AutoimmunityAutoimmunity

• Immune system has evolved to Immune system has evolved to discriminate between discriminate between selfself and and non-selfnon-self or discriminate or discriminate between between safesafe and and dangerousdangerous signals signals

• Ability developed during fetal Ability developed during fetal life, during the ontogeny of life, during the ontogeny of the immune systemthe immune system

• Termed Termed tolerancetolerance, a form of , a form of censorship of the immune systemcensorship of the immune system

• Deletion (Deletion (clonal deletionclonal deletion) or ) or functional inactivation (functional inactivation (clonal clonal anergyanergy) of developing ) of developing lymphocytes that possess lymphocytes that possess antigenic receptors with high antigenic receptors with high affinity for self-antigensaffinity for self-antigens

Central and Peripheral ToleranceCentral and Peripheral Tolerance

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

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

BB Cell Tolerance to Self AntigensCell Tolerance to Self Antigens

Developing B lymphocytes recognizing cell-associated self Developing B lymphocytes recognizing cell-associated self antigens are effectively deleted.antigens are effectively deleted.

Developing B lymphocytes recognizing soluble self antigens Developing B lymphocytes recognizing soluble self antigens are less efficiently deleted.are less efficiently deleted.

B Cell Tolerance to Self AntigensB Cell Tolerance to Self Antigens

Sequestered AntigensSequestered Antigens

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

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

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

These are not seen by the developing These are not seen 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 activationin the periphery results in their activation

Examples of Sequestered AntigensExamples of Sequestered Antigens

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

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

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

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

Autoimmune DiseasesAutoimmune DiseasesSelf-reactive lymphocytes (the Self-reactive lymphocytes (the forbidden forbidden clonesclones) should be eliminated from the ) should be eliminated from the immunological repertoireimmunological repertoire..

DDiseases involving an immunological response to iseases involving an immunological response to normal tissue – termed autoimmunity or autoimmune normal tissue – termed autoimmunity or autoimmune diseases.diseases.

Original concept – the receptors of Original concept – the receptors of lymphocytes with specificity for foreign lymphocytes with specificity for foreign antigens underwent mutation – results in a antigens underwent mutation – results in a new class of receptors with specificity new class of receptors with specificity for self-antigensfor self-antigens..It is now clear that autoantibodies and self-reactive T It is now clear that autoantibodies and self-reactive T cells are cells are normalnormal components of the immune repertoire components of the immune repertoire..

Autoimmunity with Diseases

Results from:

1- Mistake in selection of B cell and T cells

2- Broken tolerance3- Antibody, and T cell activation

against self antigens

The Spectrum of autoimmune Diseases

Hashimoto’s thyroiditis Pernicious anaemia Insulin dependent diabetes

Myasthenia gravis Multiple sclerosis

Ulcerative colitisRheumatoid arthritis

Systemic lupus erythematous

Systemic Organ specific

Pathology of Autoimmune DiseasesPathology of Autoimmune Diseases

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

Disease processes and tissue damage are due to Disease processes and tissue damage are due to Type IIType II and and Type IIIType III hypersensitivity reactions. hypersensitivity reactions.

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

Disease process and tissue damage due to Disease process and tissue damage due to Type IVType IV hypersensitivity reactionshypersensitivity reactions..

Autoimmune Diseases due toAutoimmune Diseases due toType II HypersensitivityType II Hypersensitivity

Autoimmune DiseasesA. Type II (Cytotoxic) Autoimmune Reactions

Involve antibody reactions to cell surface molecules, without cytotoxic destruction of cells.– Grave’s Disease:

• Antibodies attach to receptors on thyroid gland and stimulate production of thyroid hormone.

• Symptoms: Goiter (enlarged thyroid) and bulging eyes.

– Myasthenia gravis: • Progressive muscle weakness. Antibodies block

acetylcholine receptors at neuromuscular synapse.• Today most patients survive when treated with drugs

or immunosuppressants.

B. Type III (Immune Complex) Autoimmune Reactions– Systemic Lupus Erythematosus:

• Name derived from red skin rash on face. • Autoantibodies react against DNA, blood cells,

neurons, and other tissues. • When cells die, immune complexes form and deposit

under skin, joints, in kidneys, blood vessels, and central nervous system.

• Inflammation interferes with normal function of these sites (arthritis, rash, kidney damage).

• Most patients die from kidney damage.• No cure. Symptoms treated with anti-inflammatory

and immunosuppressive drugs.

Type III (Immune Complex) Autoimmune Reactions (Continued)– Rheumatoid Arthritis:

• Cause unknown, but microbial mimicry may be involved.

• IgM autoantibodies (rheumatoid factors) against IgG form complexes in joint, leading to inflammation and cartilage damage.

• Often causes finger and joint deformities.• No cure. Symptoms treated with anti-inflammatory

(aspirin) and immunosuppressive drugs. Physical therapy keeps joints movable. Surgical replacement of joints may be necessary.

Rheumatoid ArthritisMorning stiffness, joint swelling, subcutaneous rheumatic nodes,

Auto antibodies.Associated with HLA-DR4.Molecular mimicry with bacterial antigen

T cells found to react with auto-antigen

IgM auto-antibodiesAnti nuclear antibodies

C. Type IV (Cell-Mediated) Autoimmune Reactions (Continued)

– Insulin-dependent (Type I or Juvenile) Diabetes Mellitus:

Makes up 10% of diabetes cases. Characterized by insufficient insulin production due to immunological destruction of insulin-secreting cells of the pancreas by T cells. Usually develops before the age of 15. Treated with insulin injections.

• Symptoms: Hyperglycemia, abnormal Hunger, increased thirst, Polyuria, and glycosuria

• Immune component: Antibody against insulin, and glutamic acid decorboxylase (GADD)

• Cellular infiltrates of CD4+ and CD8 + T cells

• Inflammatory cytokines in lessons.

• Rota virus, Coxsackie virus

Multiple Sclerosis: Demyelinating disease, early sign neuritis

Immune component: Myelin specific antibodies in cerebral fluidAntibody dependent cellular cytotoxicity in tissue damage

CD4 +T cell mediated diseaseTh1 cytokines are associated with disease, Th2 cytokines are protective. Broken tolerance in APC by infectionEpitope spreading

corona virus detected in serum of MS patients.

Proposed Mechanisms of AutoimmunityProposed Mechanisms of Autoimmunity