Skip to main content

Advertisement

SpringerLink
Log in

The Role of the Gut Microbiota in the Pathogenesis of Antiphospholipid Syndrome

  • Antiphospholipid Syndrome (D Erkan, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Infectious triggers are associated with the induction of transient antiphospholipid antibodies. One therefore wonders if microbes that permanently colonize us play a role in the pathogenesis of antiphospholipid syndrome (APS). The microbiota represents the collection of all microorganisms colonizing humans and is necessary for normal host physiology. The microbiota, however, is a constant stress on the immune system, which is tasked with recognizing and eliminating pathogenic microbes while tolerating commensal populations. A growing body of literature supports a critical role for the commensal-immune axis in the development of autoimmunity against colonized barriers (e.g., gut or skin) and sterile organs (e.g., pancreas or joints). Whether these interactions affect the development and sustainment of autoreactive CD4+ T cells and pathogenic autoantibodies in APS is unknown. This review provides an overview of the current understanding of the commensal-immune axis in autoimmunity with a focus on the potential relevance to APS. Additionally, we discuss emerging findings supporting the involvement of the gut microbiota in a spontaneous model of APS, the (NZW × BXSB)F1 hybrid, and formalize hypotheses to explain how interactions between the immune system and the microbiota may influence human APS etiopathogenesis.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7(7):688–93.

    PubMed Central  PubMed  Google Scholar 

  2. Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet. 2012;13(4):260–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124(4):837–48.

    CAS  PubMed  Google Scholar 

  4. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–95.

    CAS  PubMed  Google Scholar 

  6. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121–41.

    CAS  PubMed  Google Scholar 

  7. Mathis D, Benoist C. Microbiota and autoimmune disease: the hosted self. Cell Host Microbe. 2011;10(4):297–301.

    CAS  PubMed  Google Scholar 

  8. Vieira SM, Pagovich OE, Kriegel MA. Diet, microbiota and autoimmune diseases. Lupus. 2014;23(6):518–26.

    CAS  PubMed  Google Scholar 

  9. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome. Lancet. 2010;376(9751):1498–509.

    CAS  PubMed  Google Scholar 

  10. Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Annals of the Rheumatic Diseases. 2014.

  11. Erkan D, Derksen WJM, Kaplan V, Sammaritano L, Pierangeli SS, Roubey R, et al. Real world experience with antiphospholipid antibody tests: how stable are results over time? Ann Rheum Dis. 2005;64(9):1321–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Biggioggero M, Meroni PL. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun Rev. 2010;9(5):A299–304.

    PubMed  Google Scholar 

  13. Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood. 2011;118(17):4714–8.

    CAS  PubMed  Google Scholar 

  14. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306.

    CAS  PubMed  Google Scholar 

  15. Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmunity Reviews. 2014.

  16. De Laat HB, Derksen RH, Urbanus RT, Roest M, de Groot PG. beta2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome. Blood. 2004;104(12):3598–602.

    PubMed  Google Scholar 

  17. Nimpf J, Wurm H, Kostner GM. Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation. Thromb Haemost. 1985;54(2):397–401.

    CAS  PubMed  Google Scholar 

  18. Miyakis S, Giannakopoulos B, Krilis SA. Beta 2 glycoprotein I—function in health and disease. Thromb Res. 2004;114(5–6):335–46.

    CAS  PubMed  Google Scholar 

  19. Maiti SN, Balasubramanian K, Ramoth JA, Schroit AJ. Beta-2-glycoprotein 1-dependent macrophage uptake of apoptotic cells. Binding to lipoprotein receptor-related protein receptor family members. J Biol Chem. 2008;283(7):3761–6.

    CAS  PubMed  Google Scholar 

  20. Ioannou Y, Zhang JY, Passam FH, Rahgozar S, Qi JC, Giannakopoulos B, et al. Naturally occurring free thiols within beta 2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress-induced cell injury. Blood. 2010;116(11):1961–70.

    CAS  PubMed  Google Scholar 

  21. Agar C, de Groot PG, Morgelin M, Monk SD, van Os G, Levels JH, et al. beta(2)-glycoprotein I: a novel component of innate immunity. Blood. 2011;117(25):6939–47. This study demonstrates that LPS binds to domain V of β2GPI, changing its conformation, which prompts clearance of the complex by macrophages. This paper also shows that β2GPI is inversely correlated with temperature rise and inflammatory markers in healthy subjects injected with LPS.

    CAS  PubMed  Google Scholar 

  22. de Groot PG, Meijers JC. Beta(2)-glycoprotein I: evolution, structure and function. J Thromb Haemost. 2011;9(7):1275–84.

    PubMed  Google Scholar 

  23. de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood. 2005;105(4):1540–5.

    PubMed  Google Scholar 

  24. Ioannou Y, Pericleous C, Giles I, Latchman DS, Isenberg DA, Rahman A. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum. 2007;56(1):280–90.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Blank M, Shoenfeld Y, Cabilly S, Heldman Y, Fridkin M, Katchalski-Katzir E. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci U S A. 1999;96(9):5164–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Blank M, Krause I, Fridkin M, Keller N, Kopolovic J, Goldberg I, et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest. 2002;109(6):797–804.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Murthy V, Willis R, Romay-Penabad Z, Ruiz-Limon P, Martinez-Martinez LA, Jatwani S, et al. Value of isolated IgA anti-β2-glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome. Arthritis Rheum. 2013;65(12):3186–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Adachi Y, Inaba M, Sugihara A, Koshiji M, Sugiura K, Amoh Y, et al. Effects of administration of monoclonal antibodies (anti-CD4 or anti-CD8) on the development of autoimmune diseases in (NZW x BXSB)F1 mice. Immunobiology. 1998;198(4):451–64.

    CAS  PubMed  Google Scholar 

  29. Hattori N, Kuwana M, Kaburaki J, Mimori T, Ikeda Y, Kawakami Y. T cells that are autoreactive to beta2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals. Arthritis Rheum. 2000;43(1):65–75.

    CAS  PubMed  Google Scholar 

  30. Yoshida K, Arai T, Kaburaki J, Ikeda Y, Kawakami Y, Kuwana M. Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome. Blood. 2002;99(7):2499–504.

    CAS  PubMed  Google Scholar 

  31. Arai T, Yoshida K, Kaburaki J, Inoko H, Ikeda Y, Kawakami Y, et al. Autoreactive CD4+ T-cell clones to beta2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site. Blood. 2001;98(6):1889–96.

    CAS  PubMed  Google Scholar 

  32. Kuwana M, Matsuura E, Kobayashi K, Okazaki Y, Kaburaki J, Ikeda Y, et al. Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells. Blood. 2005;105(4):1552–7.

    CAS  PubMed  Google Scholar 

  33. Yamaguchi Y, Seta N, Kaburaki J, Kobayashi K, Matsuura E, Kuwana M. Excessive exposure to anionic surfaces maintains autoantibody response to beta(2)-glycoprotein I in patients with antiphospholipid syndrome. Blood. 2007;110(13):4312–8.

    CAS  PubMed  Google Scholar 

  34. Agostinis C, Biffi S, Garrovo C, Durigutto P, Lorenzon A, Bek A, et al. In vivo distribution of β2 glycoprotein I under various pathophysiologic conditions. Blood. 2011;118(15):4231–8.

    CAS  PubMed  Google Scholar 

  35. Rand JH. The antiphospholipid syndrome. Annu Rev Med. 2003;54:409–24.

    CAS  PubMed  Google Scholar 

  36. Levine JS, Subang R, Nasr SH, Fournier S, Lajoie G, Wither J, et al. Immunization with an apoptotic cell-binding protein recapitulates the nephritis and sequential autoantibody emergence of systemic lupus erythematosus. J Immunol. 2006;177(9):6504–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–33.

    CAS  PubMed  Google Scholar 

  38. Giannakopoulos B, Mirarabshahi P, Qi M, Weatherall C, Qi JC, Tanaka K, et al. Deletion of the antiphospholipid syndrome autoantigen β2-glycoprotein I potentiates the lupus autoimmune phenotype in a Toll-like receptor 7-mediated murine model. Arthritis Rheumatol. 2014;66(8):2270–80. This study demonstrates both the protective and pleiotropic role of β2GPI in animal models susceptible to lupus. In addition to inducing thrombosis, autoantibodies against β2GPI may interfere with clearance pathways, which could induce antinuclear systemic autoimmunity.

    CAS  PubMed  Google Scholar 

  39. Giannakopoulos B, Passam F, Rahgozar S, Krilis SA. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood. 2007;109(2):422–30.

    CAS  PubMed  Google Scholar 

  40. Cruz-Tapias P, Blank M, Anaya JM, Shoenfeld Y. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24(4):389–93.

    CAS  PubMed  Google Scholar 

  41. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013;368(11):1033–44. Detailed summary of the current understanding of APS pathogenesis.

    CAS  PubMed  Google Scholar 

  42. Sebastiani GD, Galeazzi M, Morozzi G, Marcolongo R. The immunogenetics of the antiphospholipid syndrome, anticardiolipin antibodies, and lupus anticoagulant. Semin Arthritis Rheum. 1996;25(6):414–20.

    CAS  PubMed  Google Scholar 

  43. Sanchez ML, Katsumata K, Atsumi T, Romero FI, Bertolaccini ML, Funke A, et al. Association of HLA-DM polymorphism with the production of antiphospholipid antibodies. Ann Rheum Dis. 2004;63(12):1645–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Sestak A, O’Neil KM. Familial lupus and antiphospholipid syndrome. Lupus. 2007;16(8):556–63.

    PubMed  Google Scholar 

  45. De Angelis V, Scurati S, Raschi E, Liutkus A, Belot A, Borghi MO, et al. Pro-inflammatory genotype as a risk factor for aPL-associated thrombosis: report of a family with multiple anti-phospholipid positive members. J Autoimmun. 2009;32(1):60–3.

    PubMed  Google Scholar 

  46. Kamboh MI, Wang X, Kao AH, Barmada MM, Clarke A, Ramsey-Goldman R, et al. Genome-wide association study of antiphospholipid antibodies. Autoimmune Dis. 2013;2013:761046.

    PubMed Central  PubMed  Google Scholar 

  47. Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41(2):296–310.

    CAS  PubMed  Google Scholar 

  48. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122(1):107–18.

    CAS  PubMed  Google Scholar 

  49. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569–73. This study demonstrates that short-chain fatty acids, independent of specific bacteria, exert a protective effect against colitis by inducing FOXP3+ CD4+ T cells. The production of short-chain fatty acids promotes intestinal homeostasis and health.

    CAS  PubMed  Google Scholar 

  50. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, de Roos P, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451–5.

    CAS  PubMed  Google Scholar 

  51. Cebula A, Seweryn M, Rempala GA, Pabla SS, McIndoe RA, Denning TL, et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013;497(7448):258–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Goto Y, Panea C, Nakato G, Cebula A, Lee C, Diez MG, et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity. 2014;40(4):594–607.

    CAS  PubMed  Google Scholar 

  54. Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014;510(7503):152–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagan AJ, Pepper M, et al. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Sci. 2012;337(6101):1553–6. This study is the first to demonstrate that gut insults with either pathogens or chemical irritation can lead to commensal-specific memory T cells in vivo.

    CAS  Google Scholar 

  56. Fagarasan S, Kawamoto S, Kanagawa O, Suzuki K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol. 2010;28:243–73.

    CAS  PubMed  Google Scholar 

  57. Benckert J, Schmolka N, Kreschel C, Zoller MJ, Sturm A, Wiedenmann B, et al. The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific. J Clin Invest. 2011;121(5):1946–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee JM, et al. Microbial colonization influences early B-lineage development in the gut lamina propria. Nature. 2013;501(7465):112–5. This study is the first to demonstrate commensal influence on B cell lineage development outside of the bone marrow. The development of B cells in the lamina propria was a novel finding which implicates that commensals can influence the mature B cell repertoire.

    CAS  PubMed  Google Scholar 

  59. Haas A, Zimmermann K, Graw F, Slack E, Rusert P, Ledergerber B, et al. Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection. Gut. 2011;60(11):1506–19.

    CAS  PubMed  Google Scholar 

  60. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011;108(13):5354–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37(1):158–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM, et al. Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol. 2013;14(4):372–9. This study demonstrated that Th17 cells convert to follicular helper T cells in the gut, which are necessary for the production of T cell dependent antigen-specific IgA responses in the intestine.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Kunisawa J, Kiyono H. Alcaligenes is commensal bacteria habituating in the gut-associated lymphoid tissue for the regulation of intestinal IgA responses. Front Immunol. 2012;3:65.

    PubMed Central  PubMed  Google Scholar 

  64. Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010;32(6):815–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4615–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. 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 U S A. 2011;108(28):11548–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–12.

    CAS  PubMed  Google Scholar 

  68. Munz C, Lunemann JD, Getts MT, Miller SD. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol. 2009;9(4):246–58.

    PubMed Central  PubMed  Google Scholar 

  69. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med. 1999;341(27):2068–74.

    CAS  PubMed  Google Scholar 

  70. Oldstone MB. Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases. Monoclon Antib Immunodiagn Immunother. 2014;33(3):158–65.

    CAS  PubMed  Google Scholar 

  71. Ang CW, Jacobs BC, Laman JD. The Guillain-Barre syndrome: a true case of molecular mimicry. Trends Immunol. 2004;25(2):61–6.

    CAS  PubMed  Google Scholar 

  72. Cunningham MW. Streptococcus and rheumatic fever. Curr Opin Rheumatol. 2012;24(4):408–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Fae KC, da Silva DD, Oshiro SE, Tanaka AC, Pomerantzeff PM, Douay C, et al. Mimicry in recognition of cardiac myosin peptides by heart-intralesional T cell clones from rheumatic heart disease. J Immunol. 2006;176(9):5662–70.

    CAS  PubMed  Google Scholar 

  74. Guilherme L, Oshiro SE, Fae KC, Cunha-Neto E, Renesto G, Goldberg AC, et al. T-cell reactivity against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun. 2001;69(9):5345–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Blank M, Krause I, Magrini L, Spina G, Kalil J, Jacobsen S, et al. Overlapping humoral autoimmunity links rheumatic fever and the antiphospholipid syndrome. Rheumatol. 2006;45(7):833–41.

    CAS  Google Scholar 

  76. Gharavi AE, Pierangeli SS, Espinola RG, Liu X, Colden-Stanfield M, Harris EN. Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo. Arthritis Rheum. 2002;46(2):545–52.

    CAS  PubMed  Google Scholar 

  77. van Os GM, Meijers JC, Agar C, Seron MV, Marquart JA, Akesson P, et al. Induction of anti-beta2-glycoprotein I autoantibodies in mice by protein H of Streptococcus pyogenes. J Thromb Haemost. 2011;9(12):2447–56.

    PubMed  Google Scholar 

  78. Yuki N, Susuki K, Koga M, Nishimoto Y, Odaka M, Hirata K, et al. Carbohydrate mimicry between human ganglioside GM1 and Campylobacter jejuni lipooligosaccharide causes Guillain-Barre syndrome. Proc Natl Acad Sci U S A. 2004;101(31):11404–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Ausubel LJ, Kwan CK, Sette A, Kuchroo V, Hafler DA. Complementary mutations in an antigenic peptide allow for crossreactivity of autoreactive T-cell clones. Proc Natl Acad Sci U S A. 1996;93(26):15317–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Wooldridge L, Ekeruche-Makinde J, van den Berg HA, Skowera A, Miles JJ, Tan MP, et al. A single autoimmune T cell receptor recognizes more than a million different peptides. J Biol Chem. 2012;287(2):1168–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J, et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell. 2014;157(5):1073–87. Extensive in vitro study demonstrating that cross-reactivity occurs if key residues are conserved within a target sequence. This suggest that this phenomenon might be more widespread than previously thought but difficult to detect with conventional homology searches.

    CAS  PubMed  Google Scholar 

  82. Trama AM, Moody MA, Alam SM, Jaeger FH, Lockwood B, Parks R, et al. HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria. Cell Host Microbe. 2014;16(2):215–26. Commensal cross-reactive antibodies against HIV gp41 envelope protein develop in both patients and healthy donors, supporting commensal antigens that influence B cell reactivity. Additionally, this study showed that an E. coli intracellular protein RNA polymerase can give rise to antibodies that are cross-reactive to gp41. This supports a role for commensal antigens, both extracellular and intracellular, in the development of the B cell repertoire.

    CAS  PubMed  Google Scholar 

  83. Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM. Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity. 2013;38(2):373–83. This study demonstrates that human influenza- and HIV-specific CD4+ T cells are present in unexposed individuals due to cross-reactivity with environmental and commensal antigens.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Asherson RA, Cervera R. Antiphospholipid antibodies and infections. Ann Rheum Dis. 2003;62(5):388–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Amin NM. Antiphospholipid syndromes in infectious diseases. Hematol/Oncol Clin N Am. 2008;22(1):131–43.

    Google Scholar 

  86. Hang LM, Izui S, Dixon FJ. (NZW x BXSB)F1 hybrid. A model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med. 1981;154(1):216–21.

    CAS  PubMed  Google Scholar 

  87. Mizutani H, Engelman RW, Kinjoh K, Kurata Y, Ikehara S, Matsuzawa Y, et al. Calorie restriction prevents the occlusive coronary vascular disease of autoimmune (NZW x BXSB)F1 mice. Proc Natl Acad Sci U S A. 1994;91(10):4402–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Faith JJ, McNulty NP, Rey FE, Gordon JI. Predicting a human gut microbiota’s response to diet in gnotobiotic mice. Science (New York, NY). 2011;333(6038):101–4.

  89. Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011;474(7351):327–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonzalez A, Fontana L, et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Sci. 2011;332(6032):970–4.

    CAS  Google Scholar 

  91. Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1(6):6ra14.

    PubMed Central  PubMed  Google Scholar 

  92. Zhang C, Li S, Yang L, Huang P, Li W, Wang S, et al. Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat Commun. 2013;4:2163.

    PubMed Central  PubMed  Google Scholar 

  93. Amital H, Gilburd B, Shoenfeld Y. Probiotic supplementation with Lactobacillus casei (Actimel) induces a Th1 response in an animal model of antiphospholipid syndrome. Ann N Y Acad Sci. 2007;1110:661–9.

    CAS  PubMed  Google Scholar 

  94. Vieira SM, Yu, A.; Pagovich, O.E.; Tiniakou, E.; Sterpka, J.; Kriegel, M.A. Depletion of the gut microbiota prevents β2-glycoprotein I antibody production and mortality in a model of antiphospholipid syndrome. Arthritis Rheum; October 1, 2013. p. S1-S1331. An abstract describing the first in vivo evidence that the gut microbiota is involved in the pathogenesis of APS based on antibiotic depletion studies.

  95. Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012;8(6):337–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Kato LM, Kawamoto S, Maruya M, Fagarasan S. Gut TFH and IgA: key players for regulation of bacterial communities and immune homeostasis. Immunol Cell Biol. 2014;92(1):49–56.

    CAS  PubMed  Google Scholar 

  97. Kawamoto S, Tran TH, Maruya M, Suzuki K, Doi Y, Tsutsui Y, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Sci. 2012;336(6080):485–9.

    CAS  Google Scholar 

  98. Dantas G, Sommer MO, Degnan PH, Goodman AL. Experimental approaches for defining functional roles of microbes in the human gut. Annu Rev Microbiol. 2013;67:459–75.

    CAS  PubMed  Google Scholar 

  99. Ahern PP, Faith JJ, Gordon JI. Mining the human gut microbiota for effector strains that shape the immune system. Immunity. 2014;40(6):815–23.

    CAS  PubMed  Google Scholar 

  100. 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):220ra11. Important work demonstrating novel tools to parse the effects of specific gut bacteria on host physiology including regulatory T cell numbers.

    PubMed Central  PubMed  Google Scholar 

  101. Engen SA, Valen Rukke H, Becattini S, Jarrossay D, Blix IJ, Petersen FC, et al. The oral commensal streptococcus mitis shows a mixed memory Th cell signature that is similar to and cross-reactive with Streptococcus pneumoniae. PLoS ONE. 2014;9(8):e104306.

    PubMed Central  PubMed  Google Scholar 

  102. Geiger R, Duhen T, Lanzavecchia A, Sallusto F. Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells. J Exp Med. 2009;206(7):1525–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Szymula A, Rosenthal J, Szczerba BM, Bagavant H, Fu SM, Deshmukh US. T cell epitope mimicry between Sjögren’s syndrome antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol. 2014;152(1–2):1–9. Using murine T cell hybridomas, this study demonstrates that several commensal peptides and one commensal recombinant protein can cross-react with the lupus and Sjögren’s syndrome autoantigen Ro60 that is also one of the most frequent antigen specificities of antinuclear antibodies (ANAs) in healthy subjects.

    CAS  PubMed  Google Scholar 

  104. Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med. 2009;60:471–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol. 2012;30:149–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Asherson RA, Cervera R, Piette JC, Shoenfeld Y, Espinosa G, Petri MA, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine. 2001;80(6):355–77.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank all members of the Kriegel lab for constructive discussions on this topic and Andrew Yu and Dr. Amar Manvar for critical review of the manuscript. This work was supported by grants from the National Institutes of Health (NIH) (K08 AI095318), the Yale Rheumatic Diseases Research Core (NIH P30 AR053495), the Women’s Health Research at Yale, the O’Brien Center at Yale (NIH P30DK079310), the Arthritis National Research Foundation (all to M.A.K.), and the Yale Interdisciplinary Immunology Training Program (NIH T32AI07019) (to W.E.R.).

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

William E. Ruff, Silvio M. Vieira, and Martin A. Kriegel declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, 300 George St, Suite 353G, New Haven, CT, 06511, USA

    William E. Ruff, Silvio M. Vieira & Martin A. Kriegel

  2. Section of Rheumatology, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    Martin A. Kriegel

Authors
  1. William E. Ruff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvio M. Vieira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin A. Kriegel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin A. Kriegel.

Additional information

This article is part of the Topical Collection on Antiphospholipid Syndrome

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruff, W.E., Vieira, S.M. & Kriegel, M.A. The Role of the Gut Microbiota in the Pathogenesis of Antiphospholipid Syndrome. Curr Rheumatol Rep 17, 472 (2015). https://doi.org/10.1007/s11926-014-0472-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11926-014-0472-1

Keywords

Search

Navigation