AUTOIMMUNITYAUTOIMMUNITY

Dr. Anand Kumar &Dr. Anand Kumar & Dr. R.. A. Siddique Dr. R.. A. Siddique

N.D.R.I., Karnal N.D.R.I., Karnal

(Haryana)(Haryana) India, 132001India, 132001

Email-Email-riazndri@gmail.comriazndri@gmail.com

Self/Non-self Discrimination

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

Autoimmunity• 5 % to 7% adult affected.5 % to 7% adult affected.

• Two third women.Two third women.

• More than 40 human More than 40 human diseases autoimmune in diseases autoimmune in origin.origin.

AUTOIMMUNITY & AUTOIMMUNITY & LEFT-HANDEDNESSLEFT-HANDEDNESS

• LEFT handed individuals more LEFT handed individuals more affected.affected.

• 11% of left handed & 4% of right 11% of left handed & 4% of right handed.handed.

• Reasons for this are obscure. Reasons for this are obscure. • left-handedness & immune left-handedness & immune

malfunction may both result from malfunction may both result from abnormal endocrine function in fetal abnormal endocrine function in fetal life.life.

1) Tissue destructionDiabetes: CTLs destroy insulin-producing b-cells in pancreas2) Antibodies block normal functionMyasthenia gravis: Ab binds acetylcholine receptors3) Antibodies stimulate inappropriate functionGraves’ disease: Ab binds TSH receptorMimics thyroid-stimulating hormoneActivates unregulated thyroid hormone production4) Antigen-antibody complexes affect functionRheumatoid arthritis:IgM specific for Fc portion of IgGIgM-IgG complexes deposited in joints inflammation

Effects of autoimmunity

Causes of Causes of autoimmunityautoimmunity

• 1) Release of sequestered Ag1) Release of sequestered Ag• Smoking can trigger Goodpasture’s syndromeSmoking can trigger Goodpasture’s syndrome• Alveolar basement membrane normally not Alveolar basement membrane normally not

exposed toexposed to• immune systemimmune system• Smoking damages alveoli, exposes collagenSmoking damages alveoli, exposes collagen• Anti-collagen Ag damages lung and kidneyAnti-collagen Ag damages lung and kidney• Anti-sperm Ab produced in some men after Anti-sperm Ab produced in some men after

vasectomyvasectomy• Injection of myelin basic protein (MBP) Injection of myelin basic protein (MBP)

produces MS-like EAEproduces MS-like EAE• in micein mice• May be triggered by injury or infectionMay be triggered by injury or infection

Causes of Causes of autoimmunityautoimmunity

• 2) Immune stimulation2) Immune stimulation

• Microbial infection stimulates APCs carrying self AgMicrobial infection stimulates APCs carrying self Ag

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

Mechanisms of Mechanisms of autoimmunityautoimmunity

• Ag released from hidden location.Ag released from hidden location.

• Antigen generated by molecular Antigen generated by molecular changes.changes.

• Molecular mimicry.Molecular mimicry.

• Alteration in Ag processing.Alteration in Ag processing.

• Infection.Infection.

• Genetic factors.Genetic factors.

Mechanisms of Mechanisms of autoimmunityautoimmunity

• Lymphocytes abnormalities.Lymphocytes abnormalities.

• Failure of central tolerance.Failure of central tolerance.

• Overcome of peripheral Overcome of peripheral tolerance.tolerance.

• Polyclonal lymphocytes Polyclonal lymphocytes activation.activation.

Ag related from hidden Ag related from hidden locationlocation

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 Antigen generated by molecular changeschanges

• Development of completely new epitopes on normal protein. Development of completely new epitopes on normal protein.

eg RF immuno conglutinineeg RF immuno conglutinine..Mech of formation of RF :Mech of formation of RF : Ab + Ag Ab + Ag

new epitopes exposed on Fc region of new epitopes exposed on Fc region of AbAb

Stimulate the formation of Rf Stimulate the formation of Rf

Establishment of disease like Establishment of disease like rheumatiod rheumatiod artheritis and SLEartheritis and SLE

Molecular mimicryMolecular mimicry• Sharing of epitopes between an Sharing of epitopes between an

infectious agent and its host.infectious agent and its host.

• Antibodies directed against the Antibodies directed against the infectious infectious

agents starts reacting with normal agents starts reacting with normal self Ag.self Ag.

• Triggers autoimmunity.Triggers autoimmunity.

Alteration in Ag processingAlteration in Ag processing

• A T cell may fail to develop A T cell may fail to develop tolerance to an self Ag simply tolerance to an self Ag simply because it is not efficiently because it is not efficiently procured.procured.

• If something happens to improve If something happens to improve the processing, an autoimmune the processing, an autoimmune disease may be triggered.disease may be triggered.

• This usually happens at the site This usually happens at the site of inflamation resulting in of inflamation resulting in modified Ab.modified Ab.

• Eg. Thyrotoxicosis , diabetese.Eg. Thyrotoxicosis , diabetese.

InfectionInfection

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

This may be due to :This may be due to :• Polyclonal lymphocyte activation.Polyclonal lymphocyte activation.

• inhanced stimulation of co stimulator.inhanced stimulation of co stimulator.

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

GENETIC FACTORSGENETIC FACTORS• The important genes that regulate the development of The important genes that regulate the development of

autoimmunity are located within MHC.autoimmunity are located within MHC.• MHC have got critical role in maturation of T cell & MHC have got critical role in maturation of T cell &

induction of IR .induction of IR .• MHC ll genes are directly responsible for auto antigen MHC ll genes are directly responsible for auto antigen

processing and presentation.processing and presentation.• The structure of Ag binding groove will determine , if The structure of Ag binding groove will determine , if

specific Ag will trigger an AU response.specific Ag will trigger an AU response.• Eg. Diabetes mellitus in dog: Eg. Diabetes mellitus in dog: DLA-A3, A7, A10 and DLA-B4DLA-A3, A7, A10 and DLA-B4 SLE: DLA- A7SLE: DLA- A7

POLYARTHRITIS: DLA- A7POLYARTHRITIS: DLA- A7

Lymphocytes Lymphocytes abnormalitiesabnormalities

• Primary abnormalities either in B cell or T Primary abnormalities either in B cell or T cell.cell.

• Since these cells are critical regulators of Since these cells are critical regulators of all IR.all IR.

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

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

Failure of central tolerenceFailure of central tolerence

Inside primary lymphoid organ;Inside primary lymphoid organ; positive selectionpositive selection

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

Failure of central tolerance starts AU Failure of central tolerance starts AU

diseases. diseases.

POLYCLONAL LYMPHOCYTE POLYCLONAL LYMPHOCYTE ACTIVATIONACTIVATION

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

• LPS- LPS- POLYCLONAL B CELL POLYCLONAL B CELL ACTIVATORACTIVATOR

• BACTERIAL SUPER ANTIGEN- BACTERIAL SUPER ANTIGEN-

POLYCLONAL T CELL POLYCLONAL T CELL ACTIVATORACTIVATOR

Damage to immunologically privileged sites can lead to autoimmunity

Rheumatiod ArthritisRheumatiod Arthritis

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

• This result in loss of function. This result in loss of function.

• Affects 1% of adults.Affects 1% of adults.

Treatment for Treatment for autoimmunityautoimmunity

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

• Removal of thymus (some MG patients)Removal of thymus (some MG patients)• Plasmapheresis (remove Ab-Ag Plasmapheresis (remove Ab-Ag

complexes)complexes)• T-cell vaccination (activate suppressing T T-cell vaccination (activate suppressing T

cells??)cells??)• Block MHC with similar peptideBlock MHC with similar peptide• anti-CD4 monoclonal Abanti-CD4 monoclonal Ab• anti-IL2R monoclonal Abanti-IL2R monoclonal Ab