Lecture 11 MECHANISMS OF AUTOIMMUNITY 20072008 Jan eromski

Lecture 11 MECHANISMS OF AUTOIMMUNITY 2007/2008 Jan Żeromski

POINTS TO BE DISCUSSED • Autoimmunity versus autoimmune disease • Features of autoimmune disease (AD) • Organ-specific and non organ-specific AD • Experimental animal models • Genetic background of AD • Effects of environment on the induction of AD • Cellular mechanisms and treatment of AD

AUTOIMMUNITY VS. AUTOIMMUNE DISEASE Autoimmunity • Existence of harmless self-reactive lymphocytes and antibodies • Potentially reversible • Incidence higher in older age • Significance unclear, possibly physiological Autoimmune disease • Dependent on genetic viral and hormonal factors • Features of severe tissue damage • Clinical symptoms • Protracted course but usually fatal • Familiar clustering

AUTOIMMUNE DISEASE – KEY CONCEPTS • Recognition of autoantigens by lymphocytes is critical • Tissue destruction not just autoimmune cells must be present • AD involve self-reactive T cells • AD induction almost always depends on triggering of autoreactive CD 4+ T cells

MECHANISMS OF BREAKING OF SELF-TOLERANCE • Disruption of self or tissue barrier • Infection of antigen presenting cell • Binding of pathogen to self antigen • Molecular mimicry • superantigen

EXAMPLES 0 F ORGAN-SPECIFIC AND NON ORGAN-SPECIFIC (SYSTEMIC) AUTOIMMUNE DISEASES Organ-specific • Hashimoto thyroiditis • Thyrotoxicosis • Addison’s disease • Atrophic gastritis • Juvenile diabetes mellitus • Multiple sclerosis Non organ-specific • Systemic lupus (SLE) • Rheumatoid arthritis (RA) • Scleroderma • Dermatomyositis • Mixed connective tissue disease (MCTD) • Sjögren’s syndrome

ORGAN-SPECIFIC AND NON ORGANSPECIFIC AUTOIMMUNE DISEASES Organ-specific Non organ- specific (systemic) • Autoimmune attack vs. • Widespread self-antigens are targets for self-antigens of given autoimmune attack organ • It results in a damage of • Damage affects such structures as blood organ structure and vessels, cell nuclei etc. function • Treatment is focused on • Treatment is aimed to inhibit excessive the replacement of activation of the immune organ function system

EXPERIMENTAL ANIMAL MODELS OF AUTOIMMUNE DISEASES Three categories: 1. Spontaneously occurring AD (systemic lupus in New Zealand mice ([NZBx. NZW]F 1) 2. Diseases induced by exogenous action such as immunization (experimental allergic encephalomyelitis – EAE, CIA, EAU) 3. Diseases due to genetic manipulation such as in knockout (IL-2, Fas) or transgenic (bcl-2, HLA-B 27) animals (SLE, RA, IBD)

AUTOREACTIVE T CELLS ARE PRESENT IN LYMPHOID TISSUES AND BLOOD • • • Central tolerance does not delete T cells autoreactive to organ-sequestered antigens and cryptic epitopes Subset of these T cells are potentially pathogenic These T cells must be kept tolerant by: a. b. c. d. elimination maintenance of immunologic ignorance functional inactivation (anergy) suppression

AD ARE COMPLEX GENETIC TRAITS • Multiple genes determine susceptibility to AD • No particular gene is necessary or sufficient for disease expression (relatively low gene penetrance) • MHC and multiple non-MHC genes are involved • Epistasis (interaction of susceptibility genes) • Genetic alleles increasing susceptibility are relatively frequent in the general population

EXAMPLES OF GENE DEFECTS IN AUTOIMMUNITY • Multiple sclerosis – particular alleles of HLA-DR (DRB 1*1501, DRB 5*0101) • Systemic lupus – lack of C 1 q and C 4 • Genetically determined low expression of given self-antigen in the thymus • Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)

IMPACT OF ENVIRONMENTAL TRIGGERS ON INDUCTION OF AD • Virus clustering (RA, Sjögren’s s. , SLE, MS) • Infectious microorganisms (molecular mimicry – see later) • Geographic clustering • Sun exposure (SLE) • Exogenous estrogens, sex hormones in general

MOLECULAR MIMICRY Definition: Determinants of infectious agent mimic a host antigen and trigger self-reactive T-cell clones to attack host tissues. Examples: Stromal keratitis due to herpes simplex virus type I Rheumatic fever due to group A streptococcus SLE due Epstein-Barr virus cross reactive with nuclear Sm antigen Lyme artrhritis due Borrelia burgdorferi reactive with LFA-1 (lymphocyte function antigen-1)

EPITOPE SPREADING • Definition: Initial response to one self determinant (one peptide) could expand to involve additional determinants on the same molecule as well as additional self-proteins. It explains how a response to one cryptic epitope can mature into a full-blown autoimmune response • Examples: – anti-Sm to U 1 RNP – anti Ro/SS-A to anti-La/SS-B – lead to lupus-like disease

HLA CLASS II EXPRESSION ON TISSUE CELLS IN AUTOIMMUNE DISEASES • Hashimoto thyroiditis – follicular cells of the thyroid • Type I diabetetes – beta cells of Langerhans islets • Primary biliary cirrhosis – cells of billiary ducts • Autoimmune hepatitis – hepatocytes

HLA CLASS II EXPRESSION ON TISSUE CELLS IN AUTOIMMUNE DISEASES - 2 • Rheumatoid arthritis – synovial cells • Sjogren’ syndrome –epithelium of salivary ducts • Multiple sclerosis – glial cells • Chronic iridoscleritis – pigment epithelium of retina • Crohn’s disease – epithelium of small intestine

OTHER FACTORS FAVORING AUTOIMMUNITY 1. Overproduction and/or dysregulation of cytokines 2. Disturbances of apoptosis 3. Adjuvant effect of microorganisms 4. Pre-existing defects in the target organ 5. Direct stimulation of autoreactive cells by foreign antigen

PATHOGENICITY OF HUMAN AUTOANTIBODIES • • Autoimmune blood dyscrasias Antiphospholipid syndrome Myasthenia gravis Thyrotoxicosis (Graves disease) Male infertility Anti-receptor mediated diabetes mellitus Goodpasture’s syndrome Immune complexes (SLE, RA)

DIAGNOSTIC STEPS IN SYSTEMIC LUPUS • • Immunoglobulin level (↑ >90%) Complement components level (↓ 60%) Anti-nuclear antibodies(ANA)(1: 80< 95%) Anti-ds DNA Ab (90 -95%) Rheumatoid factor (30%) Immune complex deposits in the skin(60%) „ „ „ in kidney (90%)

THERAPY OF AUTOIMMUNE DISEASES: I. SELF-ANTIGEN SPECIFIC 1. Antibodies vs. autoreactive TCR 2. Vaccine containing autoreactive TCR 3. Administration of peptides – TCR antagonists 4. Parenteral infusion of autoantigen or c. DNA 5. Oral administration of autoantigen Comment: all above are at the stage of experiment

THERAPY OF AUTOIMMUNE DISEASES: II. ANTIGEN NON-SPECIFIC 1. Monoclonal antibodies vs. T cells -CD 2, CD 3, CD 4 2. Antibodies vs. CD 28, CD 40 L (modulation of T cell – APC interaction) 3. Antibodies vs. cell adhesion molecules (VLA-4, ICAM-1) and chemokines 4. Intravenous infusion of immunoglobulin (IVIG) 5. Neutralization of proinflammatory cytokines 6. Administration of anti-inflammatory cytokines

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