2. Tolerance
* It is a specific immunologic unresponsiveness
• immune system does not attack an antigen. It can be either
'natural' or 'self tolerance', where the body does not mount
an immune response to self antigens, or 'induced tolerance',
where tolerance to external antigens can be created by
manipulating the immune system
• * Unresponsiveness to self antigens is known as auto
tolerance
* Both B-cells and T-cells participate in tolerance
* But T-cells play the primary role
3. Central Tolerance
Clonal–deletion:
Central tolerance occurs during lymphocyte development and
operates in the thymus and bone marrow. Here, T and B
lymphocytes that recognize self antigens are deleted before
they develop into fully immunocompetent cells, preventing
autoimmunity. This process is most active in fetal life in
thymus, but continues throughout life as immature
lymphocytes are generated.
* This involves the killing of T-cells and B-cells that react
against antigens present in the fetus at that time
4. Peripheral Tolerance
• T-cell tolerance (clonal anergy):
• Peripheral tolerance is immunological tolerance
developed after T and B cells mature and enter the
periphery.
* Some self-reactive T cells are not killed in thymus
* Functional inactivation of surviving self-reactive T
cells
5. Tolerance
* B-cells become tolerant to self by two mechanisms:
1) Clonal deletion
Probably while B-cell precursors are in bon marrow
2) Clonal anergy
B cells in the periphery
* Tolerance in B-cells is less complete than in T-cells
* The most autoimmune diseases are mediated by antibodies
6. Factors Influencing The Induction Tolerance
1) Immunologic maturity of the host:
Neonates are immunologically immature and well
accept allograft that would be rejected by mature host
2) Structure and dose of antigen:
a- Simple molecules induce tolerance more readily than
complex ones
b- Very high and very low doses of antigen may result
in tolerance
7. Factors Influencing The Induction Tolerance
3) T-cells become tolerant more readily and remain
tolerant longer than B-cells
4) The continuous presence of antigen helps to
maintain tolerance
5) Administration of immunosuppressive drugs enhances
tolerance as in transplantation
8. Clinical Importance of Tolerance
1) Organ transplantation:
Introduction of tolerance may help in prevention of rejection
2) Tumor development:
Tolerance to tumor antigen results in growth of the
tumor without being detected by the immune mechanisms
3) Autoimmune disorders:
Distraction of self-tolerance results in autoimmune disease
10. Autoimmune Diseases
* Autoimmune diseases occur due to breakdown of
the mechanisms that maintain auto tolerance
* Auto-antibodies and self reactive T-cells are
produced, resulting in tissue damage by several
mechanisms
11. Etiology Of Autoimmune Diseases
1) Genetic predisposition:
- Familial incidence of autoimmune diseases
- Most of them appear to be associated with certain
MHC genes, specially MHC II genes
e.g. Rheumatoid arthritis is associated with DR4(HLA-DR4)
Thyroiditis with DR5
Multiple sclerosis with DR2
SLE with DR2/DR3
Type I diabetes with DR3/DR4
Ankylosing spondylitis with B27
SLE : Systemic lupus erythematosus (, often abbreviated to SLE or lupus, is
a chronic systemic autoimmune disease (or autoimmune connective tissue
disease) that can affect any part of the body.
Ankylosing spondylitis ; chronic, inflammatory arthritis and autoimmune
disease. It mainly affects joints in the spine and the sacroiliac in the pelvis, and
can cause eventual fusion of the spine.
MHC class II, DR4
13. Etiology Of Autoimmune Diseases
2) Exposure to infectious antigens that cross react
with self antigens
- An immune response to these antigen will result
in immune attack against self antigens
e.g. Antibodies against M protein of Streptococcus pyogens may
react with heart valves and cause Rheumatic fever
3) Alteration of self antigens or the appearance of new antigens
under the effect of drugs, chemicals, or viral infections
4) Hormonal influences play a role e.g. SLE affects women 10
times more than men
14. Mechanisms Of Disease Production
* The disease may be organ specific
e.g Hashimoto thyroiditis
* The disease may be systemic
e.g. SLE or rheumatoid arthritis
1) Binding of an autoantibody to host cells result in
complement fixation and tissue destruction
e.g. Haemolytic anemia (Type II hypersensitivity)
15. Mechanisms Of Disease Production
2) Formation of immune complexes and their
deposition in tissues, joints, kidney and skin
The immune complexes fix complement resulting in
tissue damage
e.g. SLE and rheumatoid arthritis (Type III hyper.)
3) DTH reactions (delayed-type hypersensitivity (Type IV)) due to
auto reactive T-cells
e.g. Ulcerative colitis, multiple sclerosis and type I diabetes
Multiple sclerosis ; is an inflammatory disease in which the fatty myelin sheaths
around the axons of the brain and spinal cord are damaged
Diabetes mellitus type 1 (Type 1 diabetes) is a form of diabetes mellitus that results
from autoimmune destruction of insulin-producing beta cells of the pancreas.
16. Laboratory Diagnosis
1- There is elevated serum immunoglobulins
2- Complement levels may be decreased
3- Immune complexe detected in serum or organ biopsy
4- Auto antibodies can be detected in serum
e.g. anti-nuclear, anti-smooth muscles, Rh factor
and anti-mitochondrial Ab
5- Testing for antibodies specific to particular Ag,
involved in organ specific diseases (anti-thyroid Ab)
17.
18. The pathology in autoimmune diseases due to antibody may be a result of
A) the formation of antigen —antibody complexes.
B) antibody blocking a cell receptor.
C) antibody-induced phagocytosis.
D) antibody-induced complement mediated lysis.
E) Any of the above.
Most autoimmune diseases are caused by a
A) single genetic defect.
B) known infectious organism.
C) constellation of genetic and environmental events.
D) hormonal dysregulation.
E) B-cell defect
The following is/are possible mechanism(s) for the recognition of self-components
by the immune system in autoimmune diseases:
A) alteration of a self-antigen so it is recognized as foreign
B) leakage of sequestered self-antigen
C) loss of suppressor cells
D) infection with a microorganism that carries a cross-reactive antigen
E) Any of the above.
