Mechanisms of AutoimmunityMechanisms of Autoimmunity

Immunology UnitDepartment of Pathology

College of Medicine

Objectives

• Autoimmunity results from activation of immune response against self antigens.

• To learn how immunological tolerance (central and peripheral) is induced against self antigens for maintaining normal health.

• To gain understanding of various factors contributing to the breakdown of immunological tolerance and development of autoimmunity.

• Gender predilection in autoimmunity is a well known phenomenon and is briefly described.

A condition that occurs when the immune system

mistakenly attacks and destroys healthy body tissue

Autoimmunity

AutoimmunityAutoimmunityImmune system has evolved to Immune system has evolved to discriminate discriminate

betweenbetween

Self and Non-selfSelf and Non-self

Tolerance to self is acquired by:Tolerance to self is acquired by:

A)A) DeletionDeletion (clonal deletion) (clonal deletion) OROR

B) B) Functional inactivationFunctional inactivation (clonal anergy) (clonal anergy) of developing lymphocytes that possess of developing lymphocytes that possess antigenic receptors with high affinity for antigenic receptors with high affinity for self-antigensself-antigens..

Mediated by auto-reactive T cells and auto-reactive B cells (auto-antibodies)

Educated T-cellAutoreactive cell

Central Tolerance

Peripheral Tolerance of T LymphocytesPeripheral Tolerance of T Lymphocytes

Autoreactive T-cells

blood barrier

Normal tissueSelf AgSelf Ag

Failure of Immune Tolerance

(Development of Autoimmunity)

Induction of Autoimmunity“Proposed Mechanisms!”

1.1.Sequestered antigensSequestered antigens2.2.Molecular mimicryMolecular mimicry3.3.Inappropriate class II MHC Inappropriate class II MHC

expression on none-expression on none-antigen presenting cellsantigen presenting cells

4.4.Polyclonal B cell activationPolyclonal B cell activation

1. Sequestered antigens

• Some self-antigens are sequestered Some self-antigens are sequestered (hidden) in specialized tissues.(hidden) in specialized tissues.

• These are These are not seen not seen by the developing by the developing immune system – will not induce self-immune system – will not induce self-tolerance.tolerance.

• Exposure of T cells to these normally Exposure of T cells to these normally sequestered/tissue-specific self-antigens sequestered/tissue-specific self-antigens in the periphery results in their activation.in the periphery results in their activation.

Examples of Examples of SequesteredSequestered Antigens Antigens

Myelin basic proteinMyelin basic protein (MBP), associated (MBP), associated with MSwith MS

Sperm-associated antigensSperm-associated antigens in some in some individuals following vasectomyindividuals following vasectomy

Lens and cornealLens and corneal proteins of the eye proteins of the eye following infection or traumafollowing infection or trauma

Heart muscle antigensHeart muscle antigens following following myocardial infarctionmyocardial infarction

• Viruses and bacteria possess antigenic Viruses and bacteria possess antigenic determinants that are very similar, or even determinants that are very similar, or even identical, to normal host cell components.identical, to normal host cell components.

• This phenomenon, known as This phenomenon, known as molecular molecular mimicrymimicry, occurs in a wide variety of , occurs in a wide variety of organisms.organisms.

• Molecular mimicry may be the Molecular mimicry may be the initiating step initiating step in a variety of autoimmune diseases.in a variety of autoimmune diseases.

2. Molecular Mimicry 2. Molecular Mimicry (Cross-reacting Antigens)(Cross-reacting Antigens)

Examples of Molecular MimicryExamples of Molecular Mimicry

3. Inappropriate Expression of3. Inappropriate Expression ofClass II MHC MoleculesClass II MHC Molecules

• Class II MHC ordinarily expressed Class II MHC ordinarily expressed on on antigen presenting cellsantigen presenting cells, such , such as macrophages, dendritic cells as macrophages, dendritic cells and B cells.and B cells.

• Abnormal expression of MHC Abnormal expression of MHC determinants allows the determinants allows the recognition of these auto-antigens recognition of these auto-antigens by self-reactive T cells.by self-reactive T cells.

Inappropriate Expression ofInappropriate Expression ofClass II MHC MoleculesClass II MHC Molecules

• This may occur due to the local This may occur due to the local production of production of IFN-IFN-, which is known , which is known to increase class II MHC expression to increase class II MHC expression on a variety of cells.on a variety of cells.

• The inducer of IFN-The inducer of IFN- under these under these circumstances could be a circumstances could be a viral viral infectioninfection..

Type I Diabetes: Pancreatic β cells express abnormally high levels of

MHC I and MHC II (?)

Normal Pancreas Pancreas with Insulitis

4. Polyclonal B Cell Activation4. Polyclonal B Cell Activation

Viruses and bacteriaViruses and bacteria can induce can induce nonspecific polyclonal nonspecific polyclonal B cellB cell activation, activation,

including:including:  

-- Certain gram negative bacteriaCertain gram negative bacteria-- Herpes simplex virus.Herpes simplex virus.-- CytomegalovirusCytomegalovirus-- Epstein Barr VirusEpstein Barr Virus-- Human immunodeficiency virus Human immunodeficiency virus

(HIV)(HIV)  

These viruses induce the These viruses induce the proliferation proliferation of numerous clones of B cellsof numerous clones of B cells to to secrete IgM in the absence of a secrete IgM in the absence of a requirement for CD4 T cell help.requirement for CD4 T cell help.

Polyclonal activation leads to the Polyclonal activation leads to the activation of self-reactive B cellsactivation of self-reactive B cells and and autoantibody production.autoantibody production.

Patients with Patients with infectious mononucleosis infectious mononucleosis (caused by EBV) and AIDS (HIV) have a (caused by EBV) and AIDS (HIV) have a variety of auto-antibodies.variety of auto-antibodies.

•Hormonal Factors– About 90% of autoimmune diseases

occur in women – cause not known– In animal models estrogen can induce

B cells to enhance formation of anti-DNA antibodies

– SLE either appears or exacerbates during pregnancy

Nature Immunology  2, 777 - 780 (2001)

Drug Induced Lupus Erythematosus

• Lupus erythematosus like syndrome develops inpatients receiving a variety of drugs such as– Hydralazine (used for hypertension), – Procainamide, – Isoniazid – Penicillin

• Many are associated with the development of anti-nuclear antibodies (ANAs)

• Renal and CNS involvement is uncommon

• Anti-histone antibodies are frequently present

Take home message

• Normal healthy state is maintained by immunological tolerance against self antigens at central and peripheral levels

• Autoimmune diseases result from the breakdown of immunological tolerance to self antigens

• Certain autoimmune diseases exhibit strong association with female gender

Thank you