AUTOIMMUNITY- I

Autoimmunity Part-1 a. Define and classify autoimmunity At the end of the session the student should be able to: a. Define and classify autoimmunity b. Explain Immunological tolerance c. Discuss the mechanism of autoimmunity Suggested readings: Robbins’s basic pathology, 8th edition.

I. Autoimmune disease Definition is a problem of Self/Non-self Discrimination Autoimmune disease - an immune reaction against “self-antigens”: Failure of SELF RECOGNITION Failure of SELF TOLERANCE can be single organ or multisystem diseases. can be more than one autoantibody in a given disease.” Just like we said “EVERY disease is a genetic disease”, we can also say “EVERY disease is an ‘immune’ disease

Autoimmunity Frequently in women (2\3 of cases) vs men. Left handed vs Right handed. Secondary to certain diseases? More than 40 human diseases autoimmune in origin. “true” autoimmunity, difficult to ascertained. Autoimmunity- considered as grouped under immune-mediated inflammatory diseases. This indicate the role of chronic inflammation in autoimmunity Pathogenesis.

Autoimmune diseases Classification immune-mediated inflammatory diseases classify as follow: 1) Diseases mediated by antibodies and immune complexes: - Organ specific - Non-organ specific (multi-organs) 2) Diseases mediated by T cells:

II. Autoimmune disease Classification Immune-mediated inflammatory diseases divided: Diseases mediated by antibodies and immune complexes a) Organ specific autoimmune: Autoimmune hemolytic anemia Myasthenia gravis Graves’ disease. Goodpasture syndrome. b) Systemic “Non organ specific” autoimmune: SLE c) Disease cause by reaction to microbial Ag - Polyarteritis nodosa

II. Autoimmune disease Classification Second: Diseases mediated by T cells a) Organ-specific autoimmune diseases DM- type-1 Multiple sclerosis. b) Systemic autoimmune diseases SLE Rheumatoid arthritis. Sjogren syndrome. c) Diseases caused by autoimmunity or by reactions to microbial antigens - Inflammatory myopathies - inflammatory bowel disease

Autoimmunity Part-1 a. Define and classify autoimmunity At the end of the session the student should be able to: a. Define and classify autoimmunity b. Explain Immunological tolerance c. Discuss the mechanism of autoimmunity Suggested readings: Robbins’s basic pathology, 8th edition.

Immunological “self” tolerance Definition: Lack of immune responsiveness to an individual’s own tissue antigens. Mechanism of self tolerance: Classified into Tow types: I. CENTRAL tolerance- (Thymus- T cells and BM: B cells). II. Peripheral tolerance- (Secondary lymphoid tissue, sites of inflammation)

Immunological “self” tolerance I. CENTRAL tolerance: defined as negative selection or deletion process Goal: elimination of self-reactive T,B cells. Mechanism: 1- Deletion of self-reactive T & B lymphocytes during their maturation in central lymphoid tissues(Thymus: T cells and BM: B cells). 2- Any self reactive cells undergoes apoptosis & death. 3- Escape cells >> peripheral tolerance. .

Immunological “self” tolerance II. PERIPHERAL tolerance: definition: handling of escape cells “central control” Role: suppression of B&T cells in peripheral tissue. Mechanisms: several mechanisms 1) Anergy – lack of co-stimulatory. 2) Peripheral Suppression - regulated by CD4 T cell 3) Deletion- post-activation induced cell death.

Immunological “self” tolerance II. PERIPHERAL tolerance- Mechanisms: Anergy -prolonged irreversible functional inactivation T-cell activation requires 2 signals. Absence of second signal (from antigen presenting cells) leads to anergy. 2) Peripheral Suppression by regulatory T -CD4 cells:- Regulatory T-cells can modulate the function of other cells. Certain cytokines elaborated from these cells e.g. IL 10, TGF beta, can affect T-cell responses. 3) Deletion (peripheral deletion) : post-activation induced cell death – apoptosis of autoreactive lymphocyte.

Autoimmunity Part-1 a. Define and classify autoimmunity At the end of the session the student should be able to: a. Define and classify autoimmunity b. Explain Immunological tolerance c. Discuss the mechanism of autoimmunity Suggested readings: Robbins’s basic pathology, 8th edition.

III. The mechanism of autoimmunity: define as Loss of self-tolerance= breakdown of tolerance Predisposition of most autoimmune diseases is due to combined effect of: 1) Combination of the inheritance of susceptibility genes. (single or multiple) . 2) Immune regulation machines- persistence and uncontrolled activation of self-reactive lymphocytes (Defective elimination\ escape tolerance \ production of antinuclear autoantibodies\ failur of clearning Imm.complex) 3) Environmental factors (tissue damage, infections, hormone, trauma, drug, radiation etc..)

Autoimmunity: Part 2 At the end of the session the student should be able to: a. List the Genetic factors in autoimmunity b. Discuss the Role of infections and tissue injury. Suggested readings: Robbins basic pathology, 8th edition. Page:138 – 139

Mechanisms of autoimmunity Genetic factors - Antigen generated by molecular changes. Infection factors. - Molecular mimicry. - Ag released from hidden location. Enviromental factors - Hormonal - Radiation, trauma, others…. We deeply covered the first two????

1) Role of Genes Susceptibility-1 HLA genes “disease-associated alleles”: b) Non-HLA gene defects c) Single gene defect

1) Role of Genes Susceptibility-1 HLA genes “disease-associated alleles”: Important genes that regulate the development of autoimmunity are located within MHC. MHC have got critical role in{ maturation of T cell} & {induction of Immune response}. MHC ll genes are responsible for auto-antigen processing and presentation. Examples: (HLA: B27, DR2,DR3,DR3\4)- SLE: DLA- A7- mechanism remain obscure

Role of Genes Susceptibility- 2. III Role of Genes Susceptibility- 2. III. The mechanism of autoimmunity- Loss of self-tolerance= breakdown of tolerance a) HLA genes “disease-associated alleles” (cont.): Mechanism: remain obscure but postulated that presence of MHC alleles defects are lead to b) Non-HLA genes: recent Family & Twins studies- reveals multiple disorders specially gene defect proved to be among monozygotic greater than > 4 times in dizygotic twins. – three recent examples.........................................cont.) 1) Affects the negative selection of T cells in the thymus . 2) Affect the development of regulatory T cells.

Role of Genes Susceptibility-3. III Role of Genes Susceptibility-3. III. The mechanism of autoimmunity- Loss of self-tolerance= breakdown of tolerance b) Non-HLA genes (cont.) Recent examples: 1- Polymorphisms in a gene called PTPN-22 (most frequently implicated with AD, a\w RA & type 1 DM. 2- Polymorphisms in the gene for NOD-2 (NOD-2 is a cytoplasmic sensor of microbes) , a\w Crohn disease. Mechanism : defect in encoded phosphatase > defect in control of tyrosine kinases activity>defect of lymphocyte responses>> excessive activation Mechanism : NOD-2 defect>> ineffective at sensing intestinal microbes>> entry of microbes>> chronic inflammatory responses against well-tolerated commensal bacteria

Role of Genes Susceptibility-4 c) Single gene mutation (rare in AD): A few number of autoimmune diseases caused by single gene defect e.g.: ( AIRE= Defect in central tolerance and IL2 and its receptor D25) Diseases example: multiple sclerosis, & other OUTCOME> These cytokines may control the maintenance of regulatory T cells

2) Role of infection: mechanisms postulated: I. up-regulate the expression of co-stimulators on APCs >> (via drugs, microorganisms) II. Molecular mimicry: Some microbes may express Ags that have the same amino acid sequences as self-antigens e.g. RHD with post- throat streptococcal infection. III. Some viruses, such as (EBV)& (HIV), cause polyclonal B-cell activation, which may result in production of autoantibodies.

2) Role of Infection (cont.): IV. Infection induce tissue injury> release hidden Ag: Tissue injury release “Emergence of sequestered antigen-= previously unscreened self Ag” - lead to “not tolerant” T cell activation. V. Cytokines-induced by Infections- that recruit lymphocytes, including potentially self-reactive lymphocytes, to sites of self-antigens. Pathogenesis of autoimmunity. Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (inflammation, other inflammatory stimuli) that promote lymphocyte entry into tissues, activation of lymphocytes, and tissue injury.

Ag related from hidden location 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

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