Advertisement

Immunology of the Microbiome: Implications for Rheumatoid Arthritis and Other Autoimmune Diseases

  • Daniel M. Altmann
  • Catherine J. Reynolds
  • Rosemary J. Boyton
Chapter

Abstract

In rheumatoid arthritis, as in many other autoimmune and inflammatory conditions, there is considerable interest in the accruing evidence that pathogenesis may involve downstream consequences of microbiota dysbiosis. From the perspective of basic immune mechanisms, emergence of these data has necessitated considerable reappraisal of notions of immune receptor recognition of the microbial environment. If host recognition, both of the pathogens that must be eliminated and also of the symbionts that must be retained in some optimal microbial community, each depends on essentially similar ligand-receptor interactions, what are the pathways that distinguish these interactions? That is, far from the immune system being shielded, ignorant or tolerant of commensals, we now think of interaction with a healthy microbiota as requiring interactions with pattern recognition receptors (PRRs) and antigen receptors, in a similar manner to pathogens. There are several levels at which the microbiota may modulate host immunity and thus, disease susceptibility. These include effects on development of specific immune subsets, effects of metabolomic bacterial products on inflammatory and immune pathways, and effects on citrullination of self-antigens and immune cross-reactivity between bacterial antigens of the microbiota and self-antigens. Many unknowns and challenges remain, not least since much of the evidence has thus far been limited to mouse models and to interaction of the gut microbiota with intestinal immune subsets. However, there is optimism that characterization of these microbiota/pathway correlates with disease will pave the way for relatively rapid introduction of new therapeutic strategies.

Keywords

Adaptive immunity Innate immunity Pattern recognition receptors Rheumatoid arthritis 

Abbreviations

GF

Germ-free

IBD

Inflammatory bowel disease

MAMP

Microbe-associated molecular pattern

NOD

Nonobese diabetic

PAMP

Pathogen-associated molecular pattern

PRR

Pattern recognition receptors

RA

Rheumatoid arthritis

SCFA

Short-chain fatty acids

SFB

Segmented filamentous bacteria

TCR

T cell receptor

References

  1. 1.
    Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol. 2011;7:​569–78.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2013;486:207–14.CrossRefGoogle Scholar
  4. 4.
    The Integrative HMO Research Network Consortium. The integrative human microbiome project: dynamic analysis of microbiome-host omics profiles during periods of human health and disease. Cell Host Microbe. 2014;16:276–89.CrossRefGoogle Scholar
  5. 5.
    Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–95.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Surana NK, Kasper DL. Deciphering the tête-à-tête between the microbiota and the immune system. J Clin Invest. 2014;124(10):4197–203.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Nutsch KM, Hsieh CS. T cell tolerance and immunity to commensal bacteria. Curr Opin Immunol. 2012;24(4):385–91.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lederberg J. Infectious history. Science. 2000;288:287–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Brown RL, Clarke TB. The regulation of host defences to infection by themicrobiota. Immunology. 2017 Jan;150(1):1–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Chu H, Mazmanian SK. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol. 2013;14(7):668–75.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bates JM, Akerlund J, Mittge E, Guillemin K. Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota. Cell Host Microbe. 2007;2(6):371–82.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Petnicki-Ocwieja T, Hrncir T, Liu YJ, Biswas A, Hudcovic T, Tlaskalova-Hogenova H, Kobayashi KS. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A. 2009;106(37):15813–8.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT. Metabolic syndrome and altered gut microbiota in mice lacking toll-like receptor 5. Science. 2010;328(5975):228–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Burrows MP, Volchkov P, Kobayashi KS, Chervonsky AV. Microbiota regulates type 1 diabetes through toll-like receptors. Proc Natl Acad Sci U S A. 2015;112(32):9973–7.  https://doi.org/10.1073/pnas.1508740112.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang S, Charbonnier LM, Noval Rivas M, Georgiev P, Li N, Gerber G, Bry L, Chatila TA. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity. 2015;43(2):289–303.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    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(5):745–57.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Flannigan KL, Ngo VL, Geem D, Harusato A, Hirota SA, Parkos CA, Lukacs NW, Nusrat A, Gaboriau-Routhiau V, Cerf-Bensussan N, Gewirtz AT, Denning TL. IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal Immunol. 2017;10(3):673–84.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hepworth MR, Monticelli LA, Fung TC, Ziegler CG, Grunberg S, Sinha R, Mantegazza AR, Ma HL, Crawford A, Angelosanto JM, Wherry EJ, Koni PA, Bushman FD, Elson CO, Eberl G, Artis D, Sonnenberg GF. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    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(3):485–98.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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(6):815–27.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK, Lafaille JJ, Littman DR. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014;510(7503):152–6.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tan TG, Sefik E, Geva-Zatorsky N, Kua L, Naskar D, Teng F, Pasman L, Ortiz-Lopez A, Jupp R, Wu HJ, Kasper DL, Benoist C, Mathis D. Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice. Proc Natl Acad Sci U S A. 2016;113(50):E8141–50.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, Kim S, Fritz JV, Wilmes P, Ueha S, Matsushima K, Ohno H, Olle B, Sakaguchi S, Taniguchi T, Morita H, Hattori M, Honda K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500(7461):232–6.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014;6(220):220–11.CrossRefGoogle Scholar
  25. 25.
    Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM, Burzyn D, Ortiz-Lopez A, Lobera M, Yang J, Ghosh S, Earl A, Snapper SB, Jupp R, Kasper D, Mathis D, Benoist C. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science. 2015;349(6251):993–7.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Geva-Zatorsky N, Sefik E, Kua L, Pasman L, Tan TG, Ortiz-Lopez A, Yanortsang TB, Yang L, Jupp R, Mathis D, Benoist C, Kasper DL. Mining the human gut microbiota for immunomodulatory organisms. Cell. 2017;168(5):928–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Girschick HJ, Guilherme L, Inman RD, Latsch K, Rihl M, Sherer Y, Shoenfeld Y, Zeidler H, Arienti S, Doria A. Bacterial triggers and autoimmune rheumatic diseases. Clin Exp Rheumatol. 2008;26(1 Suppl 48):S12–7.PubMedGoogle Scholar
  28. 28.
    Neumann VC, Grindulis KA, Hubball S, McConkey B, Wright V. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial. Br Med J (Clin Res Ed). 1983;287(6399):1099–102.CrossRefGoogle Scholar
  29. 29.
    Kohashi O, Kuwata J, Umehara K, Uemura F, Takahashi T, Ozawa A. Susceptibility to adjuvant-induced arthritis among germfree, specific-pathogen-free, and conventional rats. Infect Immun. 1979;26(3):791–4.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Rath HC, Herfarth HH, Ikeda JS, Grenther WB, Hamm TE Jr, Balish E, Taurog JD, Hammer RE, Wilson KH, Sartor RB. Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats. J Clin Invest. 1996;98(4):945–53.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014;26:101–7.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, Rostron T, Cerundolo V, Pamer EG, Abramson SB, Huttenhower C, Littman DR. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, Hirota K, Matsushita M, Furuta Y, Narazaki M, Sakaguchi N, Kayama H, Nakamura S, Iida T, Saeki Y, Kumanogoh A, Sakaguchi S, Takeda K. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016;68(11):2646–61.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21(8):895–905.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Li K, Bihan M, Methé BA. Analyses of the stability and core taxonomic memberships of the human microbiome. PLoS One. 2013;8(5):e63139.  https://doi.org/10.1371/journal.pone.0063139.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J, MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M’rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bäckhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM, Versalovic J, Young V, Finlay BB. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe. 2012;12(5):611–22.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, MetaHIT Consortium, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20(2):159–66.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Pianta A, Arvikar SL, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017;127(8):2946–56.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Daniel M. Altmann
    • 1
  • Catherine J. Reynolds
    • 1
  • Rosemary J. Boyton
    • 1
  1. 1.Department of MedicineHammersmith Hospital, Imperial College LondonLondonUK

Personalised recommendations