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Autoimmunity - autoimmune diseases Roland Jonsson Broegelmann Research Laboratory RJ13.

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Presentation on theme: "Autoimmunity - autoimmune diseases Roland Jonsson Broegelmann Research Laboratory RJ13."— Presentation transcript:

1 Autoimmunity - autoimmune diseases Roland Jonsson Broegelmann Research Laboratory RJ13

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

3 Autoinflammation no response against own tissue Autoinflammation no response against own tissue (antigen) utilize the innate immune system reaction without any cause granulocytes – monocytes intense episodes with inflammation symptoms: fever, redness, joint effusion RJ13

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

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

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

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

10 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

11 Genetic Predisposition Autoantibodies, Onset of Autoimmunity Pathological Injury Clinical Disease DiseaseDisease Clinical Presentation Environmental Triggers

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

13 Definition of autoimmune disease - Autoantibodies - Autoreactive T cells - Autoimmune process primarily RJ13

14 Witebsky’s criteria (1957) How to prove autoimmune disease? Witebsky’s criteria (1957) How to prove autoimmune disease? 1.Antibodies should be detectable 2.Autoantigens should be identified 3.Experimental induction of antibodies against the antigen 4.Induceable disease in an experimental model RJ13

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

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

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

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

19 Disease HLA AlleleRelative Risk* Rheumatoid arthritisDR4 6 IDDMDR3 5 DR4 5-6 DR3/DR420 Chronic active hepatitisDR314 Sjögren´s syndromeDR3 + DQ10 Coeliac diseaseDQ2/DQ810 Dermatitis herpetiformisDR350 Ankylosing spondylitisB *Relative risk: Probability of individuals with a particular HLA allele(s) to develop a disease compared with individuals lacking that allele(s). HLA-association immunologic diseases

20 1.crossreactivity 2.defect cleaning from apoptotic cells 3.”hidden” selfantigen 4.modified autoantigen 5.viral infections 6.selection in the thymus 7.immunoregulatory defects Theories around development of autoimmune disease RJ13

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

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

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

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

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

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

30 Criteria for Classification of Rheumatoid Arthritis 1.Morning stiffness 2.Arthritis of three or more joint areas 3.Arthritis of hand joints 4.Symmetric arthritis 5.Rheumatoid nodules 6.A. Serum rheumatoid factor B. Anti-CCP (anti-cykl. citrull. prot.) 7.Radiographic changes RJ13

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32 Waaler-Rose test Erik Waaler ( )

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

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

36 Criteria for Classification of 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 e.g. anti-DNA, anti-Sm 11. Antinuclear antibody (homogenous, speckled, peripheral or nucleolar) RJ13

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

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

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

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45 Anti-dsDNA AbAnti-ssDNA AbAnti-Histone Ab Fig 26.4

46 Criteria for Classification of Sjögren’s syndrome 1.Ocular symptoms 2.Oral symptoms 3.Ocular signs 4.Histopathologic features 5.Salivary gland involvement 6.Autoantibodies (anti-Ro/SSA or anti-La/SSB) RJ13

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

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52 Activated B cells

53 Immunogenetic Predisposition ?Sialotropic virus Hormonal predisposition Impaired Secretion Autoreactive CD4+ T cell Epithelial cell B cell activation Dry eyes/ mouth/nose/ Etc. Extraglandular disease Autoantibodies: ANA Anti-Ro/La RF, Anti-M3R Additional trigger or susceptibility factor? Lymphoma Chemokines, cytokines, MMPs Elevated INF- , IL-6, IL-10, TNF- , etc. IL-2, IFN- , IL-10 Adapted from Price and Venables, 1995 Susceptibility & triggers? Activation, apoptosis, autoantigen release, antigen presentation Lymphocytic infiltration, decreased apoptosis? Clinical Features


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