AUTOIMMUNITY

Self/Non-self Discrimination

Autoimmunity is a problem of self/non-self discrimination.

Frequence of AI

• 5 % to 7% adult affected.

• Two third women.

• More than 40 human diseases autoimmune in origin.

1) Tissue destructionDiabetes: CTLs destroy insulin-producing beta-cells in pancreas

2) Antibodies block normal functionMyasthenia gravis: Ab binds acetylcholine receptors

3) Antibodies stimulate inappropriate functionGraves’ disease: Ab binds TSH receptorMimics thyroid-stimulating hormoneActivates unregulated thyroid hormone production

4) Antigen-antibody complexes affect functionRheumatoid arthritis:IgM specific for Fc portion of IgGIgM-IgG complexes deposited in joints inflammation

Mechanisms of AI

Onset of autoimmunity

1) Release of sequestered Ag

- Smoking can trigger Goodpasture’s syndrome

Alveolar basement membrane normally not exposed system

Smoking damages alveoli, exposes collagen

Anti-collagen Ag damages lung and kidney

- Anti-sperm Ab produced in some men after vasectomy

- Injection of myelin basic protein (MBP) produces multiple sclerosis – like disease in mice

- May be triggered by injury or infection

Onset of autoimmunity

2) Immune stimulation

Microbial infection stimulates APCs carrying self Ag

High level of APCs with “second signal” breaks anergy

Mechanisms of autoimmunity

Ag released from hidden location

Antigen generated by molecular changes

Molecular mimicry

Alteration in Ag processing

Infection

Genetic factors

Mechanisms of autoimmunity

Lymphocytes abnormalities

Failure of central tolerance

Overcome of peripheral tolerance

Polyclonal lymphocytes activation

Ag released from hidden location

Many self Ag are found in hidden location eg. bone joints

CNS,testes, eye.

Damage of tissue

Hidden Ag released

Reaches blood stream

Encounter Ag sensitive cells

Stimulate autoimmunity

Antigen generated by molecular changes

RFs are immunoglobulins of any isotype with antibody activity directed against antigenic sites on the Fc portion of IgG molecules

Molecular mimicry

• Sharing of epitopes between an infectious agent and its host.

• Antibodies directed against the infectious agents starts reacting with normal self Ag.

• Triggers autoimmunity.

Alteration in Ag processing

• A T cell may fail to develop tolerance to an self Ag in the thymus.

• Stimulation of Ag processing can stimulate autoimmune T cells and trigger autoimmune disease.

• This usually happens at the site of inflammation.

• Examples: Thyrotoxicosis , diabetes.

Infection

• Here autoimmunity is not due to infectious agent itself ,but results from dis-regulation of host immune response by the microbes.

This may be due to :

Polyclonal lymphocyte activation.

Enhanced stimulation of co stimulator.

Alteration of self Ag(cross reactive neo-Ag).

GENETIC FACTORS

• HLA genes are directly responsible for auto antigen processing and presentation.

Example: HLA B27 morbus Bechterew spondylarthritis

Lymphocytes abnormalities

• Primary abnormalities either in B cell or T cell.• Since these cells are critical regulators of immune system

• HLA presentation of all antigenic peptide to these cells will be defective, in case the cells are abnormal.

• Abnormalities in lymphocytes could affect any one of the mechanism that normally maintains self tolerance.

Failure of central tolerence

Inside primary lymphoid organs - positive selection

- negative selection -> Deletion of self reacting T cells in thymus

Failure of central tolerance starts autoimmune diseases.

POLYCLONAL LYMPHOCYTE ACTIVATION

Stimulation of non deleted self reacting lymphocytes. These are activated by some activators-

LPS- POLYCLONAL B CELL ACTIVATOR

BACTERIAL SUPER ANTIGEN-

POLYCLONAL T CELL ACTIVATOR

Damage to immunologically privileged sites can lead to autoimmunity

Graves` disease

Rheumatiod Arthritis

• Auto-immune disorder which results in inflammation of the synovial lining of the joint and cartilage destruction.

• This result in loss of function.

• Affects 1% of adults.

Treatment for autoimmunity

Immunosuppression (e.g., prednisone, cyclosporin A)

Removal of thymus (some myasthenia gravis patients)

Plasmapheresis (remove Ab-Ag complexes)

T-cell vaccination (irradiated autologous autoreactive T-cell lines or

clones >> activate suppressing T cells??)

Block MHC with similar peptide

anti-CD4 monoclonal Ab

anti-IL2R monoclonal Ab