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Autoimmunity - autoimmune diseases

Autoimmunity - autoimmune diseases. Roland Jonsson Broegelmann Research Laboratory. RJ13. Autoimmunity - - response to own tissue (antigen). - tissue damage a/o reduced function - spesific adaptive immune response against own antigen. Autoimmune disease. RJ13.

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Autoimmunity - autoimmune diseases

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  1. Autoimmunity - autoimmune diseases Roland Jonsson Broegelmann Research Laboratory RJ13

  2. Autoimmunity -- response to own tissue (antigen) • - tissue damage a/o reduced function • - spesific adaptive immune response against own antigen Autoimmune disease RJ13

  3. Autoinflammation no response against own tissue (antigen)utilize the innate immune systemreaction without any causegranulocytes – monocytesintense episodes with inflammationsymptoms: fever, redness, joint effusion RJ13

  4. Examples of autoinflammatoric diseaseFamilial Mediterranean Fever (FMF)Neonatal Onset Multisystem Inflammatory Disease (NOMID)Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)Behçet’s Disease RJ13

  5. Autoimmunity CD28 B7 Naiv autoreaktiv T- hjelpercelle IL-4 IL-12 Immundeviasjon Th1 Th2 Autoreaktive Th1-celler som utskiller IFN-g og TNF og gir inflammasjon. Kan forårsake autoimmun sykdom Autoreaktive Th2-celler som beskytter mot utvikling av autoimmune sykdommer Immunedeviation – development of “harmless” Th2-cells protects Autoimmune dis. Protects against autoimmunity

  6. Cytokines (1) CD4+ T cells: Th1: IL-2, IFN- Th2: IL-4, IL-5, IL-13 Th3/Tr: IL-10, TGF- Th17: IL-17 RJ13

  7. Naïve T cell Fates of CD4 T cells Th1 (IFN-g):Host defense (IC pathogens) autoimmunity STAT4 T-bet IL-12 Th2 (IL-4, IL-5,IL-13): Host defense (parasites), Allergy, asthma STAT6 GATA3 c-maf Th17 (IL-17): Host defense (EC pathogens) Inflammation Autoimmunity RORgt TGF-b IL-23 Foxp3 T-reg (TGF-b, IL-10) Immunosuppression

  8. Cytokines (2) Pro-inflammatory: IL-1, IL-6, TNF-, IL-12, IL-18, (IFN-, chemokines) Anti-inflammatory: IL-4, IL-10, IL-13, TGF- RJ13

  9. Autoimmune diseases • 5-7% of the population • nearly all organsystems in the body • can be involved • can be asymptomatic for a long time • varieable disease expression RJ13

  10. Clinical Presentation Di sease Environmental Triggers Pathological Injury Genetic Predisposition Autoantibodies, Onset of Autoimmunity Clinical Disease

  11. Fig 26.1 Thyreoidea: Hashimotos thyreoiditt Binyrebark: Idiopatisk binyrebarksvikt Nyre: Nefrotoksisk glomerulonefritt Pancreas: Diabetes mellitus, type I Ventrikkel: Pernisiøs anemi Muskel: Myasthenia gravis Hud: Bulløse hudsykdommer

  12. Definition of autoimmune disease • Autoantibodies- Autoreactive T cells- Autoimmune process primarily RJ13

  13. Witebsky’s criteria (1957)How to prove autoimmune disease? • Antibodies should be detectable • Autoantigens should be identified • Experimental induction of antibodies against the antigen • 4. Induceable disease in an experimental model RJ13

  14. Adaptive immune response – endogenous antigen - Difficult to eliminate the antigen - Sustained immuneresponse Result - chronic inflammation RJ13

  15. Classification of autoimmune diseases (1) Organspesific Type I diabetes mellitus Goodpasture’s syndrome Multippel sklerose Grave’s disease Hashimotos thyreoiditt Autoimmun perniciøs anemiAddison’s disease Vitiligo Myastenia gravis RJ13

  16. Classification of autoimmune diseases (2) Systemic Reumatoid artritt Sklerodermi Sjögrens syndrom Polymyositt Systemisk lupus erythematosus RJ13

  17. What triggers autoimmunity? • - Environmental factors • - Genetic factors (espes. MHC) RJ13

  18. HLA-association immunologic diseases Disease HLA Allele Relative Risk* Rheumatoid arthritis DR4 6 IDDM DR3 5 DR4 5-6 DR3/DR4 20 Chronic active hepatitis DR3 14 Sjögren´s syndrome DR3 + DQ 10 Coeliac disease DQ2/DQ8 10 Dermatitis herpetiformis DR3 50 Ankylosing spondylitis B27 90-100 *Relative risk: Probability of individuals with a particular HLA allele(s) to develop a disease compared with individuals lacking that allele(s).

  19. Theories around development of autoimmune disease • 1. crossreactivity • defect cleaning from apoptotic cells • 3. ”hidden” selfantigen • 4. modified autoantigen • 5. viral infections • 6. selection in the thymus • 7. immunoregulatory defects RJ13

  20. Molekylær etterligning TCR TCR Selvpeptid Viruspeptid Kontakt- residuer Kontakt- residuer MHC MHC En naiv T-celle med en bestemt TCR reagerer på viruspeptid. Ekspansjon av effektorcelle Samme TCR kryssreagerer på et selvpeptid med lignende kontaktresiduer Crossreactivity 22.5

  21. Cytokines - imbalance Th1: IL-2, IFN- Th2: IL-4, IL-5, IL-13 Th3/Tr: IL-10, TGF- Th17: IL-17 RJ13

  22. Risk for autoimmune disease controlled by the environment – and genetic factors, esp. MHC • - Twinstudies • - Familystudies • - Inbred mousestrains RJ13

  23. A pedigree including monozygotic twins and their mother with pSS AIB 02 Bolstad et al., J Rheumatol 2000;27:2264-2266.

  24. Autoimmune diseases transferrable over the placenta – NB! IgG - Myastenia gravis - Grave’s disease - Thromocytopenic purpura - Neonatal lupus o/e congenital heartblock - Pemphigus vulgaris RJ13

  25. Diagnostics – prognosis in autoimmune diseases • - Autoantibodies in diagnostics – marker • - Prognosis (timelag) until disease develops RJ13

  26. Criteria for Classification of Rheumatoid Arthritis • 1. Morning stiffness • Arthritis of three or more joint areas • 3. Arthritis of hand joints • 4. Symmetric arthritis • 5. Rheumatoid nodules • A. Serum rheumatoid factor • B. Anti-CCP (anti-cykl. citrull. prot.) • 7. Radiographic changes RJ13

  27. Waaler-Rose test Erik Waaler (1903-1997)

  28. Revmatoid artritt Normal Synovialvev Pannus som vokser innover og eroderer brusk og ben Ben Ben Betent villøst synovialvev, med infiltrerende lymfocytter, makrofager, plasmaceller. Brusk Brusk Kimsenter Økt synovialvæske: autoantistoffer, immun-komplekser og RA-celler. Normal, enkeltlaget synovialhinne RA B cells GC FDC Kollagen type IV Fig 26.5

  29. Joints affected in RA Halsvirvler PIP-leddene MCP-leddene Skulder Kne Ankel Vristledd Fot Fingre Fig 26.6

  30. Criteria for Classification of Systemic Lupus Erythematosus • 8. Neurologic disorder • 9. Hematologic disorder • Immunologic disorder e.g. anti-DNA, anti-Sm • Antinuclear antibody (homogenous, speckled, peripheral or nucleolar) • 1. Malar rash • 2. Discoid rash • 3. Photosensitivity • 4. Oral ulcers • 5. Arthritis • 6. Serositis • 7. Renal disorder RJ13

  31. Clinical Presentation Environmental Triggers Pathological Injury SLE Genetic Predisposition Clinical Disease Autoantibodies, Onset of Autoimmunity

  32. Feber SLE Eksantem Sår i munnhulen Pleuritt Pericarditt Immunkompleks glomerulonefritt Leddsmerter Proteinuri, hematuri Anemi Fig 26.2

  33. 1. Serum As tilsettes permeabiliserte celler 2. ANA binder kjernen, ubundet As vaskes bort 3. FITC konjugert sekundærantistoff mot humant Ig tilsettes 4. Ubundet sekundær As vaskes bort Negativ ANA Positiv ANA Positiv ANA 5. Kjernefarging avleses ved immunfluorescens, FITC gir grønn farge. ANA test Fig 26.3

  34. Anti-Histone Ab Anti-dsDNA Ab Anti-ssDNA Ab Fig 26.4

  35. Criteria for Classification of Sjögren’s syndrome • 1. Ocular symptoms • 2. Oral symptoms • 3. Ocular signs • 4. Histopathologic features • 5. Salivary gland involvement • Autoantibodies (anti-Ro/SSA or anti-La/SSB) RJ13

  36. Sjögren’s syndrome Exocrine glands that are affected: Tårekjertler: Keratokonjunctivitis sicca Spyttkjertler: Xerostomi, munnsår Luftveier: Bronkitt, lungebetennelse Fig 26.9

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