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PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Autoimmune Disorders Xuan (Linda) Li, Asianne Lee, Do Won Park, Yuxing Sun What is an autoimmune disorder? • More than 80 types of autoimmune disorders affect 5% of the population • Immune system turns its defense against body’s own tissues → B and T cells react against ‘self’ • Tolerance - ability of immune system to distinguish between self-antigens and other antigens • Autoimmune diseases arise to due a breakdown in tolerance 2 Common Diseases and Symptoms • Common diseases include: • Rheumatoid arthritis: joints • Type 1 Diabetes: pancreas • Lupus: chromatin • Scleroderma: skin • Autoimmune diseases can affect many body parts. • Common symptoms include: fatigue, malaise, joint pain, and rash 3 Pathogenesis of Autoimmune disorders Normally growth of clones stopped by multiple checkpoints In autoimmune disorders, mutation disrupts one or more checkpoint allowing self-recognizing lymphocyte growth 4 Rheumatoid Arthritis (RA) • Chronic, progressive, inflammatory autoimmune disease associated with articular, extra-articular and systemic effects • Affects 0.5-1% of the adult population in developed regions • Characterized by: • Synovial inflammation • Autoantibody production • Cardiovascular, pulmonary, psychological, and skeletal disorders 5 RA Pathogenesis • Innate immune response is activated by self-antigens and CD4+ T-cells are activated • T cells secrete cytokines (IL-2 and IFN-γ) that infiltrate the synovial membrane • B-cells contribute to pathogenesis by making autoantibodies and cytokines, including TNF-α • Macrophages activated by cytokines produce more cytokines (TNF-α, IL-1, IL-6) 6 7 Roles of cytokines in RA • Inflammation • TNF-α, IL-1, IL-6 mediate inflammation and cell migration • Recruit neutrophils • Bone destruction • IL-6 promotes osteoclastogenesis • Anemia • IL-6 induces production of hepcidin → hypoferraemia → anemia • Fatigue and depression • TNF-α, IL-1, IL-6 Dysregulation of corticotropin-releasing hormone 8 RA Therapies: Abatacept 9 Scleroderma: Pathogenesis 10 Scleroderma Processes that lead to clinical and pathologic manifestations: 1. Severe fibroproliferative vascular lesions of small arteries and arterioles, 2. Excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and various internal organs 3. Alterations of humoral and cellular immunity. 11 Scleroderma - clinical symptoms Skin Raynaud’s Phenomenon Joint/ Pain Heart 12 Therapeutics ● No cure for autoimmune diseases ● Use drugs to control symptoms ● 1. Relieve Pain ○ Corticosteroid ■ Glucocorticoids ■ Mineralocorticoids ○ NSAIDs ■ Ibuprofen ■ Aspirin ● 2. Suppress Immune System ○ Immunosuppressant 13 How NSAIDs work 14 Autoimmune suppressive drug • Inhibits the proliferation of T cells • Drugs include • Azathioprine • Ciclosporin 15 Summary • Autoimmune disorders occur when the immune system attacks the body’s own tissues • Rheumatoid arthritis is a condition where synovial inflammation is due to autoantibody and pro-inflammatory cytokine production • Cytokines are responsible for the effects of RA • Inflammation, bone destruction, anemia, fatigue and depression • Abatacept blocks T-cell activation by interfering with CD80-CD28 interaction • Scleroderma is a condition where collagen is produced and accumulates in connective tissue due to overactivation of immune system • • TGF-B stimulate ECM synthesis, induce generation of myofibroblast, produce protease inhibitors, which prevent ECM breakdown. No cure for Autoimmune diseases, drugs are used to control symptons • NSAIDs (Ibuprofen) • Immunosuppressant (Azathioprine, Ciclosporin) 16 References 1. Bellone, Matteo, Autoimmune Disease: Pathogenesis. Encyclopedia of Life Sciences. 1: 1-8 2. Choy, Ernest (2011), Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology, 51: v3-v11 3. Goodnow CC (2007), Multistep Pathogenesis of Autoimmune Disease. Cell, 130: 25-35. 4. Jimenez, Sergio (2015) Scleroderma. http://emedicine.medscape.com/article/331864-overview#a3 (accessed Oct 16/16) 5. Jon A Kobashigawa and Jignesh K Patel. Immunosuppression for heart transplantation: where are we now? Nature Clinical Practice Cardiovascular Medicine (2006) 3, 203-212 doi:10.1038/ncpcardio0510 6. Jones Hopkins Medicine . Scleroderma Treatment Options. http://www.hopkinsscleroderma.org/patients/scleroderma-treatment-options/ (accessed Oct.. 13/16) 7. Martin, Laura J (2016) Autoimmune Disorders. https://medlineplus.gov/ency/article/000816.htm (accessed Oct. 14/16) 8. McInnes IB, Schett G (2011) The Pathogenesis of Rheumatoid Arthritis. N Engl J Med, 365: 2205-2219. 9. Shiel, William (2016) Raynaud’s Phenomenon. http://www.medicinenet.com/raynauds_phenomenon/article.htm (accessed Oct 15/16) 10. Veillee A, Davidson D (2014) Immunology: When lymphocytes run out of steam. Nature, 510, 222-223 17