Tolerance

Immunogen (non-self)

Immune response (cells, antibodies)

Tolerogen (self)

No Immune response (tolerance)

Non-self molecules: will induce

immune-response or tolerance
Determinant

Immune response

Tolerance

Physical form of Ag Large, aggregated, Soluble, small, less

complex
complex
Route of Ag
administration

Intramuscular

Oral

Dose

Optimal

Very large or very

small

Age of responding
animal

Older and
immunological
mature

New born,
immunological
immature

Immunological features of tolerance

Tolerance is different from immuno-suppression
and immunodeficiency
It is an immunological process in response to an
active antigen
Specific like immune response
Can exist in T cell, B cell or both
Tolerance at T cell: longer lasting, can be
induced with low amount of tolerogen
Requirement for maintenance of tolerance:
Tolerance induction to single or multiple epitopes
in a tolerogen

Mechanisms for induction of tolerance

to self-antigens
Clonal deletion
Clonal anergy
Clonal ignorance

Failure of tolerance
Natural failure in autoimmune diseases:
Breakdown of bodys tolerance to self
antigens Immune response against selfantigens
Artificial failure
Drugs, X-rays

Termination of experimentally induced

tolerance
By prolonged absence of tolerogen
By treatments (X-rays) leading to
damaged immune system

Auto-immunity (damage to the self)

Classification of autoimmune
diseases:
Organ specific
Non-organ specific

Classification of Auto-immune diseases

Organ Specific
Self-antigens induce
antibodies specific to
an organ
Effects due to Ab
mediated cell lysis
Specific organ
damaged
Myasthenia Gravis,
Pernicious anemia,
Hashimotos thyroiditis

Non-organ specific
Self-antigens induce
non- specific
antibodies
Due to deposition of
Ag-Ab complexes
Connective tissue
related damage
Rheumatoid Arthritis

B cells (Antibodies) and Effector T cells (and

their products) are involved in damage in
autoimmune disease
T dependent autoimmune diseases
Prevention of autoimmune diseases by
regulation of auto-reactive T helper cells
AutoantigenT helper T cytotoxic autoimmune

disease
B cell autoantibody

Genetic factors and auto-immune

diseases
Occur in clusters in certain families
Association with HLA specificities
Addisons disease:
HLA from DR3
Rheumatoid arthritis:
HLA from DR4
HLA: B8, B27, DR2, DR5, etc. have also
been linked to other auto-immune disease

Hormonal factors and auto-immune

diseases
SLE (Systemic lupus erythematosus)
more in woman during their reproductive
phase

Mechanisms of tissue damage/injury in

auto-immune diseases
1. Release of inflammatory mediators and
cell lysis
Cell lysis: Complement pathway or ADCC
by K cells

2. Formation of immune complexes

Auto-antibodies + antigens = immune complexes

Deposition of immune complexes in tissues,

joints, blood vessels
Fix complement and cause inflammation

3. Cell mediated auto-immune response

Auto-reactive T cells

Kill the self-cells directly

Secrete lymphokines

Amplify inflammatory
responses

Etiology of auto-immune diseases

1. Exposure of sequestered antigens
Tissue damage/injury

Antigens are exposed

Emergence of auto-antibodies
Examples: Antibodies against
1. Lens protein after the eye injury
2. Sperm after vasectomy
3. Heart muscle antigens after heart surgery

2. Modification of self-antigen
Self-antigen: Host is tolerant

Altered self-antigen: Host is not tolerant

Emergence of auto-immune diseases

Alteration by bacterial viral infection

Immune response against blood group antigens in
Mycoplasma pneumoniae infection

Alteration by drugs
Auto-immune haemolytic anaemia due to
-Methyl dopa

modifies RBC; B cell react and lyse

3. Molecular mimicry
Due to availability of cross-reacting
antigens from exogenous microbial
systems
Example:
Envelope proteins on Yersinia enterolytica
share epitopes with extracellular domain
of human thyroid-stimulating hormone
(TSH)

4. Defective regulation by TH cells

In immune response to non-self
T helper cells B cells to produce Ab

In tolerance to self-antigens
T helper cells remain inactive and do not activate B cells to
produce Ab

Possible reason for generation of auto-immune

response:
T helper cells initially tolerant to a specific antigen
turn activated and stimulate B cells to produce
auto-antibodies

Defective T suppressor cells

T suppressor cells inhibit B cells from producing Ab

In tolerance to self-antigens
T suppressor cells remain active and inhibit B cells to
produce auto-antibody

Possible reason for generation of auto-immune

response:
T suppressor cells initially active with respect to a
self antigen turn inactivated and can not inhibit B
cells from producing auto-antibodies

5. Polyclonal B cell activation

Adjuvant properties in microorganisms
(e.g. bacterial lipopolysaccharides,
mycobacterial cell wall antigens)

Stimulate several clones of B cells in a

non-selective and non-specific manner

6. Abnormal expression of MHC II

during viral infection
TH cells are deleted for self-antigens: clonal deletion
Self-neural and endocrine antigens, TH cells are not deleted

escape into the peripheral tissues

Will react with self antigens in combination with MHC II

Normally prevented because of limited distribution of MHC

II

Increases MHC II in viral infection auto-immune diseases

Myasthenia Gravis

(Grave muscle weakness)

An auto-immune disease causing muscle

weakness and fatigue ability
Caused by a defect in the transmission of
nerve signals to muscles at neuromuscular junctions
Normal immune system:
ACH as neurotransmitter

Symptoms
Muscle weakness
Involves muscles that control eye and eyelid
movement, facial expression, chewing,
talking, breathing, and swallowing.
The thymus gland is abnormal in most MG
cases. Some people carry thymomas
(benign tumors of the thymus gland)
Being an autoimmune disease, it may occur
in combination with other autoimmune
conditions such as rheumatoid arthritis,
pernicious anemia, autoimmune thyroiditis,
etc.

Acetylcholine (ACH)
receptors (ACH-r)
on (released from nerve the muscle
endings)

Muscle contractions
In Mys-Gravis auto-antibodies are generated:
against Acetylcholine receptors (Ach-r)
against MuSk

No transmission of neuromuscular signal

Neonatal myasthenia
Congenital myasthenia
Ocular myasthenia
Myasthenic crisis

Treatment
Drugs to enhance nerve-muscle communication
(e.g. pyridostigmine).
Immunosuppressive drugs to suppress immune
system, and hence the production of autoantibodies.
Thymectomy: surgical removal of the thymus
gland in patients with or without tumors.
Plasmapheresis: Blood is taken from the patient,
filtered to remove the abnormal antibodies.
Purified blood is re-transfused.

Asthma: an example of local

anaphylaxis
IgE antibodies bind to basophils/mast cells

Allergen binds to IgE

Granules undergo exocytosis

Asthma: The bronchi constricted; Difficulty in

breathing
Symptoms: wheezing and cough
Allergen

lungs

mast cells in the lung undergo exocytosis

releasing histamine and leukotrienes

smooth muscle cells of the bronchi contract and

narrow the lumen of the bronchi: Early phase of
the disease

Onset of late phase of the disease

Accumulation of inflammatory cells (e.g
eosinophils) and production of mucus (that
blocks airways). With repeated attacks,
the lining of the bronchi becomes
damaged

Presence of T helper cells of asthma

patients are largely of the Th2 type not Th1
type
Th2 helper cells: help B cells make IgE
antibodies by synthesizing IL-4 and IL-13,
which promote class switching
release IL-5 which attracts eosinophils
and other inflammatory cells to the site,
producing the late phase of the response

Treatment
1. Corticosteroids: To reduce the
inflammation of the late phase
2. Cromolyn sodium: to inhibit exocytosis of
mast cells thus blocking the release of
histamine and leukotrienes
3. Use of leukotriene inhibitors

Possible future treatments

Anti-IgE antibodies: interfere with the
binding of IgE to mast cells, e.g.,
Omalizumab (Xolair)
Drugs that bind to IL-4 and IL-13 to
prevent IgE synthesis.
Treatments that stimulate the production
of Th1 cells. Th1 cells secrete interferongamma, a powerful inhibitor of Th2 cells.

Rheumatoid arthritis
Non-organ specific auto-immune
disease
can lead to long-term joint damage,
results in chronic pain, loss of function and
disability

 Caused by the inflammation of the lining, or

synovium, of the joints

Progresses in 3 stages
Swelling of the synovium, redness,
stiffness, pain around the joints

 Rapid growth of cells, causes synovium to

thicken (Pannus)
Release of enzymes: digest bones and
cartilege; loss of size, shape and function

 Being a systemic disease, it can affect other organs in

the body (skin, heart, lung, muscle, etc.)
Role of gender?
The disease affects women 3 times more than men
Signs and symptoms

Morning stiffness

Polyarthritis

Symmetric arthritis

Rheumatoid nodules: Nodules are firm, pea-sized

masses made up of inflammatory by-products; not painful
and can occur anywhere in the body

Immunological basis
1. Rheumatoid factor:
An antibody produced during the inflammation
Mainly IgM but also IgG and IgA produced by the
B cells and plasma cells in the synovial
membrane
2. A number of cytokines are produced in the
disease
Pro-inflammatory: IL1, IL6, TNF, GM-CSF, IL15
etc

 Diagnosis
Latex test: Measurement of Rheumatoid
factor
Sedimentation rate test of blood: for
testing the status of inflammation

Treatment
Disease modifying antirheumatic drugs
(DMARDs)

Anti-inflammatory drugs

Analgesics

Antibodies for blocking TNF, IL1

Weight
loss,
replacement)

surgery

(knee/joint