Transcript AUTOIMMUNITY

AUTOIMMUNITY
Dr. Anand Kumar &
Dr. R.. A. Siddique
N.D.R.I., Karnal
(Haryana)
India, 132001
[email protected]
Self/Non-self Discrimination
Autoimmunity is
a problem of
self/non-self
discrimination.
Autoimmunity
• 5 % to 7% adult affected.
• Two third women.
• More than 40 human diseases
autoimmune in origin.
AUTOIMMUNITY & LEFTHANDEDNESS
• 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.
Effects of autoimmunity
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
Causes of autoimmunity
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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 MSlike EAE
• in mice
• May be triggered by injury or infection
Causes 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 related from hidden location
Many self Ag are found in hidden location eg. C N S ,TESTES ,EYE
(CORNEA)
organ damage
Hidden Ag released
Reaches blood stream
Encounter Ag sensitive cells
Stimulate autoimmunity
Antigen generated by molecular changes
• Development of completely new epitopes on normal protein. eg RF immuno
conglutinine.
Mech of formation of RF :
Ab + Ag
new epitopes exposed on Fc region of Ab
Stimulate the formation of Rf
Establishment of disease like rheumatiod
artheritis and SLE
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 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.
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.
• inhanced stimulation of co stimulator.
• Alteration of self Ag(cross reactive neo-Ag)
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
POLYARTHRITIS: DLA- A7
Lymphocytes abnormalities
• Primary abnormalities either in B cell or T cell.
• Since these cells are critical regulators of all IR.
• MHC 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 organ;
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positive selection
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negative selection (Deletion of self reacting T
cells in thymus apoptosis).
Failure of central tolerance starts AU diseases.
POLYCLONAL LYMPHOCYTE ACTIVATION
• Stimulation of non deleted self reacting lymphocytes.
These are activated by some activators• LPSPOLYCLONAL B CELL ACTIVATOR
• BACTERIAL SUPER ANTIGENPOLYCLONAL T CELL ACTIVATOR
Damage to immunologically
privileged sites can lead to
autoimmunity
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
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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