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AUTOIMMUNITY�

Dr. Anand Kumar &

Dr. R.. A. Siddique

N.D.R.I., Karnal

(Haryana)

India, 132001

Email-riazndri@gmail.com

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Self/Non-self Discrimination

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

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Autoimmunity

  • 5 % to 7% adult affected.

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  • Two third women.

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  • More than 40 human diseases autoimmune in origin.

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AUTOIMMUNITY & LEFT-HANDEDNESS

  • LEFT handed individuals more affected.
  • 11% of left handed & 4% of right handed.
  • Reasons for this are obscure.
  • left-handedness & immune malfunction may both result from abnormal endocrine function in fetal life.

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1) Tissue destruction

Diabetes: CTLs destroy insulin-producing b-cells in pancreas

2) Antibodies block normal function

Myasthenia gravis: Ab binds acetylcholine receptors

3) Antibodies stimulate inappropriate function

Graves’ disease: Ab binds TSH receptor

Mimics thyroid-stimulating hormone

Activates unregulated thyroid hormone production

4) Antigen-antibody complexes affect function

Rheumatoid arthritis:

IgM specific for Fc portion of IgG

IgM-IgG complexes deposited in joints inflammation

Effects of autoimmunity

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Causes of autoimmunity�

  • 1) Release of sequestered Ag
  • Smoking can trigger Goodpasture’s syndrome
  • Alveolar basement membrane normally not exposed to
  • immune 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 MS-like EAE
  • in mice
  • May be triggered by injury or infection

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Causes of autoimmunity�

  • 2) Immune stimulation

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  • Microbial infection stimulates APCs carrying self Ag

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  • High level of APCs with “second signal” breaks anergy

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Mechanisms of autoimmunity

  • Ag released from hidden location.

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  • Antigen generated by molecular changes.

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  • Molecular mimicry.

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  • Alteration in Ag processing.

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  • Infection.

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  • Genetic factors.

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Mechanisms of autoimmunity

  • Lymphocytes abnormalities.

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  • Failure of central tolerance.

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  • Overcome of peripheral tolerance.

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  • Polyclonal lymphocytes activation.

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Ag related from hidden location

Many self Ag are found in hidden location eg. C N S ,TESTES ,EYE (CORNEA)

organ damage

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Hidden Ag released

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Reaches blood stream

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Encounter Ag sensitive cells

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Stimulate autoimmunity

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Antigen generated by molecular changes��

  • Development of completely new epitopes on normal protein. eg RF immuno conglutinine.

Mech of formation of RF :

Ab + Ag

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new epitopes exposed on Fc region of Ab

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Stimulate the formation of Rf

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Establishment of disease like rheumatiod artheritis and SLE

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Molecular mimicry��

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

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  • Antibodies directed against the infectious

agents starts reacting with normal self Ag.

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  • Triggers autoimmunity.

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Alteration in Ag processing�

  • A T cell may fail to develop tolerance to an self Ag simply because it is not efficiently procured.
  • If something happens to improve the processing, an autoimmune disease may be triggered.
  • This usually happens at the site of inflamation resulting in modified Ab.
  • Eg. Thyrotoxicosis , diabetese.

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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.

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  • inhanced stimulation of co stimulator.

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

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GENETIC FACTORS

  • The important genes that regulate the development of autoimmunity are located within MHC.
  • MHC have got critical role in maturation of T cell & induction of IR .
  • MHC ll genes are directly responsible for auto antigen processing and presentation.
  • The structure of Ag binding groove will determine , if specific Ag will trigger an AU response.
  • Eg. Diabetes mellitus in dog:

DLA-A3, A7, A10 and DLA-B4

SLE: DLA- A7

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POLYARTHRITIS: DLA- A7

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Lymphocytes abnormalities��

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

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

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

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Failure of central tolerence�

Inside primary lymphoid organ;

  • positive selection

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  • negative selection (Deletion of self reacting T cells in thymus apoptosis).

  • Failure of central tolerance starts AU diseases.

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POLYCLONAL LYMPHOCYTE ACTIVATION

  • Stimulation of non deleted self reacting lymphocytes. These are activated by some activators-
  • LPS- POLYCLONAL B CELL ACTIVATOR

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  • BACTERIAL SUPER ANTIGEN-

POLYCLONAL T CELL ACTIVATOR

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Damage to immunologically privileged sites can lead to autoimmunity

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Rheumatiod Arthritis

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

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  • This result in loss of function.

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  • Affects 1% of adults.

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Treatment for autoimmunity�

  • Immunosuppression (e.g., prednisone, cyclosporin A)
  • Removal of thymus (some MG patients)
  • Plasmapheresis (remove Ab-Ag complexes)
  • T-cell vaccination (activate suppressing T cells??)
  • Block MHC with similar peptide
  • anti-CD4 monoclonal Ab
  • anti-IL2R monoclonal Ab

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