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