The Molecular Basis for Autoimmune Diseases Dr. Adel Almogren Dept of Pathology, Immunology unit Email: [email protected] [email protected] Office:

The Molecular Basis forThe Molecular Basis forAutoimmune DiseasesAutoimmune Diseases

Dr. Adel AlmogrenDr. Adel AlmogrenDept of Pathology, Immunology unitDept of Pathology, Immunology unit

Email: Email: [email protected]: 467-1843Office: 467-1843

AutoimmunityAutoimmunity

Immune system has evolved to Immune system has evolved to discriminate between discriminate between selfself and and nonselfnonself

oror safesafe and and dangerousdangerous signals signals

Ability developed during fetal lifeAbility developed during fetal life

ToleranceTolerance, a form of censorship of the immune system, is acquired by, a form of censorship of the immune system, is acquired by

A)A) Deletion (clonal deletion) Deletion (clonal deletion) OROR

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

Central and Peripheral ToleranceCentral and Peripheral Tolerance

(Absence of(Absence ofCo-stimulation)Co-stimulation)

(Absence of(Absence ofCo-stimulation)Co-stimulation)

Peripheral Tolerance ofPeripheral Tolerance ofT LymphocytesT Lymphocytes

Peripheral B cell Tolerance Mechanisms

Autoimmune DiseasesAutoimmune Diseases

Self-reactive lymphocytes (the Self-reactive lymphocytes (the forbidden clonesforbidden clones) should be ) should be eliminated from the immunological repertoire.eliminated from the immunological repertoire.

DDiseases involving an immunological response to normal tissue – termed iseases involving an immunological response to normal tissue – termed

autoimmunity or autoimmune diseases.autoimmunity or autoimmune diseases.

Original concept – the receptors of lymphocytes with specificity for Original concept – the receptors of lymphocytes with specificity for foreign antigens underwent mutation – results in a new class of foreign antigens underwent mutation – results in a new class of

receptors with specificity for self-antigens.receptors with specificity for self-antigens.  

Autoimmune Diseases in HumansAutoimmune Diseases in Humans

Pathology of Autoimmune DiseasesPathology of Autoimmune Diseases

Most of the autoimmune diseases attributed to Most of the autoimmune diseases attributed to autoantibodiesautoantibodies..

Other autoimmune diseases have an Other autoimmune diseases have an autoreactive T autoreactive T cell componentcell component..

Disease processes and tissue damage are due to Disease processes and tissue damage are due to Type IIType II Type III and Type IVType III and Type IV hypersensitivity hypersensitivity

reactions.reactions.

Type II HypersensitivityType II HypersensitivityAutoimmunityAutoimmunity

Autoimmune Diseases due toAutoimmune Diseases due toType II HypersensitivityType II Hypersensitivity

Type III HypersensitivityType III HypersensitivityAutoimmunityAutoimmunity

Autoimmune Diseases due toAutoimmune Diseases due toType III HypersensitivityType III Hypersensitivity

Type IV HypersensitivityType IV Hypersensitivity

Autoimmune Diseases due toAutoimmune Diseases due toType IV HypersensitivityType IV Hypersensitivity

Organ specific AI diseases:

(mediated by direct cellular damage)

a) Hashimoto thyroiditis: Autoabs & T DTH

b) Autoimmune Anaemia: Pernicious A, A hemolytic A, Drug—induced A.

c) Goodpasture’s syndrome

d) Insulin dep. DM (IDDM)

the second category is:

(mediated by stimulating or blocking autoantibodies)

1) Graves’ disease

2) Myasthenia gravis

Grave’s Disease•Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH)•The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine•A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid•The auto-antibodies are called long-acting thyroid stimulating hormones

Myasthenia gravis

Motor end-plates of muscles

Systemic AI diseases :I. SLE

SLE patient

II. Multiple sclerosis: affects CNS. autoreactive T cells– myelin sheath of nerve fibers

Individuals with the DR2&DR3 variant of MHC genes are most susceptible to the disease.

Individuals with the DR2&DR3 variant of MHC genes are most susceptible to the disease.

Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes.

This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.

Rheumatoid arthritis (RA) affects peripheral joints and may cause destruction of both cartilage and bone. The disease affects mainly individuals carrying the DR4 variant of MHC genes.

This fact can lead to better prognoses and in aiding efforts to change immune reactions that involve the DR4 variant while leaving other reactions intact.

III. RA

Proposed Mechanisms ofProposed Mechanisms ofAutoimmunityAutoimmunity

Release of Sequestered AntigensRelease of Sequestered Antigens

Induction of tolerance in self-reactive T cells occurs through the exposure of immature T cells Induction of tolerance in self-reactive T cells occurs through the exposure of immature T cells to self-antigens in the thymus.to self-antigens in the thymus.

The elimination/silencing of all self-reactive T cells requires that all self-antigens be presented The elimination/silencing of all self-reactive T cells requires that all self-antigens be presented within the thymic environment.within the thymic environment.

Some self-antigens are sequestered in specialized tissues and may not be expressed in the Some self-antigens are sequestered in specialized tissues and may not be expressed in the thymus.thymus.

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

Exposure of T cells to these normally sequestered/tissue-specific self-antigens in the Exposure of T cells to these normally sequestered/tissue-specific self-antigens in the

periphery results in their activation.periphery results in their activation.

Examples of Sequestered AntigensExamples of Sequestered Antigens

Myelin basic protein (MBP), associated Myelin basic protein (MBP), associated with MS.with MS.

Sperm-associated antigens in some Sperm-associated antigens in some individuals following vasectomy.individuals following vasectomy.

Lens and corneal proteins of the eye Lens and corneal proteins of the eye following infection or trauma.following infection or trauma.

Heart muscle antigens following Heart muscle antigens following myocardial infarction.myocardial infarction.

Cross-reacting AntigensCross-reacting Antigens(Molecular Mimicry)(Molecular Mimicry)

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

This phenomenon, known as This phenomenon, known as molecular mimicrymolecular mimicry, occurs in a wide , occurs in a wide variety of organisms.variety of organisms.

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

Examples of Molecular MimicryExamples of Molecular Mimicry

Inappropriate Expression ofInappropriate Expression ofClass II MHC MoleculesClass II MHC Molecules

The elimination of self-reactive T cells involves contact with APC presenting The elimination of self-reactive T cells involves contact with APC presenting self-peptides within the thymic environment.self-peptides within the thymic environment.Results in deletion or functional inactivation.Results in deletion or functional inactivation.

Highly tissue specific proteins not expressed within the thymus, do not induce Highly tissue specific proteins not expressed within the thymus, do not induce clonal deletion or tolerance.clonal deletion or tolerance.

T cells will not respond in the periphery if the tissue expressing these specific T cells will not respond in the periphery if the tissue expressing these specific proteins does not express class II MHC molecules.proteins does not express class II MHC molecules.

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

The aberrant expression of MHC determinants allows the recognition of these The aberrant expression of MHC determinants allows the recognition of these autoantigens by self-reactive T cells.autoantigens by self-reactive T cells.

Results from the local production of IFN-Results from the local production of IFN-, which is known to increase class II , which is known to increase class II MHC expression on a variety of cells.MHC expression on a variety of cells.

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

Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II (?)

MHC II – APC only! This may hypersensitize TH cells to β cell peptides.

Normal Pancreas Pancreas with Insulitis

Polyclonal B Cell ActivationPolyclonal B Cell Activation

Viruses and bacteria can induce nonspecific polyclonal B cell Viruses and bacteria can induce nonspecific polyclonal B cell activation, includingactivation, including::

  Certain gram negative bacteriaCertain gram negative bacteria

Herpes simplex virus.Herpes simplex virus.CytomegalovirusCytomegalovirus

Epstein Barr VirusEpstein Barr VirusHuman immunodeficiency virus (HIV)Human immunodeficiency virus (HIV)

  Induce the proliferation of numerous clones of B cells to secrete IgM in the Induce the proliferation of numerous clones of B cells to secrete IgM in the

absence of a requirement for CD4 T cell help.absence of a requirement for CD4 T cell help.Polyclonal activation leads to the activation of self-reactive B cells and Polyclonal activation leads to the activation of self-reactive B cells and

autoantibody production.autoantibody production.Patients with mononucleosis (caused by EBV) and AIDS (HIV) have a Patients with mononucleosis (caused by EBV) and AIDS (HIV) have a

variety of autoantibodies.variety of autoantibodies.