Environmental, genetic and immunological determinants of Rheumatoid Arthritis

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1 University of Zurich University Hospital of Zurich Environmental, genetic and immunological determinants of Rheumatoid Arthritis FORALLVENT Symposium Basel, 2007 Diego Kyburz, M.D. Division of Rheumatology University Hospital of Zurich, Switzerland

2 Rheumatoid arthritis Disease characteristics Genetic basis of RA Immunopathogenesis of RA Environmental factors RA and the hygiene hypothesis

3 RA: Characteristics of disease Joint pain Morning stiffness Joint swelling and tenderness Limitation of joint mobility

4 Klinische Slides

5 Joint inflammation pannus cartilage bone

6 RA: course of disease Untreated joint inflammation results in Cartilage and bone damage Joint deformity Loss of function disability

7 Bone erosions in RA

8 Joint destruction

9 Joint deformities in RA

10 RA Diagnosis

11 Genetic basis of RA Twin studies 15-30% concordance heritability 50-60% MHC-association of RA HLA-DRB1 0401, 0101 Shared epitope QKRAA in HLA-DRB1

12 Genetic basis of RA Shared epitope QKRAA in HLA-DRB1 PTPN22 Tyrosine phosphatase MHC2TA MHC class II transactivator PADI4 Peptidylarginine deiminase type 4

13 Immunopathogenesis of RA Evidence for autoimmunity MHC-dependence: T-cell involvement Autoantibody production Rheumatoid factor Anti-CCP antibodies Can precede the disease by years

14 Immunopathogenesis of RA Rheumatoid factor Autoantibodies with affinity against host IgG In approx. 80% of RA patients Correlates with severity of disease Anti-CCP ab Directed against citrullinated proteins/peptides Highly specific for RA (together with RF >90%) Causal role or epiphenomenon?

15 B-cell directed therapy for RA % patients MTX Rituximab Rituximab + CTX Rituximab + MTX J. Edwards, N Engl J Med 2004 ACR20 ACR50 ACR70

16 T-cell costimulation blockade Genovese et al, N Engl J Med 2005

17 Role of cytokines in RA TNF- is a pivotal cytokine in the pathogenesis of RA Mediates pathologic inflammation Mediates joint destruction Mediates systemic, extra-articular symptoms of inflammation Regulates levels of adhesion molecules responsible for leukocyte migration

18

19 Immunopathogenesis of RA T-cell and B-cell dependent disease Activation of innate immune system Cytokines play a key role Chronic synovitis Inflammatory cells, cytokine/chemokine production Pannus formation Cartilage and bone destruction What triggers disease?

20 Environmental factors Risk of RA 50% explained by genetic factors Environmental factors/gene environment interactions other 50%?

21 Environmental factors Smoking Association with RA susceptibility first described 1987 Vessey et al, Contraception 1987 Smoking influences disease severity Smoking and shared epitope of HLA are linked Padyukov et al, Arthritis Rheum 2004 RR of RF+ RA: Never smokers with SE genes 2.8 Current smokers without SE genes 2.4 Current smokers with SE genes 7.5 Current smokers with double SE genes 15.7

22 Smoking and RA Relative Risk of developing RA SE: shared epitope of HLA A: anti-ccp positive Pts B: anti-ccp neg. Pts Klareskog et al Arthritis Rheum 2006

23 Gene-environment interaction Smoking increases risk for RA in SE-positive individuals Smoking and SE only increase risk for anti- CCP pos. RA, not for anti-ccp neg. RA Mechanism?

24 Smoking induces citrullination Bronchoalveolar lavage cells A: smoker D: non-smoker Klareskog et al Arthritis Rheum 2006

25 Model for the etiology of RA

26 Does immunity to citrullinated antigens cause arthritis? J Clin Invest 2006, 4, p.961

27 Environmental factors Infections Candidates: EBV, M. tuberculosis, E.coli, Parvovirus B19, retroviruses No consistent association of RA with infectious agent Increased expression of Toll like receptors in the RA synovium

28 Toll like receptor expression in farmers and Non-farmers children Lauener et al, Lancet 2002, 360, p465

29 Expression of TLR2 mrna in RA synovial tissue anti-sense probe sense control probe Seibl et al. 2003, Am J Pathol

30 TLRs and arthritis? Induction of arthritis by TLR ligands Injection of PGN or CpG DNA Deng 1999 Nat Med, Liu 2001 Arthritis Res, Svelander 2004 Arthritis Rheum Streptococcal cell wall arthritis Joosten et al, J Immunol 2003 Collagen induced arthritis Lee et al, Int Immunol 2005 Induction of rheumatoid factor autoantibody production via TLR9 Leadbetter et al, Immunity 2002 Detection of TLR ligands in joints of RA patients Van der Heijden 2000, Arthritis Rheum

31 TLRs and their ligands Exogenous ligand Endogenous ligand TLR-1 mycobacterial lipoprotein, lipopeptides unknown TLR-2 peptidoglycan, lipoproteins, yeast zymosan, HSP70, GP96, necrotic cells TLR-3 viral dsrna, poly(i:c) mrna TLR-4 LPS, respiratory syncytial virus HSP60/70, GP96, hyaluronan surfactant prot.a, fibronectin TLR-5 Flagellin unknown TLR-6 Mycoplasma lipoproteins, lipoteichoic acid unknown peptidoglycan TLR-7 ssrna, imiquimod, resiquimod ssrna TLR-8 ss RNA ssrna TLR-9 CpG DNA dsdna in IC TLR-10 unknown unknown

32 Necrotic cells as source of mrna 17% PI Necrotic cells are abundant in the synovial fluid

33 RNA released from necrotic SF cells acts as TLR3 ligand X fold IFN- mrna induction relative to control IFN- CXCL10 CCL5 IL-6 * * CXCL10 (pg/ml) * * 1. Necrotic SFC Chloroquine Benzonase CCL5 (pg/ml) * * IL-6 (ng/ml) * * Brentano et al, Arthritis Rheum 2005

34 Endogenous TLR ligands may contribute to joint inflammation and destruction Necrotic cells dsrna TLR3 IkB IFN- CXCL10 CCL5 IL-6 Inflammation Joint destruction NF-kB NUCLEU S IRF-3 Synovial fibroblast putative feedback loop

35 Exposure to infections early in life? Hygiene hypothesis Animal models Adjuvant arthritis incidence increased in germfree reared mice Kohashi et al, Infect Immun 1979 Clinical studies in humans Urbanisation associated with increased incidence of RA Chou et al, J Rheumatol 1994

36 Infectious exposure during infancy and risk of rheumatoid factor Sharing of bedroom as a child associated with reduced risk of RF positivity (in women) Edwards et al, Ann Rheum Dis 2006 Increased hygiene associated with autoantibody production

37 Do Th1 and Th2 diseases coexist? Controversial data Decreased prevalence of atopy in RA Allanora et al, Lancet 1988, Hilliquin et al, Rheumatology 2000 Asthma incidence increased in RA Kero et al, J Allergy Clin Immunol 2001 No evidence for inverse relationship between atopy and Th1 mediated autoimmune disorders Sheik et al, J Allergy Clin Immunol 2003

38 Kero et al, J Allergy Clin Immunol, 2001, p.781

39 Th1 Th2 paradigm too simplistic

40 T cell subsets T-cell differentiation T H 17 Treg

41 Nature 441, May 2006 Treg TH17: dichotomy similar to Th1/Th2 IL-6 inhibits Treg cell formation in vitro IL-6 + TGFb induce TH17 differentiation in the absence of IL-6, TGFb induces Treg formation

42 T-regulatory cells in RA J Exp Med 200, August 2004

43 T reg cell function is impaired in RA A B C D A effector T cells T reg cells fail to suppress cytokine production of T cells and monocytes in vitro in active RA Anti-TNF Tx reverses the T reg defect B effector T cells and regulatory T cells mixed 1:1 C monocytes D monocytes and reg T cells mixed 1:1

44 Maini et al, Arthritis Rheum 2006, 9, p 2817

45 Conclusions Genetic factors account for 50% of risk for RA HLA-DR genes, Non-MHC genes (PTNP22 etc) Environmental factors Smoking is a risk factor associated with HLA-DR No evidence for association with single infectious agent Infections in early childhood may be protective

46 Conclusions No inverse relationship between atopy and RA Th1-Th2 paradigm too simplistic Th17 Treg balance may be more important Evidence for defect in Treg function in RA

47 Thank you for your attention

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