Download Autoimmune Disorders

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
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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
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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
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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
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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)
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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
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RA Therapies: Abatacept
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Scleroderma: Pathogenesis
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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.
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Scleroderma - clinical symptoms
Skin
Raynaud’s Phenomenon
Joint/ Pain
Heart
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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
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How NSAIDs work
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Autoimmune suppressive drug
• Inhibits the
proliferation of T cells
• Drugs include
• Azathioprine
• Ciclosporin
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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)
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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
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