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Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies

Nature Medicine volume 21, pages 730–738 (2015)Cite this article

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Abstract

Recent advances in genome-wide association studies (GWAS) across autoimmune and immune-mediated diseases have augmented our understanding of pathogenic mechanisms underlying these diseases. This has further highlighted their heterogeneous nature, both within and between diseases. Furthermore, varying responses to therapy have also served to underline the importance of this heterogeneity in the manner in which these diseases are diagnosed and treated. Here we discuss our current understanding of the shared pathways of autoimmunity, including the tumor necrosis factor (TNF), major histocompatibility complex (MHC), interleukin 23 receptor (IL23R) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) pathways. In addition, we summarize effective specific therapies tested across major autoimmune diseases, highlighting the insight they have provided into disease mechanisms and their implications for potential future improvements.

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Figure 1: Timeline of pathogenicity and therapeutic interventions in autoimmune diseases.

Debbie Maizels/Nature Publishing Group

Figure 2: Levels of therapeutic targeting across autoimmunity.

Debbie Maizels/Nature Publishing Group

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References

  1. Hradetzky, S. et al. The human skin-associated autoantigen alpha-NAC activates monocytes and dendritic cells via TLR-2 and primes an IL-12-dependent Th1 response. J. Invest. Dermatol. 133, 2289–2292 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Harlow, L., Fernandez, I., Soejima, M., Ridgway, W.M. & Ascherman, D.P. Characterization of TLR4-mediated auto-antibody production in a mouse model of histidyl-tRNA synthetase-induced myositis. Innate Immun. 18, 876–885 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Kopp, P. The TSH receptor and its role in thyroid disease. Cell. Mol. Life Sci. 58, 1301–1322 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Ross, G.L., Barland, P. & Grayzel, A.I. The immunoglobulin class of anti-DNA antibodies: detection by a fluorometric immunoassay: clinical and pathological correlations in SLE. J. Rheumatol. 5, 373–383 (1978).

    CAS  PubMed  Google Scholar 

  5. Klareskog, L., Catrina, A.I. & Paget, S. Rheumatoid arthritis. Lancet 373, 659–672 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Salvetti, M., Ristori, G., Bomprezzi, R., Pozzilli, P. & Leslie, R.D. Twins: mirrors of the immune system. Immunol. Today 21, 342–347 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Bogdanos, D.P. et al. Twin studies in autoimmune disease: genetics, gender and environment. J. Autoimmun. 38, J156–J169 (2012).

    Article  PubMed  Google Scholar 

  8. Fraga, M.F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl. Acad. Sci. USA 102, 10604–10609 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stein, E.A. et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108–1118 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Sabatine, M.S. et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1500–1509 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Robinson, J.G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Blom, D.J. et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N. Engl. J. Med. 370, 1809–1819 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. McDonagh, J. Statin-related cognitive impairment in the real world: you'll live longer, but you might not like it. JAMA Intern. Med. 174, 1889 (2014).

    Article  PubMed  Google Scholar 

  14. Dick, H.M. HLA and disease. Introductory review. Br. Med. Bull. 34, 271–274 (1978).

    Article  CAS  PubMed  Google Scholar 

  15. Cho, J.H. & Gregersen, P.K. Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med. 365, 1612–1623 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Parkes, M., Cortes, A., van Heel, D.A. & Brown, M.A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661–673 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Brennan, F.M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNF-α antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Gregory, A.P. et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508–511 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354, 1932–1939 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Present, D.H. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1405 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Targan, S.R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. Crohn's Disease cA2 Study Group. N. Engl. J. Med. 337, 1029–1035 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Chaudhari, U. et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357, 1842–1847 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Mease, P.J. Tumour necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann. Rheum. Dis. 61, 298–304 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gorman, J.D., Sack, K.E. & Davis, J.C. Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N. Engl. J. Med. 346, 1349–1356 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Sfikakis, P.P. Behcet's disease: a new target for anti-tumour necrosis factor treatment. Ann. Rheum. Dis. 61 Suppl 2, ii51–ii53 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kontoyiannis, D., Pasparakis, M., Pizarro, T.T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Kuchroo, V.K. et al. T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu. Rev. Immunol. 20, 101–123 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Ferber, I.A. et al. Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J. Immunol. 156, 5–7 (1996).

    CAS  PubMed  Google Scholar 

  31. Lemmel, E.M., Obert, H.J. & Hofschneider, P.H. Low-dose γ-interferon in treatment of rheumatoid arthritis. Lancet 1, 598 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Williams, R.O., Williams, D.G., Feldmann, M. & Maini, R.N. Increased limb involvement in murine collagen-induced arthritis following treatment with anti-interferon-γ. Clin. Exp. Immunol. 92, 323–327 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Ahern, P.P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cho, J.H. The genetics and immunopathogenesis of inflammatory bowel disease. Nat. Rev. Immunol. 8, 458–466 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nair, R.P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat. Genet. 41, 199–204 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Reveille, J.D. et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bowes, J. et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat. Commun. 6, 6046 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl. Acad. Sci. USA 108, 9560–9565 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pidasheva, S. et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS ONE 6, e25038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Griffiths, C.E. et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N. Engl. J. Med. 362, 118–128 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Gottlieb, A. & Narang, K. Ustekinumab in the treatment of psoriatic arthritis: latest findings and clinical potential. Ther. Adv. Musculoskelet. Dis. 5, 277–285 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sandborn, W.J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367, 1519–1528 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. OP025. A randomized, double-blind placebo-controlled phase 2a induction study of MEDI2070 (anti-p19 antibody) in patients with active Crohn's disease who have failed anti-TNF antibody therapy. J. Crohns Colitis 9 Suppl 1, S15–S16 (2015).

  49. Krueger, J.G. et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J. Allergy Clin. Immunol. (2015).

  50. Criswell, L.A. et al. Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) Collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stanford, S.M. & Bottini, N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat. Rev. Rheumatol. 10, 602–611 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hasegawa, K. et al. PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303, 685–689 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Arechiga, A.F. et al. Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling. J. Immunol. 182, 3343–3347 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37, 1317–1319 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, J. et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat. Genet. 43, 902–907 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Zikherman, J. et al. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J. Immunol. 182, 4093–4106 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Cui, J. et al. Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis. PLoS Genet. 9, e1003394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Breedveld, F. The value of early intervention in RA–a window of opportunity. Clin. Rheumatol. 30 Suppl 1, S33–S39 (2011).

    Article  PubMed  Google Scholar 

  60. Goekoop-Ruiterman, Y.P. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 52, 3381–3390 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Leonardi, C.L. et al. Etanercept as monotherapy in patients with psoriasis. N. Engl. J. Med. 349, 2014–2022 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Krueger, G.G. et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Langley, R.G. et al. Secukinumab in plaque psoriasis–results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Gottlieb, A.B. et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J. Immunol. 175, 2721–2729 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Nestle, F.O., Kaplan, D.H. & Barker, J. Psoriasis. N. Engl. J. Med. 361, 496–509 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Mease, P.J. et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N. Engl. J. Med. 370, 2295–2306 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Littman, D.R. & Rudensky, A.Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Krueger, J.G. Hiding under the skin: a welcome surprise in psoriasis. Nat. Med. 18, 1750–1751 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. O'Connor, W. Jr. et al. A protective function for interleukin 17A in T cell–mediated intestinal inflammation. Nat. Immunol. 10, 603–609 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kühn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    Article  PubMed  Google Scholar 

  72. Li, M.O. & Flavell, R.A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li, M.O., Wan, Y.Y. & Flavell, R.A. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Hooper, L.V., Littman, D.R. & Macpherson, A.J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fung, T.C., Artis, D. & Sonnenberg, G.F. Anatomical localization of commensal bacteria in immune cell homeostasis and disease. Immunol. Rev. 260, 35–49 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sonnenberg, G.F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Glocker, E.O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zielinski, C.E. et al. Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 484, 514–518 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Poddubnyy, D., Hermann, K.G., Callhoff, J., Listing, J. & Sieper, J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann. Rheum. Dis. 73, 817–823 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. McInnes, I.B. et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1-year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382, 780–789 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. McInnes, I.B. et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann. Rheum. Dis. 73, 349–356 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Baeten, D. et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–1713 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Schett, G., Elewaut, D., McInnes, I.B., Dayer, J.M. & Neurath, M.F. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat. Med. 19, 822–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Belasco, J. et al. Comparative genomic profiling of psoriatic arthritis synovium versus skin lesions. Arthritis Rheumatol. 67, 934–944 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Onengut-Gumuscu, S. et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cooper, J.D. et al. Seven newly identified loci for autoimmune thyroid disease. Hum. Mol. Genet. 21, 5202–5208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Trynka, G. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193–1201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kuehn, H.S. et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345, 1623–1627 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zeissig, S. et al. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut (2014).

  92. Genovese, M.C. et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N. Engl. J. Med. 353, 1114–1123 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Sandborn, W.J. et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 143, 62–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Kaser, A. Not all monoclonals are created equal—lessons from failed drug trials in Crohn's disease. Best Pract. Res. Clin. Gastroenterol. 28, 437–449 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Hu, X. et al. Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Farh, K.K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Edwards, J.C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Hauser, S.L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Wendling, D. et al. Rituximab treatment for spondyloarthritis. A nationwide series: data from the AIR registry of the French Society of Rheumatology. J. Rheumatol. 39, 2327–2331 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Song, I.H. et al. Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial. Arthritis Rheum. 62, 1290–1297 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Leiper, K. et al. Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis. Gut 60, 1520–1526 (2011).

    Article  PubMed  Google Scholar 

  102. Kandala, N.B. et al. Belimumab: a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis. BMJ Open (2013).

  103. Fattah, Z. & Isenberg, D.A. Recent developments in the treatment of patients with systemic lupus erythematosus: focusing on biologic therapies. Expert Opin. Biol. Ther. 14, 311–326 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Collins, F.S. Reengineering translational science: the time is right. Sci. Transl. Med. 3, 90cm17 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Collins, F.S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Shankar, G., Shores, E., Wagner, C. & Mire-Sluis, A. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol. 24, 274–280 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Weinblatt, M. et al. Selective co-stimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann. Rheum. Dis. 66, 228–234 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Genovese, M.C. et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum. 50, 1412–1419 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. MacArthur, D.G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nicolae, D.L. et al. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 6, e1000888 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fairfax, B.P. et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).

  114. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bach, J.F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    Article  PubMed  Google Scholar 

  116. Pritchard, J.K. & Di Rienzo, A. Adaptation—not by sweeps alone. Nat. Rev. Genet. 11, 665–667 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kau, A.L., Ahern, P.P., Griffin, N.W., Goodman, A.L. & Gordon, J.I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Scher, J.U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Jacobs, J. The Jewish Encyclopedia: A Guide to its Contents, an Aid to its Use (Funk & Wagnalls, 1906).

    Google Scholar 

  122. Quintana-Murci, L. & Clark, A.G. Population genetic tools for dissecting innate immunity in humans. Nat. Rev. Immunol. 13, 280–293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Aaltonen, K.J. et al. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS ONE 7, e30275 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lichtenstein, G.R. et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am. J. Gastroenterol. 107, 1409–1422 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

J.H.C. is supported by US National Institutes of Health grants U01 DK62429, U01 DK062422, R01 DK092235, SUCCESS, by he Helmsley Charitable Trust and by the Sanford J. Grossman Charitable Trust.

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Authors and Affiliations

  1. Department of Genetics, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Judy H Cho

  2. Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Judy H Cho

  3. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

    Marc Feldman

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  1. Judy H Cho
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Correspondence to Judy H Cho.

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The Kennedy Institute and M.F. receive royalties on patents using combination therapies of methotrexate plus anti-TNF.

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Cho, J., Feldman, M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nat Med 21, 730–738 (2015). https://doi.org/10.1038/nm.3897

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