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Failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection, may lead to autoimmunity in genetically predisposed individuals.
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Common Features of Autoimmune Diseases
- 1. Chronicity
- 2. Idiopathic
- 3. Linkage to MHC HLA alleles
- 4. Female predilection
- 5. Autoantibodies, including ANAs (antinuclear Ab)
- 6. Coincidence of other autoimmune diseases
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Three Important Autoimmune Disease to know
- 1. Systemic Lupus Erythematosis (SLE)
- 2. Sjogren’s syndrome
- 3. Systemic Sclerosis
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Autoimmune Diseases - mediated by Ab
- * Organ-specific
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Autoimmune atrophic gastritis of pernicious anemia
- Myasthenia gravis
- Graves disease
- Goodpasture syndrome
- * Systemic
- SLE
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Autoimmune Diseases - mediated by T cells
- * Organ-specific
- Type 1 diabetes mellitus
- Multiple sclerosis
- Hashimoto thyroiditis
- Crohn disease
- * Systemic
- Rheumatoid arthritis
- Systemic sclerosis (scleroderma)
- Sjögren syndrome
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Autoimmune Diseases - suspected autoimmune origin
- * Organ-specific
- Primary biliary cirrhosis
- Autoimmune (chronic active) hepatitis
- * Systemic
- Polyarteritis nodosa
- Inflammatory myopathies
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Immunologic self-tolerance
- * Central tolerance
- Differentiating T-cell reacts with self-Ag in thymus - some deleted via apoptosis, some without very high affinity develop into Treg (CD25, FOXP3), some slipped out.
- Self-reacting B-cell in bone marrow - die, or goes through Ag editing, or slipped out
- * Periphery tolerance
- Anergy - self-reacting T/B cell is shut down because the lack of costimulatory signals, TH cell, etc.
- Suppression by regulatory - Treg suppress the self-reacting activity
- Activation-induced cell death - certain pathway is activated when self-reaction happens, which eventually kill the cell. Fas, mitochondrial pathway
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Pathogenesis of autoimmunity
- genetic susceptibility -> failure of self-tolerance -> self-reactive lymphocytes (SRL)
- During infection or tissue damage, tissue APCs are activated -> attract SRL into tissues -> activation of SRL -> tissue injury, autoimmunity
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HLA (Human Leukocyte Antigen) allele plays an important role in some autoimmune diseases
- Different HLA types have different odds ratios
- Rheumatoid arthritis - DRB1, OR 4-12
- Type 1 diabetes - DRB1-0301/0401 haplotype, OR 35
- Ankylosing spondylitis - B27, OR 100-200
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Rheumatoid factors
autoantibody act against IgG, mainly IgM, can be others too.
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Non-HLA genes associated with autoimmune diseases
- PTPN22, protein tyrosine phosphatase - RA, TID, IBD - affecting negative selection
- IL23R - inflammatory bowel disease, psoriasis, and ankylosing spondylitis - IL23 receptor for TH17
- CTLA4 - TID, RA - affect T cell response and Treg activity
- IL2RA (CD25) - MS, TID
- NOD2 - IBD - react to commensal bacteria
- ATG16, Autophagy genes - IBD
- IRF5, IFIH I - SLE - produce type I Interferon
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11 criteria involved in diagnosing systemic lupus erythematosus
- 1. Malar rash
- 2. Discoid rash
- 3. Photosensitivity
- 4. Oral ulcers
- 5. Arthritis
- 6. Serositis
- 7. Renal disorder
- 8. Neurologic disorder
- 9. Hematologic disorder
- 10. Immunologic disorder
- 11. Antinuclear antibody
- 4 or more necessary
- female, childbearing age, black
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Model for the pathogenesis of SLE
- genetic propensity - reactive to self nuclear antigens
- environmental triggers (UV, etc) - damage - apoptosis - defective clearance of apoptotic bodies - more nuclear antigens
- autoreactive B and T cells activated - nuclear antigens taken in and engage TLRs: DNA, TLR-9; RNA, TLR-7
- Further stimulate B cells - act on own DNA
- ANA-nuclear Ag Can also activate dendritic cells - produce type 1 interferons and be APC
- persistent high-level anti-nuclear IgG antibody production
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autoimmune diseases - Autoantibodies
- SLE - anti- dsDNA, histones, phospholipid, parts of ribonuclear body: Sm, RNP UI, SS-A, SS-B
- Sjorgren syndrome - anti- SS-A, SS-B
- Syestemic sclerosis - anti- Scl-70 (DNA topoisomerase I), centromere
- ...
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Focal lupus nephritis, with necrotizing lesions in glomerulus
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Diffuse lupus nephritis, with marked global increase in cellularity throughout the glomerulus
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Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes
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SLE involving skin
- Liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction
- deposits of immunoglobulin along the dermoepidermal junction
- butterfly rash
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Sjögren syndrome
- lesions in the salivary glands, lacrimal glands
- germinal centers outside of the lymph node and the spleen
- dry eyes, dry mouth, dryness, various other conditions
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Pathogenesis of systemic sclerosis
- Injury to endothelial cells
- T cells - cytokines to activate fibroblasts and stimulate collagen production, resulting in fibrosis, including TGF-β, IL-13, platelet-derived growth factor (PDGF)
- endothelial proliferation and intimal fbrosis, Endothelial injury and microvascular disease are commonly present in the lesions of SS, causing chronic ischemia
- B cell activation and antibodies produced - anti-Scl 70, anticentromere Ab.
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Systemic sclerosis
- progressive fibrosis involving the skin, gastrointestinal tract, and other tissues.
- prominent in skin, dense collagen deposition in the dermis
- extensive subcutaneous fibrosis - clawlike flexion deformity & cutaneous ulcerations
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Papillon-Lefèvre syndrome
- Single gene mutation - Cathepsin C
- Advanced periodontal disease
- Palmar-plantar keratodermas - palms, plantar, elbow
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For age-related macular degeneration, 5 loci explained 50% heritability.
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