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

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

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

Naiv autoreaktiv T- hjelpercelle 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

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

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

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

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

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

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

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

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

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

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

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

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

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 Specific HLA antigens have been associated with various human diseases, for instance the B27 antigen confers a 90 -100 fold increased risk for ankylosing spondylitis, and DR3 a 10-fold risk for SS. In addition to what is mentioned on this slide, the DR2 antigen confers a 3 fold increased risk for lupus, and a 4-fold risk for multiple sclerosis. Increased frequencies of both HLA-DR2 and DR3 have been found in primary SS, in contrast to secondary SS where for instance patients with secondary SS and rheumatoid arthritis have increased HLA-DR4. *Relative risk: Probability of individuals with a particular HLA allele(s) to develop a disease compared with individuals lacking that allele(s).

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

Samme TCR kryssreagerer på et selvpeptid med lignende kontaktresiduer Molekylær etterligning TCR TCR Viruspeptid Selvpeptid 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

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

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

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

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

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

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

Waaler-Rose test Erik Waaler (1903-1997)

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

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

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

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

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

ANA test 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

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

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

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

Activated B cells

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