Gen Path L27, 28

  1. Failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection, may lead to autoimmunity in genetically predisposed individuals.
  2. 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
  3. Three Important Autoimmune Disease to know
    • 1. Systemic Lupus Erythematosis (SLE)
    • 2. Sjogren’s syndrome
    • 3. Systemic Sclerosis
  4. 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
  5. 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
  6. Autoimmune Diseases - suspected autoimmune origin
    • * Organ-specific
    • Primary biliary cirrhosis
    • Autoimmune (chronic active) hepatitis
    • * Systemic
    • Polyarteritis nodosa
    • Inflammatory myopathies
  7. 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
  8. 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
  9. 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
  10. Rheumatoid factors
    autoantibody act against IgG, mainly IgM, can be others too.
  11. 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
  12. 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
  13. 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
  14. 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
    • ...
  15. Focal lupus nephritis, with necrotizing lesions in glomerulus
  16. Diffuse lupus nephritis, with marked global increase in cellularity throughout the glomerulus
  17. Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes
  18. 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
  19. 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
  20. 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.
  21. 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
  22. Papillon-Lefèvre syndrome
    • Single gene mutation - Cathepsin C
    • Advanced periodontal disease
    • Palmar-plantar keratodermas - palms, plantar, elbow
  23. For age-related macular degeneration, 5 loci explained 50% heritability.
Author
neopho
ID
323735
Card Set
Gen Path L27, 28
Description
Gen Path L27 Autoimmunity L28 Genetics
Updated