dominantly expressed.
Inheritance of HLA
Significance of MHC molecules:
1. Antigen presentation
2. MHC I molecules enable cell to be target for
Cytotoxic T cell
MHC II molecules enable Helper T cells to
give help to B cells, Tc, NK & macrophages
3. Graft rejection.

4. Susceptibility to certain inflammatory

or auto-immune diseases:
• B27: ankylosing spondylitis
• DR4: rheumatoid arthritis
• DR3: systemic lupus erythematosus

5. Forensic uses: disputed paternity.

 Minor Histocompatibility Complex

• Group of genes which code for antigens

that cause a weaker rejection reaction
than the MHC group of antigens.
Types of Grafts
Summary of antigens responsible for graft
rejection

1. ABO blood group antigens

2. Major histocompatibility antigens (MHC)

3. Minor histocompatibility antigens

 Types & Mechanisms of
Graft Rejection

I. Acute Rejection

II. Hyperacute Rejection

III. Chronic (Late) Rejection

I. Acute Rejection:

• Commonest type.

• After days or weeks (Why?)

• Occurs in cases of HLA (MHC) incompatibility.

Mechanism:
Type IV hypersensitivity (Cell Mediated).
II. Hyperacute rejection:
• Most severe and acute form.

• Within minutes (Why?)

• Caused by pre-formed antibodies to ABO

antigens or MHC I antigens.
III. Chronic (Late) Rejection:

– Months or years after transplantation.

– Severity & speed depends on:

- Genetic differences between donor and recipient.

- Efficiency of immunosuppressive therapy.

Mechanism:
• Low-grade cell-mediated hypersensitivity.
• Deposition of Ag-Ab complexes.
 Graft versus Host disease (GVHD)
• Graft reacts against recipient
(The usual is recipient against
graft).

When?
• When recipient is
immunocompromised &
graft has immunocompetent
cells, e.g., typically in bone
marrow grafts.
 How to prevent GVHD?

• Proper tissue typing

• Immunosuppressive drugs

• Removal of mature T cells from grafted bone

marrow
 How to Prevent Rejection?
I. Proper selection of donor.

II. Immunosuppressive therapy to

recipient.

III. Induction of tolerance in recipient.

I. Selection of donor:

1. ABO matching: to prevent hyperacute rejection by

anti-ABO antibodies.

2. Histocompatibility Testing:
A. Lymphocytotoxicity Test
B. Molecular methods

3. Mixed lymphocyte reaction (MLR)

II. Immunosuppressive therapy:

• Prevention or treatment.
• For ordinary graft rejection or GVHD.
• For maintenance or during episodes only.
• Disadvantage: ↑↑ infection.
• Examples:
1. Corticosteroids: anti-inflammatory.

2. Inhibitors of T cell cytokine production:

e.g., Tacrolimus & cyclosporine.

3. Ant-proliferative drugs →
↓DNA production → ↓ lymphocyte proliferation
→↓ IR against graft
e.g., Azathyoprine & methotrexate.

4. Monoclonal antibodies against CD3:

→ block T cell function.
III. Induction of antigen-specific tolerance:

• Low-dose or high dose tolerance.

• Better than immunosuppression (Why?).

• Still experimental.
 Summary of Measures to Prevent Rejection

ABO
matching

Serological
Proper selection of Tissue
Donor Typing
Molecular

Compatibility
Testing by MLR
Measures
Immunosuppressive
Therapy

Induction of Antigen-Specific
Tolerance
Tumour Immunology
 Introduction

• Tumours are considered an foreign and are exposed to

rejection mechanisms by the body.

• Tumour rejection mechanism represents a means by

which the body cells could be kept under immuno-
surveillance.

• Immuno-surveillance is the ability of the immune

system to prevent the development of most tumours
through early recognition & destruction of tumour cells.
 Tumour Antigens

• They are surface membrane molecules on

tumour cells.

• May be antigenically new.

• Can be recognized by the immune system.

 Tumour Antigens’ Groups
2 Groups:
◼ Tumour-specific antigens (TSAs):
- They are expressed on tumour cells but not on
normal cell can induce an active immune
response.

- They have been identified on:

1. Tumours induced by viral transformation (e.g., HPV, EBV)
2. Tumours resulting from genetic mutations (due to
exposure to carcinogenic chemicals, X-ray, etc.)
 Tumour Antigens’ Groups
• Tumour-associated antigens (TAAs):
- These antigens are relatively restricted (but not
unique) to tumour cells & may also be present on
normal tissue may not be able to stimulate an
effective immune response.

- They may be:

1. Normal self proteins found in excessive amounts
on tumour cells (e.g., HER2 is a certain receptor
found on normal cells in very low amounts, but is
overexpressed in some breast tumours.
2. Proteins normally expressed only on embryonic
cells but reappear on tumour cells in adults, i.e.,
oncofaetal antigens (e.g., alpha fetoprotein, CEA).
 Effector Mechanisms Involved in Tumour
Immunology
◼ Innate Immunity:
Monocytes/Macrophages Important role
◼ Antigen presentation, cytokine secretion, ADCC.
◼ Direct cytotoxicity of the tumour cells (by releasing TNF-α, nitric
oxide & hydrogen peroxide).
Natural Killer (NK) Cells
◼ Direct killing.
◼ Antibody-dependent cellular cytotoxicity (ADCC).
◼ Specific Immunity
Cytotoxic T (Tc) cells recognize antigens in association with class I MHC
molecules on tumour cells & kill them: The most important role
T-helper (Th) cells secrete cytokines (including IL-2: activate Tc cells, NK cells
& B cells, IFN-Ɣ: activate macrophages & NK cells & TNF: directly toxic to tumour cells).
B Cells
◼ Complement fixation & lysis of tumour cells.
◼ ADCC.
 Tumour Evasion 1
1. Immunocompromised Host.

2. Tumours localized at sites inaccessible to the

immune system e.g., CNS.

3. Certain tumours (virally-induced) lack or are

poor in expression of MHC I molecules.
 Tumour Evasion 2
4. Viruses block expression of co-stimulatory
molecules (e.g. B7) by antigen-presenting cells.
 Tumour Evasion 3
5. Factors related to tumour antigens:
• Antigens are non- or low-immunogenic.
• Small amount of antigen to stimulate the immune
system.
• Antigens not processed & therefore not presented with
MHC.
• Some tumours may shed their antigens (soluble Ags)
which block antibodies & T cells from reacting with the
tumour cells (decoys).
 Tumour Evasion 4
6. Blocking antibodies: Non-cytolytic (non-complement
fixing) antibodies in the serum may bind to the tumour
antigens, making them inaccessible to complement fixing
antibodies. This prevents complement-mediated lysis of
tumour cells.

7. Fibrin coating leads to masking of tumour antigens.

8. Some tumours may secrete substances, (e.g.,TGF-β)

that suppress the immune response directly.
 Tumour Immunodiagnostics
◼ TAAs can be very useful tumour markers in the diagnosis &
follow-up of various tumours.

An ideal tumour marker is:

1. Only from tumour tissue.
2. Specific for a given tumour type.
3. Early detectable upon tumour formation.
4. Concentration in blood proportional to the tumour
mass.
5. Present in all patients with the tumour.
 Tumour Markers
• Carcinoembryonic antigen (CEA); found in colon carcinomas.
• α-Foetoprotein (AFP); found in primary hepatoma.
• β-HCG; the major clinical marker in choriocarcinoma.
• Prostate-specific antigen (PSA); in cancer prostate.
• CA 125; in ovarian cancer.
• CA 19-9; in colonic and pancreatic tumours.
• CA 15-3; in breast cancer.
• Bence-Jones proteins; in myeloma.
• Pancarcinoma antigen (TAG-72); used to localize occult tumour
secondaries.
Tumour Immunotherapy
 Approaches to Tumour Immunotherapy 1

I. Monoclonal antibodies :

• Monoclonal antibodies directed against

tumour antigens.

• Used either alone or coupled to radioisotopes,

cytotoxic drugs, toxin or cytokines.

• Advantage: delivering high doses of radioactivity

or cytotoxic drugs directly to the site of the tumour
(Magic bullet therapy).
 Approaches to Tumour Immunotherapy 3

II. Adoptive cell therapy

(infusion of tumour effector cells):
– Therapy with lymphokine-activated killer (LAK)
cells: The patient's lymphocytes (including NK cells)
are taken directly from tumour biopsies, cultured in
vitro with IL-2 then reinfused.

– Therapy with tumour-infiltrating lymphocytes: TILs

are extracted from tumour biopsies, stimulated in
vitro using IL-2 then reinfused.
 Approaches to Tumour Immunotherapy 4

III. Passive Cellular & Humoral (Combined)

Immunotherapy:

Based on the development of bispecific

(bifunctional) antibodies, which links one
antibody reacting with the tumour cell to a
second antibody reacting with a cytotoxic
effector cell, targeting the latter directly to
the tumour.
 Approaches to Tumour Immunotherapy 5
IV. Active Specific Immunotherapy
(Anti-Tumour Vaccines):
– Tumour cell vaccines: These are tumour cells taken from other
patients, irradiated then injected with BCG vaccine or other
adjuvants into the patient to stimulate a good immune response.

– Tumour antigen vaccines: Cellular immunity to specific, well-

defined antigens can be induced by using short synthetic peptides.

Active immunization against oncogenic viruses can prevent

the development of certain tumours; e.g.
1. successful mass immunization against hepatitis B virus
decreasing the incidence of primary hepatoma.
2. Immunization with human papilloma vaccine
decreasing the incidence of cancer cervix.
 Approaches to Tumour Immunotherapy 6

V. Non-specific Immunotherapy:

– Interferons (IFNs) have anti-tumour activity in leukaemia

& AIDS-associated Kaposi's sarcoma.

– Bacterial adjuvants e.g., BCG or killed suspensions of

Corynebacterium parvum have been used to treat a wide
variety of cancers, usually along with intensive
chemotherapy or radiotherapy.
 Immunodeficiency

• Primary (inborn)

• Secondary :
– Transient
– Permanent
 PHAGOCYTIC

INNATE IS COMPLEMENT

NK CELLS

PRIMARY

IMMUNODEFICIENCY T CELLS

SECONDARY

ACQUIRED IS B CELLS

T AND B CELLS
Primary Immunodeficiency
Defects of the Innate Immune System

1. Phagocytic Cell Defects:

A. Migration
Leucocyte adhesion deficiency (LAD):
Caused by defect in adhesion molecules
→ no migration of phagocytic cells to site of
infection.
→ infections of skin, mouth, respiratory tract
but no pus.
B. Engulfment: Rarely alone, usually associated
with defects in mobility.

C. Intracellular Killing
Chronic granulomatous disease (CGD):
• X-linked defect → presents in males
• Phagocytes cannot produce reactive oxygen
radicals
→ ↓ killing of intra- & extracellular bacteria
→ chronic bacterial & fungal infections &
recruitment of more phagocytes
→ lesions resembling granulomas
 2. Complement Deficiencies:

A. Early Components of classical pathway:

– ↓ elimination of immune complexes →
accumulation → damage.

B. Early Components of alternative pathway:

– Pyogenic Infections
C. Terminal Components: (C5-C9)
• For most extracellular bacteria, opsonization is
enough → no problem.

• Presents with susceptibility to Neisseria

(because these bacteria are capable of
intracellular survival, therefore, opsonization is
not enough & defense is mediated by lysis by
MAC).
D. Complement Regulatory Proteins

Example:
C1 inhibitor deficiency → Hereditary angioedema:

→↑activation by classical pathway

→ accumulation of fluid
→ swelling of epiglottis
→ suffocation
→ death
3. NK Cell Deficiency:

• ↑ viral disease
• ↑ malignant tumors
Why?
 Defects in Specific Immunity
(B &/or T lymphocytes)

1. B Cell Immunodeficiency (Antibody deficiency)

Wide range:
Complete deficiency ↔ Selective Deficiency
Examples:
X-linked agammaglobulinemia:
• Severe form of antibody deficiency in all serum Ig
isotypes.
• Manifestations:
– Symptoms appear at 5-6 months (Why?)
– Otitis, bronchitis, pneumonia & other chronic bacterial
infections
• Infections mainly with extracellular bacteria (Why?)
• Normal T cell response to viruses, but susceptibility
to some viruses ↑
Transient Hypogammaglobulinaemia of infancy

• Normal transient
hypogammaglobulinaemia
at 5-6 months.
• Delay in infant producing
its own IgG →
– Recurrent infections
– Poor response to
vaccines
2. T cell Immunodeficiency:

• Rarely manifested alone due to importance of

T cell help in humoral immune response.
Example :
• Di George Syndrome:
Congenital aplasia or
hypoplasia of thymus →
infections of all kinds
3. Combined T & B Cell Deficiency:

• Partial or complete

Complete:
Severe Combined Immunodeficiency (SCID)
Presents early in infancy →
– failure to thrive
– various infections
– continuous diarrhoea
 Secondary Immunodeficiency
• Malnutrition
• HIV → AIDS
• Viral Infections (e.g., measles)
• Severe bacterial infections (e.g., TB)
• Parasitic Infections
• Malignancies
• Chronic diseases (e.g., DM, chronic heart or kidney disease)
• Drugs: cytotoxic, steroids, immunosuppressive drugs
• Burns
• X-ray
 When to Suspect ID:

• ↑ infection frequency
• ↓ clearing of infections
• Spread of local infections
• Opportunistic infections
• Failure to thrive
• Certain tumours
Type of Infection clue to Type of Immunodeficiency

• Examples:
– B cell deficiency → pyogenic infections.

– T cell deficiency → infections with:

• intracellular bacteria
• viral infections
• Fungal infections

– Deficiency of terminal complement components:

→ Neisseria infections
 Investigations in a suspected case of
Immunodeficiency

➢Initial
• Full blood picture
• Serum Immunoglobulins
• C3

➢Detailed Investigations
• T cells
• B cells
• Complement
• Phagocyte Functions
 Detailed Investigations 1
• T cells
1. Quantitation by monoclonal antibodies against:
• CD3→ Total T cells
• CD4 → T helper
• CD8 → T cytotoxic

2. Cell proliferation in response to mitogens (Mitogens

are substances that can non-specifically stimulate
proliferation of lymphocytes).

3. Tests for cytokine production.

4. Delayed Type Hypersensitivity Skin Tests.

 Detailed Investigations 2
• B cells
1. Quantitation using antibodies against B cell
markers.

2. Measurement of immunoglobulin classes in

serum (& IgA in saliva).

3. Immunization → measuring Ab response

following vaccination.
 Detailed Investigations 3
• Complement
Total haemolytic assay:
(to measure the amount of FUNCTIONING complement by
measuring the ability of test serum to cause lysis of RBCs
coated with antibody).

• Phagocyte Functions
Tests to assess different steps:
Example:
• Migration
• Metabolic functions
• Intracellular killing
 Management of Immunodeficient Patient

General:
• Try to avoid infections.

• Give suitable immunizations (avoid live-

attenuated vaccines).

• Rapid treatment of infections with antibiotics.

Specific (according to defect):

• SCID & other severe deficiencies →

transplantation of thymus or bone marrow.

• Antibody deficiencies → Transfer of Igs.

• Cytokines:
▪ GM-CSF
▪ IFN-γ
▪ IL-2
Thank You