Autoimmunity And Tolerance

Tolerance and Autoimmune Disease Dr. Mejbah Uddin Ahmed

Autoimmunity and Tolerance Tolerance: Specific immunologic unresponsiveness to certain antigen in spite of immune system is functional is called tolerance. Both T cells and B cells participate in tolerance. But T cells play primary role in tolerance. Tolerance is Two types: a) Central tolerance. b) Peripheral tolerance.

T cell precursors

Thymus

Abnormal release of autoreactive T cells Selected T cells

Central Tolerance Peripheral Tolerance anergy / deletion/ suppression Bone marrow

Autoimmunity and Tolerance T cell tolerance: Central tolerance: Central tolerance of T cell acquire in the thymus by the process called clonal deletion. Clonal deletion: Killing of T cells that react against self MHC proteins is called clonal deletion/ negative selection.

Autoimmunity and Tolerance Peripheral tolerance: Peripheral tolerance of T cells acquire outside the thymus. Mechanism of peripheral tolerance: a) Some are killed. b) Some are inhibited. c) Some are suppressed by regulatory T cells. (Self reactive T cells die by a process of programmed cell death called apoptosis).

Autoimmunity and Tolerance Peripheral tolerance: Clonal anergy: Self reactive T cells are not activated because proper costimulation does not occur. Clonal ignorance: This means self reactive T cells ignore self antigen. May be due to physical separation or antigens are very small amount.

Costimulation: CD28, B7 and CD40L, CD 40

CD28

T cell

B7

CD4 or 8 TcR MHC CD40L

CD40

APC

Autoimmunity and Tolerance B-cell Tolerance: B cell Tolerance is less complete than T cell, So most autoimmune disorders are antibody mediated. B cells tolerance involves: a) Clonal deletion: Probably in the bone marrow. b) Clonal anergy: In the periphery.

Autoimmunity and Tolerance

Induction of Tolerance: Whether an antigen will induce tolerance or immune response, depends on: a) Immunologic maturity of host. b) Structure and dose of antigen. c) T cell become tolerant rapidly and remain longer than B cell. d) Administration of cross reacting antigen. e) Administration of immunosuppressive drugs.

Autoimmune disease • Autoimmunity is a problem of self/ nonself discrimination. • Loss of self tolerance to self antigen may result in autoimmune diseases.

Autoimmunity and Tolerance Factors causes autoimmune disease: 

Genetic:HLA-DR4 =›Rheumatoid Arthritis, HLADR27 =›Ankylosing spondylitis.

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Hormonal factors.

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Bacterial and Viral infection.

Mechanism: 

Molecular mimicry.

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Tissue damage & release of sequestered antigen.

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Alteration of normal protein due binding of drugs.

Autoimmunity and Tolerance Autoimmune diseases occurs due the following types of immune response: a) Antibody to receptors. b) Antibody to cell components other than receptors. c) Cell mediated.

Autoimmunity and Tolerance 1.

Antibody to receptors:

Disease

Target of immune response

Myasthenia gravis Graves disease

Acetylcholine receptor TSH receptor

Autoimmunity and Tolerance Antibody to cell components other than receptors: Autoimmune diseases

Target of immune response

SLE

DNA, histones

Rheumatoid Arthritis

IgG

Rheumatic fever

Heart, Joints

Hemolytic anemia

RBC membrane

AGN

Glomerular basement membrane Guillain-Barre SyndromeMyelin protein

Autoimmunity and Tolerance  Cell

mediated:

Autoimmune diseases

Target of immune system

Allergic Reaction to myelin encephalomyelitis and protein causes multiple sclerosis demyelination of brain Celiac disease

Enterocytes

Autoimmunity and Tolerance  Microbial

infection associated with Autoimmune

diseases: Bacteria: Streptococcus pyogen=› Rheumatic fever Campylobacter jejuni =› Guillain-Barre syndrome Chlamydia trachomatis =› Reiter’s syndrome, Shigella species =› Reiter’s syndrome

Autoimmunity and Tolerance Microbial infection associated with Autoimmune diseases: Viruses: Hepatitis B virus =› Multiple sclerosis Measles virus =› Allergic encephalitis Cytomegalovirus =› Scleroderma