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 & 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.
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
1) Release of sequestered Ag
Smoking can trigger Goodpastures 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
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;
positive selection
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-
LPS- POLYCLONAL B CELL ACTIVATOR
BACTERIAL SUPER ANTIGEN-
POLYCLONAL 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
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
