AUTOIMMUNITY

TEACHING OBJECTIVES 1. Understand the concept and significance of tolerance 2. Understand the concepts of autoimmunity and disease 3. Know the features of major autoimmune diseases 4. Know the theories on etiology of autoimmune diseases

Tolerance The absence of specific immune response to a particular antigen in a fully immunocompetent person. Tolerance is a mechanism which the immune system can learn Unresponsiveness to self antigens is known as autotolerance.

Tolerance to self antigens We normally do not mount a strong immune response against our own (self) antigens, a phenomenon called self-tolerance

Mechanisms of self-tolerance Tolerance is generated at 2 levels : Central tolerance which develops primarily in fetal life & occurs in primary lymphoid organs (the bone marrow & the thymus) Peripheral tolerance which develop post-natally to deal with self-reactive cells in the periphery that have escaped central tolerance.

Central tolerance During development in primary lymphoid organs , immature B & T lymphocytes that encounter , recognize and interact with high affinity with self antigens are deleted by apoptosis (clonal deletion). This process is called negative selection and ensures that self reactive B & T cells are removed from the immune cell repertoire before entering the periphery.

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Peripheral tolerance Self reactive B & T lymphocytes that have escaped central tolerance encounter several checkpoints in the periphery to prevent their activation. Several mechanisms are involved in this process : 1-Anergy : a state of metabolic arrest. It occurs when a lymphocytes recieves an antigenic signal in the absence of costimulation.

. 2-Ignorance : Tcells that escape deletion & migrate to the periphery ,may never encounter the appropriate Ag (sequestered Ag in inaccessible tissue). 3-Regulation : Subset of T cells(regulatory Tcells) inhibit the effector functions of other lymphocytes e.g.,self reactive cells.Suppression can occur through inhibitory cytokines (TGF-B , IL-10).

I 4-Homeostatic control   I 4-Homeostatic control Due to Lack of T-cells help for autoreactive B cells. As a result , autoreactive B cells do not get stimulated. If the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops.

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AUTOIMMUNITY A condition in which structural or functional damage is produced by the action of immunologically competent cells or Abs against the normal components of the body.

Autoimmunity Origins Horror autotoxicus: Literally, the horror of self-toxicity. A term coined by the German immunologist Paul Ehrlich (1854-1915) to describe the body's innate aversion to immunological self-destruction.

Features Of Autoimmune Diseases An elevated level of Igs. Deposition of Igs or their derivatives at particular sites like glomeruli. Accumulation of lymphocytes & plasma cells at the site of lesion. Benefit from corticosteroid or other immunosuppressive therapy. Genetic predisposition.

Features Of Autoimmune Diseases Occurrence of more than one type of autoimmune disorders in an individual. Higher incidence among females. Usually non-reversible (chronic) Predisposing factors Familial history. Certain HLA haplotypes - Rheumatoid Arthritis - HLA DR4

Mechanisms Of Autoimmunisation Molecular mimicry - Cross reacting foreign Ags Polyclonal B cell activation Breakdown of immunological homeostasis (tolerance) Sequestered Ags

1 .Molecular Mimicry Due to the presence of cross reacting Ags - Presence of epitopes with identical peptide sequences in some infecting micro-organisms & self Ags. e.g * Following streptococcal infection – Streptococcal M proteins and the heart muscle.

Rheumatic fever is a classic example of molecular mimicry

2. Polyclonal B-cell Activation Non-specific activation of multiple B cell clones by certain stimuli like * Chemicals - 2-mercaptoethanol * Bacterial products – PPD(purified protein derivative, LPS(LIPOPOLYSACCHARIDE) * Enzymes - trypsin * Antibiotics - nystatin * Micro-organisms - Mycoplasma, EBV, malaria Multiple non-specific Abs are formed during such conditions.

3. Breakdown Of Immunological Homeostasis Cessation of tolerance to self Ag. Enhanced helper T-cell and decreased suppressor T-cell functions

4. Release of Sequestered Ags Sequestered Ags - Certain Ags are present in closed systems (compartments) and are not accessible to the immune apparatus. e.g * Lens protein of the eye is enclosed in its capsule & does not circulate.

Dr Ekta, Microbiology

Localised Autoimmune Diseases AUTOIMMUNE DISEASES OF THE THYROID GLAND A. Hashimoto’s thyroiditis.

Localised Autoimmune Diseases AUTOIMMUNE DISEASES OF THE THYROID GLAND B. Thyrotoxicosis (Grave’s disease) - Abs against thyroglobulin

Localised Autoimmune Diseases ADDISONS’S DISEASE * antibodies to the cells of Zona Glomerulosa layer of adrenal glands Dr Ekta, Microbiology

Localised Autoimmune Diseases PERNICIOUS ANAEMIA 2 types of auto-antibodies are present - * against the parietal cells of the gastric mucosa - Atrophic gastritis, Achlorhydria. * Ab against the intrinsic factor – prevents Vit.B12 absorption.

Diabetes mellitus type-1 Localised Autoimmune Diseases Diabetes mellitus type-1 - Also called Insulin dependent diabetes or Juvenile diabetes. -Autoimmune destruction of insulin-producing (beta cells) of the pancreas -Results in total insulin deficiency. -Affects 1 in 300 children and more adults. 4

Pathophysiology: Triggers Molecular mimicry: similar epitopes between pathogen and host. -Viruses can produce proteins similar to those of the host. -Immune cells present viral protein homologous to self protein. Failure of tolerance and autoimmunity. Injury to Islet cells: macrophages provoke insulitis by release of interleukin. - HGAD65: auto antigen Coxsackie & hCMV: Viral peptides 3 3

Localised Autoimmune Diseases AUTOIMMUNE DISEASES OF THE SKIN * Pemphigus vulgaris – blistering disease of the skin - Abs to desmosomes, results in breakdown of epithelial cells AUTOIMMUNE ORCHITIS * Lymphocytic infiltration of testes and circulating Abs to the sperms & germinal cells * Follows mumps orchitis

Systemic Autoimmune Diseases Immune response to a variety of self-Ags Damage to several organs & tissue systems. Includes – SLE (systemic lupus erythematosus) RA (rheumatoid arthritis) Polyarteritis nodosa Sjogren’s syndrome

SLE Chronic , multisystem disease Auto-antibodies against cell nuclei, intra-cytoplasmic constituents, Igs & other organ-specific Ags. Extensive immune complex-mediated inflammatory lesions affecting Kidneys, Joints, Skin, Serous membrane and Lungs Women are more affected (80%), usually those of childbearing age HLA-DR2 or DR3 are predisposed to SLE Diagnosis: Antinuclear Ab - immunofluorescence Anti-DNA Ab (RIA/ ELISA)

Rheumatoid Arthritis (RA) Symmetric polyarthritis with muscle wasting and subcutaneous nodules. Associated with myocarditis, vasculitis & other disseminated lesions. Presence of a circulating auto Ab called Rheumatoid Factor (RF) RF- IgM directed against one’s own IgG Diagnosis : Latex agglutination test ( RF,CRP),ANTI-CCP(Anti-cyclic citrullinated peptide)

Sjogren’s Syndrome Triad of conjunctivitis sicca, dryness of the mouth with or without salivary gland enlargement, May occur along with other collagen diseases.

Diagnosis Diagnosis of autoimmune diseases is based on symptoms and detection of antibodies (and/or very early T cells) reactive against antigens of tissues and cells involved

Diagnosis……… Antibodies against cell/tissue associated antigens are detected by immunofluorescence Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay

Treatment The goals of treatment of autoimmune disorders are to reduce symptoms and control the autoimmune response while maintaining the body's ability to fight infections. Treatments vary widely and depend on the specific disease and symptoms

Treatment……… Anti-inflammatory (corticosteroid) and immunosuppressive drug therapy (such as cyclophosphamide, azathioprine, cyclosporine ) is the present method of treating autoimmune diseases.

Treatment…….. Extensive research is being carried out to develop innovative treatments which include: anti-TNF alpha therapy against arthritis, feeding antigen orally to trigger tolerance, anti-idiotype antibodies,, anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc.