Autoimmunity

1. Autoimmunity Dr. Mohammad Odibate

2. Definition Autoimmunity : • Is the failure of an organism in recognizing its own constituent parts as non self, which allows an immune response against its own cells and tissues. • Any disease that results from such an aberrant immune response is termed an autoimmune disease. Autoimmunity is a problem of self/non-self discrimination

3. Definition Autoimmune Diseases: • A Group of 60 to 80 chronic inflammatory diseases with genetic predisposition and environmental modulation. • Prevalence of 5% to 8% in US. • Prevalence is greater for females than males • 75% of cases. • 4th largest disease class in women.

4. Disorders of the Immune System Immunodeficiency: Too Little Hypersensitivity: Too much Autoimmunity: Misdirected

5. Effects of autoimmunity • Tissue destruction • Diabetes: CTLs destroy insulin-producing b-cells in pancreas • 2. Antibodies block normal function • Myasthenia gravis: Ab binds acetylcholine receptors • 3. Antibodies stimulate inappropriate function • Graves’ disease: Ab binds TSH receptor. Activates unregulated thyroid hormone production • 4. Antigen-antibody complexes affect function • Rheumatoid arthritis: IgM specific for Fc portion of IgG. IgM-IgG complexes deposited in joints inflammation

6. Mechanisms of autoimmunity • Ag released from hidden (sequestered) location. • Molecular mimicry. • Infection. • Genetic factors. • Lymphocytes abnormalities. • Failure of central tolerance.

7. Mechanisms of autoimmunity • Ag released from hidden (sequestered) location: Many self Ag are found in hidden location eg. CNS ,testes, eye (cornea) Organ damage Hidden Ag released Reaches blood stream Encounter Ag sensitive cells Stimulate autoimmunity

8. Mechanisms of autoimmunity • Ag released from hidden (sequestered) location: • Smoking: • Can trigger Goodpasture’s syndrome. • Alveolar basement membrane normally not exposed to immune system • Smoking damages alveoli, exposes collagen • Anti-collagen Ag damages lung and kidney B. Anti-sperm Ab: produced in some men after vasectomy.

9. Mechanisms of autoimmunity 2. Molecular mimicry Sharing of epitopes between an infectious agent and its host. Antibodies directed against the infectious agents starts reacting with normal self Ag. Triggers autoimmunity.

10. Mechanisms of autoimmunity 2. Molecular mimicry

11. Mechanisms of autoimmunity 3. Infection: Here autoimmunity is not due to infectious agent itself ,but results from disregulation of host immune response by the microbes. This may be due to : • Alteration of self Ag (cross reactive neo-Ag)

12. Mechanisms of autoimmunity 4. Genetic Factors • The important genes that regulate the development of autoimmunity are located within MHC. • MHC ll genes are directly responsible for auto antigen processing and presentation. • The structure of Ag binding groove will determine, if specific Ag will trigger an autoimmune response. • Examples: • SLE: HLA-DLA- A7 • Polyarthritis: HLA-DLA- A7

13. Mechanisms of autoimmunity 5. Lymphocytes abnormalities • Primary abnormalities either in B cell or T cell. • Since these cells are critical regulators of all immune responses . • MHC presentation of all antigenic peptide to these cells will be defective, in case the cells are abnormal. • Abnormalities in lymphocytes could affect any one of the mechanism that normally maintains self tolerance.

14. Mechanisms of autoimmunity 6. Failure of central tolerance Inside primary lymphoid organ; • Positive selection • Negative selection (Deletion of self reacting T cells in thymus apoptosis). Failure of central tolerance starts autoimmune diseases

15. Autoimmunity Classification

16. Autoimmune endocrine diseases

17. Examples of Systemic Autoimmunity • Sjogren's syndrome : • Auto-antibodies attack the glands that make tears and saliva • This causes a dry mouth and dry eyes.

18. Examples of Systemic Autoimmunity • Rheumatoid arthritis: • Rheumatoid arthritis particularly affects the small joints of the hands and feet. • There is wasting of the small muscles of the hand, swelling of the metatarsophalangeal joints and a small subcutaneous nodule on the little finger. • Onset: Insidious • Main symptoms: • Pain • Stiffness – on waking and following inactivity • Other symptoms: • Fatigue and lethargy • Low-grade fever • Weight loss

19. Examples of Organ Autoimmunity Hashimoto's Disease (Chronic lymphocytic thyroiditis ) • Effector mechanisms • Autoantibodies against thyroid gland. • Laboratory diagnosis • T3,T4 (decrease) and TSH (increase) serum levels • Autoantibodies to • Thyroid peroxidase (TPO) • Thyroglobulin • Treatment • •Replacement therapy (Levothyroxine)

20. Diagnosis • General tests • C-Reactive Protein. • Autoantibody titers (anti DNA, anti phospholipids, etc) • Presence of Rheumatoid Factor • Disease specific tests • Neurological exam – MS • Fasting glucose - Diabetes

21. Treatment for autoimmunity • Immunosuppression (e.g., prednisone, cyclosporin A) • Removal of thymus (some MG patients) • Plasmapheresis (remove Ab-Ag complexes) • T-cell vaccination (activate suppressing T cells??) • Block MHC with similar peptide • anti-CD4 monoclonal Ab • anti-IL2R monoclonal Ab

22. Immunosuppressants • Drugs that inhibit or prevent activity of the immune system • They are used in immunosuppressive therapy to: • Prevent the rejection of transplanted organs and tissues (bone marrow, heart, kidney, liver) • Treat autoimmune diseases or diseases that are most likely of autoimmune origin. • Treat some other non-autoimmune inflammatorydiseases (allergic asthma, atopic eczema).

23. Glucocorticoids • Suppress the cell-mediated immunity- act by inhibiting genes that code for various cytokines (e.g.IL-2) • Decrease cytokine production reduces the T cell proliferation. • Suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors- this diminishes both B cell clone expansion and antibody synthesis.

24. Drugs affecting the proliferation of both T cells and B cells • Cyclophosphamide -very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias • high doses cause pancytopenia and hemorrhagic cystitis • Methotrexate is a folic acid antagonist, acts during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle; used in the treatment of autoimmune diseases (RA, Crohn's disease) and in transplantations.

25. Drugs affecting the proliferation of both T cells and B cells • Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leucocytes; SLE, RA, sclerosis multiplex, transplantation • Mycophenolate mofetil – affects the enzyme that controls the purine synthesis • Used in transplantation of solid organ.

26. Drugs blocking the activation of lymphocytes • Tacrolimus - prevents the cell from transitioning from the G0 into G1 phase of the cell cycle • Used to prevent rejection reactions, atopic eczema • Cyclosporin A- inhibits calcineurin, which is responsible for activating the transcription of interleukin-2; inhibits cytokines production and interleukin release • Used to prevent rejection reactions • Side effects: nephrotoxicity, neurotoxicity, hypertension, dyslipidemia, hyperglycemia

27. Monoclonal antibodies • Monoclonal antibodies are directed towards exactly defined antigens • Daclizumab - acts by binding the IL-2a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival • used in the prophylaxis of the acute organ rejection after the bilateral kidney transplantation