Skip to main content

Advertisement

SpringerLink
Log in

Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells

  • Immunology at Mount Sinai
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Genetic composition and major histocompatibility complex polymorphisms unequivocally predispose to autoimmune disease, but environmental factors also play a critical role in precipitating disease in susceptible individuals. Notorious among these has been microbial infection. Older studies describing associations between microbial infection and autoimmune disease are now followed by new studies demonstrating correlations between susceptibility to autoimmune disease and commensal colonization of the intestinal tract. T helper 17 (TH17) cells have gained a prominent role in autoimmune disease, and notably, their development within the intestine has been linked to colonization with specific commensal bacteria. Here, we consider current views on how microbes, TH17 cells, and autoimmunity are connected. We speculate on how the intricate relationships among commensal, pathogen, and the host might ultimately determine susceptibility to autoimmune disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008;4:e1000024.

    PubMed  Google Scholar 

  2. Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med. 2011;365:1612–23.

    PubMed  CAS  Google Scholar 

  3. Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, Eric Gershwin M. Twin studies in autoimmune disease: Genetics, gender and environment. J Autoimmun. 2011. doi:10.1016/j.jaut.2011.11.003.

  4. Javierre BM, Hernando H, Ballestar E. Environmental triggers and epigenetic deregulation in autoimmune disease. Discov Med. 2011;12:535–45.

    PubMed  Google Scholar 

  5. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9:246–58.

    PubMed  Google Scholar 

  6. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139–76.

    PubMed  CAS  Google Scholar 

  7. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 2003;426:454–60.

    PubMed  CAS  Google Scholar 

  8. Akirav EM, Ruddle NH, Herold KC. The role of AIRE in human autoimmune disease. Nat Rev Endocrinol. 2011;7:25–33.

    PubMed  CAS  Google Scholar 

  9. Giraud M, Yoshida H, Abramson J, Rahl PB, Young RA, Mathis D, Benoist C. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc Natl Acad Sci USA. 2012;10:535–40.

    Google Scholar 

  10. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29.

    PubMed  CAS  Google Scholar 

  11. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachee-Chardin M, Toulon A, Bustamante J, Al-Muhsen S, Al-Owain M, Arkwright PD, Costigan C, McConnell V, Cant AJ, Abinun M, Polak M, Bougneres PF, Kumararatne D, Marodi L, Nahum A, Roifman C, Blanche S, Fischer A, Bodemer C, Abel L, Lilic D, Casanova JL. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291–7.

    PubMed  CAS  Google Scholar 

  12. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–67.

    PubMed  CAS  Google Scholar 

  13. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206:299–311.

    PubMed  CAS  Google Scholar 

  14. Bouneaud C, Kourilsky P, Bousso P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity. 2000;13:829–40.

    PubMed  CAS  Google Scholar 

  15. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172:5967–72.

    PubMed  CAS  Google Scholar 

  16. Raddassi K, Kent SC, Yang J, Bourcier K, Bradshaw EM, Seyfert-Margolis V, Nepom GT, Kwok WW, Hafler DA. Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis. J Immunol. 2011;187:1039–46.

    PubMed  CAS  Google Scholar 

  17. Yang J, Danke N, Roti M, Huston L, Greenbaum C, Pihoker C, James E, Kwok WW. CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope. J Autoimmun. 2008;31:30–41.

    PubMed  Google Scholar 

  18. van Noort JM, van Sechel A, Boon J, Boersma WJ, Polman CH, Lucas CJ. Minor myelin proteins can be major targets for peripheral blood T cells from both multiple sclerosis patients and healthy subjects. J Neuroimmunol. 1993;46:67–72.

    PubMed  Google Scholar 

  19. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711.

    PubMed  CAS  Google Scholar 

  20. Desch AN, Randolph GJ, Murphy K, Gautier EL, Kedl RM, Lahoud MH, Caminschi I, Shortman K, Henson PM, Jakubzick CV. CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J Exp Med. 2011;208:1789–97.

    PubMed  CAS  Google Scholar 

  21. Hoyne GF. Mechanisms that regulate peripheral immune responses to control organ-specific autoimmunity. Clin Dev Immunol. 2011;2011:294968.

    PubMed  Google Scholar 

  22. Teh CE, Daley SR, Enders A, Goodnow CC. T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency. Proc Natl Acad Sci USA. 2010;107:14709–14.

    PubMed  CAS  Google Scholar 

  23. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166–82.

    PubMed  CAS  Google Scholar 

  24. Maier LM, Hafler DA. Autoimmunity risk alleles in costimulation pathways. Immunol Rev. 2009;229:322–36.

    PubMed  CAS  Google Scholar 

  25. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992;356:314–7.

    PubMed  CAS  Google Scholar 

  26. Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S, Harris AW. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA. 1991;88:8661–5.

    PubMed  CAS  Google Scholar 

  27. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.

    PubMed  CAS  Google Scholar 

  28. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11:7–13.

    PubMed  CAS  Google Scholar 

  29. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011;108:5354–9.

    PubMed  CAS  Google Scholar 

  30. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol. 2012;42:102–11.

    PubMed  CAS  Google Scholar 

  31. Azevedo PM, Pereira RR, Guilherme L. Understanding rheumatic fever. Rheumatol Int. 2011. doi:10.1007/s00296-011-2152-z.

  32. Benoist C, Mathis D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nat Immunol. 2001;2:797–801.

    PubMed  CAS  Google Scholar 

  33. Christen U, Hintermann E, Holdener M, von Herrath MG. Viral triggers for autoimmunity: is the ‘glass of molecular mimicry’ half full or half empty? J Autoimmun. 2010;34:38–44.

    PubMed  CAS  Google Scholar 

  34. Rose NR, Mackay IR. Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci. 2000;57:542–51.

    PubMed  CAS  Google Scholar 

  35. McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James JA. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat Med. 2005;11:85–9.

    PubMed  CAS  Google Scholar 

  36. Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR. From infection to autoimmunity. J Autoimmun. 2001;16:175–86.

    PubMed  CAS  Google Scholar 

  37. Regner M, Lambert PH. Autoimmunity through infection or immunization? Nat Immunol. 2001;2:185–8.

    PubMed  CAS  Google Scholar 

  38. Hardy TA, Blum S, McCombe PA, Reddel SW. Guillain-barre syndrome: modern theories of etiology. Curr Allergy Asthma Rep. 2011;11:197–204.

    PubMed  Google Scholar 

  39. Steiner I, Rosenberg G, Wirguin I. Transient immunosuppression: a bridge between infection and the atypical autoimmunity of Guillain-Barre syndrome? Clin Exp Immunol. 2010;162:32–40.

    PubMed  CAS  Google Scholar 

  40. Yuki N, Kuwabara S. Axonal Guillain-Barre syndrome: carbohydrate mimicry and pathophysiology. J Peripher Nerv Syst. 2007;12:238–49.

    PubMed  CAS  Google Scholar 

  41. Moran AP. Structure and conserved characteristics of Campylobacter jejuni lipopolysaccharides. J Infect Dis. 1997;176(Suppl 2):S115–21.

    PubMed  CAS  Google Scholar 

  42. Steere AC, Drouin EE, Glickstein LJ. Relationship between immunity to Borrelia burgdorferi outer-surface protein A (OspA) and Lyme arthritis. Clin Infect Dis. 2011;52(Suppl 3):s259–65.

    PubMed  CAS  Google Scholar 

  43. Singh SK, Girschick HJ. Lyme borreliosis: from infection to autoimmunity. Clin Microbiol Infect. 2004;10:598–614.

    PubMed  CAS  Google Scholar 

  44. Guilherme L, Fae K, Oshiro SE, Kalil J. Molecular pathogenesis of rheumatic fever and rheumatic heart disease. Expert Rev Mol Med. 2005;7:1–15.

    PubMed  Google Scholar 

  45. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, van der Zee R, Telford JL, Vandenbroucke-Grauls CM, D’Elios MM, Del Prete G. Molecular mimicry between Helicobacter pylori antigens and H+, K+–adenosine triphosphatase in human gastric autoimmunity. J Exp Med. 2003;198:1147–56.

    PubMed  CAS  Google Scholar 

  46. Yamanishi S, Iizumi T, Watanabe E, Shimizu M, Kamiya S, Nagata K, Kumagai Y, Fukunaga Y, Takahashi H. Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease. Infect Immun. 2006;74:248–56.

    PubMed  CAS  Google Scholar 

  47. Muller A, Oertli M, Arnold IC. H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection. Cell Commun Signal. 2011;9:25.

    PubMed  CAS  Google Scholar 

  48. Drescher KM, Tracy SM. The CVB and etiology of type 1 diabetes. Curr Top Microbiol Immunol. 2008;323:259–74.

    PubMed  CAS  Google Scholar 

  49. Fairweather D, Rose NR. Type 1 diabetes: virus infection or autoimmune disease? Nat Immunol. 2002;3:338–40.

    PubMed  CAS  Google Scholar 

  50. Filippi CM, von Herrath MG. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: viruses, autoimmunity and immunoregulation. Clin Exp Immunol. 2010;160:113–9.

    PubMed  CAS  Google Scholar 

  51. Kawasaki T, Kawai T, Akira S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol Rev. 2011;243:61–73.

    PubMed  CAS  Google Scholar 

  52. Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol. 2009;5:219–26.

    PubMed  CAS  Google Scholar 

  53. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009;324:387–9.

    PubMed  CAS  Google Scholar 

  54. Root-Bernstein R, Vonck J, Podufaly A. Antigenic complementarity between coxsackie virus and streptococcus in the induction of rheumatic heart disease and autoimmune myocarditis. Autoimmunity. 2009;42:1–16.

    PubMed  CAS  Google Scholar 

  55. Alotaibi S, Kennedy J, Tellier R, Stephens D, Banwell B. Epstein-Barr virus in pediatric multiple sclerosis. JAMA. 2004;291:1875–9.

    PubMed  CAS  Google Scholar 

  56. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288–99.

    PubMed  Google Scholar 

  57. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, Virgin HW. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141:1135–45.

    PubMed  CAS  Google Scholar 

  58. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HWt. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259–63.

    PubMed  CAS  Google Scholar 

  59. Hill Gaston JS, Lillicrap MS. Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol. 2003;17:219–39.

    PubMed  CAS  Google Scholar 

  60. Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol. 2011;7:569–78.

    PubMed  CAS  Google Scholar 

  61. Townes JM. Reactive arthritis after enteric infections in the United States: the problem of definition. Clin Infect Dis. 2010;50:247–54.

    PubMed  Google Scholar 

  62. Townes JM, Deodhar AA, Laine ES, Smith K, Krug HE, Barkhuizen A, Thompson ME, Cieslak PR, Sobel J. Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study. Ann Rheum Dis. 2008;67:1689–96.

    PubMed  CAS  Google Scholar 

  63. Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–94.

    PubMed  CAS  Google Scholar 

  64. Targan SR, Karp LC. Defects in mucosal immunity leading to ulcerative colitis. Immunol Rev. 2005;206:296–305.

    PubMed  CAS  Google Scholar 

  65. Cong Y, Feng T, Fujihashi K, Schoeb TR, Elson CO. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci USA. 2009;106:19256–61.

    PubMed  CAS  Google Scholar 

  66. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation. Annu Rev Immunol. 2002;20:495–549.

    PubMed  CAS  Google Scholar 

  67. Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331:337–41.

    PubMed  CAS  Google Scholar 

  68. Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011;34:794–806.

    PubMed  CAS  Google Scholar 

  69. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell. 2011;145:745–57.

    PubMed  CAS  Google Scholar 

  70. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    PubMed  CAS  Google Scholar 

  71. Hase K, Takahashi D, Ebisawa M, Kawano S, Itoh K, Ohno H. Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease. PLoS One. 2008;3:e3033.

    PubMed  Google Scholar 

  72. Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol. 2008;35:1500–5.

    PubMed  CAS  Google Scholar 

  73. Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, Heuvelmans-Jacobs M, Akira S, Nicklin MJ, Ribeiro-Dias F, van den Berg WB. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Investig. 2008;118:205–16.

    PubMed  CAS  Google Scholar 

  74. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010;32:815–27.

    PubMed  CAS  Google Scholar 

  75. Monach PA, Mathis D, Benoist C. The K/BxN arthritis model. Curr Protoc Immunol Chapter 15: Unit 15 22. 2008.

  76. Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse colonies around the world–recent facts and figures. Immunol Today. 1993;14:193–6.

    PubMed  CAS  Google Scholar 

  77. Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23:447–85.

    PubMed  CAS  Google Scholar 

  78. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008;455:1109–13.

    PubMed  CAS  Google Scholar 

  79. Kranich J, Maslowski KM, Mackay CR. Commensal flora and the regulation of inflammatory and autoimmune responses. Semin Immunol. 2011;23:139–45.

    PubMed  CAS  Google Scholar 

  80. Pang IK, Iwasaki A. Control of antiviral immunity by pattern recognition and the microbiome. Immunol Rev. 2012;245:209–26.

    PubMed  CAS  Google Scholar 

  81. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Nat Acad Sci USA. 2011;108(Suppl 1):4615–22.

    PubMed  CAS  Google Scholar 

  82. Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011;479:538–41.

    PubMed  CAS  Google Scholar 

  83. Infante-Duarte C, Horton HF, Byrne MC, Kamradt T. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol. 2000;165:6107–15.

    PubMed  CAS  Google Scholar 

  84. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421:744–8.

    PubMed  CAS  Google Scholar 

  85. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–7.

    PubMed  CAS  Google Scholar 

  86. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    PubMed  CAS  Google Scholar 

  87. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10:314–24.

    PubMed  CAS  Google Scholar 

  88. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.

    PubMed  CAS  Google Scholar 

  89. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.

    PubMed  CAS  Google Scholar 

  90. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.

    PubMed  CAS  Google Scholar 

  91. Ghoreschi K, Laurence A, Yang XP, Hirahara K, O’Shea JJ. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol. 2011;32:395–401.

    PubMed  CAS  Google Scholar 

  92. Gonzalez-Garcia I, Zhao Y, Ju S, Gu Q, Liu L, Kolls JK, Lu B. IL-17 signaling-independent central nervous system autoimmunity is negatively regulated by TGF-beta. J Immunol. 2009;182:2665–71.

    PubMed  CAS  Google Scholar 

  93. Hu Y, Ota N, Peng I, Refino CJ, Danilenko DM, Caplazi P, Ouyang W. IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2010;184:4307–16.

    PubMed  CAS  Google Scholar 

  94. Ishigame H, Nakajima A, Saijo S, Komiyama Y, Nambu A, Matsuki T, Nakae S, Horai R, Kakuta S, Iwakura Y. The role of TNFalpha and IL-17 in the development of excess IL-1 signaling-induced inflammatory diseases in IL-1 receptor antagonist-deficient mice. Ernst Schering Research Foundation workshop. 2006:129–53.

  95. Lubberts E. IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine. 2008;41:84–91.

    PubMed  CAS  Google Scholar 

  96. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–6.

    PubMed  CAS  Google Scholar 

  97. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006;12:382–8.

    PubMed  Google Scholar 

  98. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011;12:383–90.

    PubMed  CAS  Google Scholar 

  99. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, Miossec P. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999;42:963–70.

    PubMed  CAS  Google Scholar 

  100. Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000;164:2832–8.

    PubMed  CAS  Google Scholar 

  101. Rasmussen TK, Andersen T, Hvid M, Hetland ML, Horslev-Petersen K, Stengaard-Pedersen K, Holm CK, Deleuran B. Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis. J Rheumatol. 2010;37:2014–20.

    PubMed  CAS  Google Scholar 

  102. Melis L, Vandooren B, Kruithof E, Jacques P, De Vos M, Mielants H, Verbruggen G, De Keyser F, Elewaut D. Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis. 2010;69:618–23.

    PubMed  CAS  Google Scholar 

  103. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8:500–8.

    PubMed  CAS  Google Scholar 

  104. Ishizu T, Osoegawa M, Mei FJ, Kikuchi H, Tanaka M, Takakura Y, Minohara M, Murai H, Mihara F, Taniwaki T, Kira J. Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis. Brain J Neurol. 2005;128:988–1002.

    Google Scholar 

  105. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol. 2008;172:146–55.

    PubMed  CAS  Google Scholar 

  106. Vaknin-Dembinsky A, Balashov K, Weiner HL. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol. 2006;176:7768–74.

    PubMed  CAS  Google Scholar 

  107. Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.

    PubMed  CAS  Google Scholar 

  108. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204:1849–61.

    PubMed  CAS  Google Scholar 

  109. Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, Sakuraba A, Kitazume MT, Sugita A, Koganei K, Akagawa KS, Hibi T. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Investig. 2008;118:2269–80.

    PubMed  CAS  Google Scholar 

  110. Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles CH, Rampton DS, Corazza GR, Monteleone G, Di Sabatino A, Macdonald TT. Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut. 2009;58:1629–36.

    PubMed  CAS  Google Scholar 

  111. Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, Bos JD. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol. 1998;111:645–9.

    PubMed  CAS  Google Scholar 

  112. Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, Bowman EP, Krueger JG. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207–11.

    PubMed  CAS  Google Scholar 

  113. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, Kane JP, Saccone S, Worthington J, Bruce I, Kwok PY, Menter A, Krueger J, Barton A, Saccone NL, Bowcock AM. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008;4:e1000041.

    PubMed  Google Scholar 

  114. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–3.

    PubMed  CAS  Google Scholar 

  115. Nunez C, Dema B, Cenit MC, Polanco I, Maluenda C, Arroyo R, de las Heras V, Bartolome M, de la Concha EG, Urcelay E, Martinez A. IL23R: a susceptibility locus for celiac disease and multiple sclerosis? Genes Immun. 2008;9:289–93.

    PubMed  CAS  Google Scholar 

  116. Hazlett J, Stamp LK, Merriman T, Highton J, Hessian PA. IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis. Genes Immun. 2011. doi:10.1038/gene.2011.80.

  117. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–78.

  118. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273–90.

    PubMed  CAS  Google Scholar 

  119. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–52.

    PubMed  CAS  Google Scholar 

  120. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955–62.

    PubMed  CAS  Google Scholar 

  121. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910–4.

    PubMed  CAS  Google Scholar 

  122. Vanden Eijnden S, Goriely S, De Wit D, Willems F, Goldman M. IL-23 up-regulates IL-10 and induces IL-17 synthesis by polyclonally activated naive T cells in human. Eur J Immunol. 2005;35:469–75.

    PubMed  CAS  Google Scholar 

  123. Neurath MF. IL-23: a master regulator in Crohn disease. Nat Med. 2007;13:26–8.

    PubMed  CAS  Google Scholar 

  124. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107.

    PubMed  CAS  Google Scholar 

  125. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12:255–63.

    PubMed  CAS  Google Scholar 

  126. Hirota K, Martin B, Veldhoen M. Development, regulation and functional capacities of Th17 cells. Semin Immunopathol. 2010;32:3–16.

    PubMed  CAS  Google Scholar 

  127. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4 + T cells. Science. 2010;327:1098–102.

    PubMed  Google Scholar 

  128. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 + T helper cells. Cell. 2006;126:1121–33.

    PubMed  CAS  Google Scholar 

  129. Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, Bowman EP, Sgambellone NM, Chan CC, Caspi RR. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205:799–810.

    PubMed  CAS  Google Scholar 

  130. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J Clin Invest. 2001;108:739–47.

    PubMed  CAS  Google Scholar 

  131. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med. 2004;200:79–87.

    PubMed  CAS  Google Scholar 

  132. Bending D, De la Pena H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, Cooke A. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Investig. 2009;119:565–72.

    PubMed  CAS  Google Scholar 

  133. Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009;39:216–24.

    PubMed  CAS  Google Scholar 

  134. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8:1390–7.

    PubMed  CAS  Google Scholar 

  135. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–73.

    PubMed  CAS  Google Scholar 

  136. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169:7104–10.

    PubMed  CAS  Google Scholar 

  137. Van Belle TL, Esplugues E, Liao J, Juntti T, Flavell RA, von Herrath MG. Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. J Immunol. 2011;187:2915–22.

    PubMed  Google Scholar 

  138. Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol. 2006;7:1151–6.

    PubMed  CAS  Google Scholar 

  139. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature. 2010;467:967–71.

    PubMed  CAS  Google Scholar 

  140. Sujino T, Kanai T, Ono Y, Mikami Y, Hayashi A, Doi T, Matsuoka K, Hisamatsu T, Takaishi H, Ogata H, Yoshimura A, Littman DR, Hibi T. Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. Gastroenterology. 2011;141:1014–23.

    Google Scholar 

  141. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139:485–98.

    PubMed  CAS  Google Scholar 

  142. Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008;4:337–49.

    PubMed  CAS  Google Scholar 

  143. Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K. ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008;455:808–12.

    PubMed  CAS  Google Scholar 

  144. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G, Snel J, Kelly D, Cerf-Bensussan N. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity. 2009;31:677–89.

    PubMed  CAS  Google Scholar 

  145. Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, Kamm MA, Weismueller J, Beglinger C, Stolte M, Wolff C, Schulze J. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53:1617–23.

    PubMed  CAS  Google Scholar 

  146. Kwon HK, Lee CG, So JS, Chae CS, Hwang JS, Sahoo A, Nam JH, Rhee JH, Hwang KC, Im SH. Generation of regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune disorders. Proc Natl Acad Sci U S A. 2010;107:2159–64.

    PubMed  CAS  Google Scholar 

  147. Livingston M, Loach D, Wilson M, Tannock GW, Baird M. Gut commensal Lactobacillus reuteri 100–23 stimulates an immunoregulatory response. Immunol Cell Biol. 2010;88:99–102.

    PubMed  Google Scholar 

  148. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011;332:974–7.

    PubMed  CAS  Google Scholar 

  149. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, Peterson DA, Stappenbeck TS, Hsieh CS. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478:250–4.

    PubMed  CAS  Google Scholar 

  150. Lee AS, Gibson DL, Zhang Y, Sham HP, Vallance BA, Dutz JP. Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice. Diabetologia. 2010;53:741–8.

    PubMed  CAS  Google Scholar 

  151. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA. 2011;108:11548–53.

    PubMed  CAS  Google Scholar 

  152. Marks BR, Nowyhed HN, Choi JY, Poholek AC, Odegard JM, Flavell RA, Craft J. Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation. Nat Immunol. 2009;10:1125–32.

    PubMed  CAS  Google Scholar 

  153. Lochner M, Berard M, Sawa S, Hauer S, Gaboriau-Routhiau V, Fernandez TD, Snel J, Bousso P, Cerf-Bensussan N, Eberl G. Restricted microbiota and absence of cognate TCR antigen leads to an unbalanced generation of Th17 cells. J Immunol. 2011;186:1531–7.

    PubMed  CAS  Google Scholar 

  154. Torchinsky MB, Garaude J, Martin AP, Blander JM. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation. Nature. 2009;458:78–82.

    PubMed  CAS  Google Scholar 

  155. Blander JM, Medzhitov R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature. 2006;440:808–12.

    PubMed  CAS  Google Scholar 

  156. Torchinsky MB, Garaude J, Blander JM. Infection and apoptosis as a combined inflammatory trigger. Curr Opin Immunol. 2010;22:55–62.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Mount Sinai School of Medicine, Immunology Institute, 1425 Madison Avenue, New York, NY, 10029, USA

    J. Magarian Blander, Miriam B. Torchinsky & Laura Campisi

Authors
  1. J. Magarian Blander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam B. Torchinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Campisi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Magarian Blander.

Additional information

Miriam B. Torchinsky and Laura Campisi have equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blander, J.M., Torchinsky, M.B. & Campisi, L. Revisiting the old link between infection and autoimmune disease with commensals and T helper 17 cells. Immunol Res 54, 50–68 (2012). https://doi.org/10.1007/s12026-012-8311-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-012-8311-9

Keywords

Search

Navigation