1. MECHANISMS OF AUTOIMMUNITY Lecture 11 2007/2008 Jan Żeromski

2. 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

3. AUTOIMMUNITY VS. AUTOIMMUNE DISEASE Autoimmunity Existence of harm- less 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

4. 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 CD4 + T cells

5. 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

6. EXAMPLES 0F 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

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

8. EXPERIMENTAL ANIMAL MODELS OF AUTOIMMUNE DISEASES Three categories: 1.Spontaneously occurring AD (systemic lupus in New Zealand mice ([NZBxNZW]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-B27) animals(SLE, RA, IBD)

9. 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.elimination b.maintenance of immunologic ignorance c.functional inactivation (anergy) d.suppression

10. 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

11. EXAMPLES OF GENE DEFECTS IN AUTOIMMUNITY Multiple sclerosis – particular alleles of HLA-DR (DRB1*1501, DRB5*0101) Systemic lupus – lack of C1q and C4 Genetically determined low expression of given self-antigen in the thymus Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)

12. 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

13. 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)

14. 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 U1RNP –anti Ro/SS-A to anti-La/SS-B – lead to lupus-like disease

15. 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

16. 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

17. 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

18. 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)

19. 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%)

20. 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 cDNA 5.Oral administration of autoantigen Comment: all above are at the stage of experiment

21. THERAPY OF AUTOIMMUNE DISEASES: II. ANTIGEN NON-SPECIFIC 1.Monoclonal antibodies vs.T cells -CD2, CD3, CD4 2.Antibodies vs. CD28, CD40L (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

22. THANK YOU & GOOD LUCK !