Behçet Syndrome and Microbes

  • Farida FortuneEmail author
  • Gulen Hatemi


Behçet syndrome (BS) is generally thought to have a complex genetic background where both innate and adaptive immune systems are activated through environmental factors including infections and autoantigens. There are clues to support the role of several different microorganisms including viruses and bacteria, which may be using a common pathway to trigger or activate the inflammation in BS through molecular mimicry. Due to the significant homology between microbial and human heat shock proteins (HSPs), it is suggested that HSPs could be such common triggers. Recent studies on microbiome of patients with BS show distinct features that may help us understand its pathogenesis.


Behçet syndrome Infections Microorganisms Virus Bacteria Microbiota Heat shock proteins Molecular mimicry 


  1. 1.
    Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behçet’s disease: a cross sectional study by exploratory factor analysis. J Rheumatol. 2002;29(11):2393–6.Google Scholar
  2. 2.
    Krause I, Leibovici L, Guedj D, Molad Y, Uziel Y, Weinberger A. Disease patterns of patients with Behçet’s disease demonstrated by factor analysis. Clin Exp Rheumatol. 1999;17(3):347–50.Google Scholar
  3. 3.
    Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with Behçet’s syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis. 2001;60:1074–6.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Karaca M, Hatemi G, Sut N, Yazici H. The papulopustular lesion/arthritis cluster of Behçet’s syndrome also clusters in families. Rheumatology (Oxford). 2012;51(6):1053–60.CrossRefGoogle Scholar
  5. 5.
    Hatemi G, Fresko I, Tascilar K, Yazici H. Increased enthesopathy among Behçet’s syndrome patients with acne and arthritis: an ultrasonography study. Arthritis Rheum. 2008;58(5):1539–45.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hatemi G, Fresko I, Yurdakul S, Ozdogan H, Yazici H, Altiok E, Yenmis G. Reply to letter by Priori et al commenting on whether Behçet’s syndrome patients with acne and arthritis comprise a true subset. Arthritis Rheum. 2010;62(1):305–6.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Hatemi G, Bahar H, Uysal S, Mat C, Gogus F, Masatlioglu S, Altas K, Yazici H. The pustular skin lesions in Behcet’s syndrome are not sterile. Ann Rheum Dis. 2004;63(11):1450–2.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Cooper C, Pippard EC, Sharp H, Wickham C, Chamberlain MA, Barker DJ. Is Behçet’s disease triggered by childhood infection? Ann Rheum Dis. 1989;48(5):421–3.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kaneko F, Oyama N, Yanagihori H, Isogai E, Yokota K, Oguma K. The role of streptococcal hypersensitivity in the pathogenesis of Behçet’s disease. Eur J Dermatol. 2008;18(5):489–98.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Yoshikawa K, Kotake S, Sasamoto Y, Ohno S, Matsuda H. Close association of Streptococcus sanguis and Behçet’s disease. Nippon Ganka Gakkai Zasshi. 1991;95(12):1261–7.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Sezer F. The isolation of a virus as the cause of Behçet’s disease. Am J Ophthalmol. 1953;36:301–6.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Evans AD, Pallis CA, Spillane JD. Involvement of the nervous system in Behçet’s syndrome: report of three cases and isolation of the virus. Lancet. 1957;2:349–53.CrossRefGoogle Scholar
  13. 13.
    Mizushima Y, Matsuda T, Hoshi K, Ohno S. Induction of Behçet’s disease symptoms after dental treatment and streptococcal antigen skin test. J Rheumatol. 1988;15:1029–30.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Lellouche N, Belmatoug N, Bourgoin P, Logeart D, Acar C, Cohen-Solal A, Fantin B. Recurrent valvular relacement due to exacerbation of Behçet’s disease by Streptococcus agalactiae infection. Eur J Intern Med. 2003;14:120–2.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Suga Y, Tsuboi R, Kobayashi S, Ogawa H. A case of Behçet’s disease aggravated by gingival infection with methicillin-resistant Staphylococcus aureus. Br J Dermatol. 1995;133(2):319–21.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Senusi A, Higgins S, Fortune F. The influence of oral health and psycho-social well-being on clinical outcomes in Behçet’s disease. Rheumatol Int. 2018;38(10):1873–83.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Senusi AA, Ola D, Mather J, Mather J, Fortune F. Behçet’s syndrome and health-related quality of life: influence of symptoms, lifestyle and employment status. Clin Exp Rheumatol. 2017;35(Suppl 108(6)):43–50.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Yay M, Çelik Z, Aksoy A, Alibaz-Öner F, Inanç N, Ergun T, et al. Oral health is a mediator for disease severity in patients with Behçet’s disease: a multiple mediation analysis study. J Oral Rehabil. 2019;46(4):349–54.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Togashi A, Saito S, Kaneko F, Nakamura K, Oyama N. Skin prick test with self-saliva in patients with oral aphthoses: a diagnostic pathergy for Behcet’s disease and recurrent aphthosis. Inflamm Allergy Drug Targets. 2011;10(3):164–70.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Fresko I, Yazici H, Bayramiçli M, Yurdakul S, Mat C. Effect of surgical cleaning of the skin on the pathergy phenomenon in Behçet’s syndrome. Ann Rheum Dis. 1993;52(8):619–20.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hatemi G, Yazici H. Behçet’s syndrome and micro-organisms. Best Pract Res Clin Rheumatol. 2011;25(3):389–406.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Inaba Y, Kurosawa M, Nishibu A, Kaneko F, Kawakami Y, Tamakoshi A, Kawamura T. Epidemiologic and clinical characteristics of Behçet disease in Japan: results from nationwide survey in 2003. Clin Exp Rheumatol. 2004;22(4 Suppl 34):S84.Google Scholar
  23. 23.
    Yurdakul S, Yazici Y. Epidemiology of Behçet’s syndrome and regional differences in disease expression. In: Yazici Y, Yazici H, editors. Behçet’s syndrome. New York: Springer; 2010. p. 35–53.CrossRefGoogle Scholar
  24. 24.
    Papoutsis NG, Abdel-Naser MB, Altenburg A, Orawa H, Kötter I, Krause L, et al. Prevalence of Adamantiades-Behçet’s disease in Germany and the municipality of Berlin: results of a nationwide survey. Clin Exp Rheumatol. 2006;24(5 Suppl 42):S125.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Mahr A, Belarbi L, Wechsler B, Jeanneret D, Dhote R, Fain O, et al. Population-based prevalence study of Behçet’s disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum. 2008;58(12):3951–9.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kappen JH, van Dijk EH, Baak-Dijkstra M, van Daele PL, Lam-Tse WK, van Hagen PM, van Laar JA. Behçet’s disease, hospital-based prevalence and manifestations in the Rotterdam area. Neth J Med. 2015;73(10):471–7.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Piga M, Mathieu A. The origin of Behçet’s disease geoepidemiology: possible role of a dual microbial-driven genetic selection. Clin Exp Rheumatol. 2014;32(4 Suppl 84):S123–9.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Çalgüneri M, Ertenli I, Kiraz S, Erman B, Çelik I. Effect of prophylactic benzathine penicillin on mucocutaneous symptoms of Behcet’s disease. Dermatology. 1996;192(2):125–8.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Çalgüneri M, Kiraz S, Ertenli I, Benekli M, Karaaslan Y, Çelik I. The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behcet’s disease. A randomized clinical trial. Arthritis Rheum. 1996;39(12):2062–5.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Kaneko F, Oyama N, Nishibu A. Streptococcal infection in the pathogenesis of Behçet’s disease and clinical effects of minocycline on the disease symptoms. Yonsei Med J. 1997;38:444–54.PubMedCrossRefGoogle Scholar
  31. 31.
    Mumcu G, Ergun T, Elbir Y, Eksioglu-Demiralp E, Yavuz S, et al. Clinical and immunological effects of azithromycin in Behcet’s disease. J Oral Pathol Med. 2005;34:13–6.CrossRefGoogle Scholar
  32. 32.
    Hamza M, Ayed K, Ben AH. Treatment of Behcet’s disease with levamisole. Arthritis Rheum. 1982;25:714–5.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Davies UM, Palmer RG, Denman AM. Treatment with acyclovir does not affect orogenital ulcers in Behcet’s syndrome: a randomized double-blind trial. Br J Rheumatol. 1988;27(4):300–2.PubMedCrossRefGoogle Scholar
  34. 34.
    Bonnet M, Ouzan D, Trepo C. Plasma exchange and acyclovir in Behçet’s disease. J Fr Ophtalmol. 1986;9(1):15–22.PubMedPubMedCentralGoogle Scholar
  35. 35.
    International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet. 1990;335(8697):1078–80.Google Scholar
  36. 36.
    Chen T, Yu WH, Izard J, Baranova OV, Lakshmanan A, Dewhirst FE. The human oral microbiome database: a web accessible resource for investigating oral microbe taxonomic and genomic information. Database (Oxford). 2010;2010:baq013.CrossRefGoogle Scholar
  37. 37.
    Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, et al. FUT2: filling the gap between genes and environment in Behçet’s disease? Ann Rheum Dis. 2015;74(3):618–24.CrossRefGoogle Scholar
  38. 38.
    Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet’s disease: a comprehensive review. J Autoimmun. 2015;64:137–48.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Yamashita Y, Takeshita T. The oral microbiome and human health. J Oral Sci. 2017;59(2):201–6.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Galeone M, Colucci R, D’Erme AM, Moretti S, Lotti T. Potential infectious etiology of Behcet’s disease. Pathol Res Int. 2012;2012:4.CrossRefGoogle Scholar
  41. 41.
    Yokota K, Hayashi S, Araki Y, Isogai E, Kotake S, Yoshikawa K, et al. Characterization of Streptococcus sanguis isolated from patients with Behcet’s disease. Microbiol Immunol. 1995;39:729–32.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Zouboulis CC. HLA-independent antibacterial host response toward Th1 immunity mediated by IL-12: a new concept for the pathogenesis of Adamantiades–Behçet’s disease. J Invest Dermatol. 2006;126:1444–7.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Oliveira R, Napoleão P, Banha J, Paixão E, Bettencourt A, da Silva BM, et al. Crosstalk between inflammation, iron metabolism and endothelial function in Behçet’s disease. Clin Hemorheol Microcirc. 2014;56(2):175–85.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Shin W, Kim HJ. Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip. Proc Natl Acad Sci U S A. 2018;115(45):E10539–47.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Seoudi N, Bergmeier LA, Drobniewski F, Paster B, Fortune F. The oral mucosal and salivary microbial community of Behçet’s syndrome and recurrent aphthous stomatitis. J Oral Microbiol. 2015;7:27150.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Gianchecchi E, Fierabracci A. Recent advances on microbiota involvement in the pathogenesis of autoimmunity. Int J Mol Sci. 2019;20(2):283.PubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kaiko GE, Stappenbeck TS. Host-microbe interactions shaping the gastrointestinal environment. Trends Immunol. 2014;35:538–48.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Ye Z, Zhang N, Wu C, et al. A metagenomic study of the gut microbiome in Behcet’s disease. Microbiome. 2018;6(1):135.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Lu LJ, Liu J. Human microbiota and ophthalmic disease. Yale J Biol Med. 2016;89(3):325–30.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Seoudi N, Bergmeier LA, Hagi-Pavli E, Bibby D, Fortune F. The seroprevalence and salivary shedding of herpesviruses in Behçet’s syndrome and recurrent aphthous stomatitis. J Oral Microbiol. 2015;7:27156.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Hasan MS, Ryan PL, Bergmeier LA, Fortune F. Circulating NK cells and their subsets in Behçet’s disease. Clin Exp Immunol. 2017;188(2):311–22.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kim DY, Cho S, Choi MJ, Sohn S, Lee ES, Bang D. Immunopathogenic role of herpes simplex virus in Behçet’s disease. Genet Res Int. 2013;2013:638273.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Behcet H. Über Rezidivierende, aphtose durch ein Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Dermatol Wochenschr. 1937;105:1152–7.Google Scholar
  54. 54.
    Eglin RP, Lehner T, Subak-Sharpe JH. Detection of RNA complementary to herpes-simplex virus in mononuclear cells from patients with Behcet’s syndrome and recurrent oral ulcers. Lancet. 1982;2(8312):1356–61.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Bonass WA, Bird-Stewart JA, Chamberlain MA, Haliburton IW. Molecular studies in Behcet’s syndrome In: Lehner T, Barnes CG, eds. Recent advances in Behcet’s disease. International Congress and Symposium Series Royal society of Medicine. 1986;103:37–41.Google Scholar
  56. 56.
    Lee S, Bang D, Cho YH, Lee ES, Sohn S. Polymerase chain reaction reveals herpes simplex virus DNA in saliva of patients with Behcet’s disease. Arch Dermatol Res. 1996;288:179–83.PubMedCrossRefGoogle Scholar
  57. 57.
    Lee ES, Lee S, Bang D, Sohn S. Herpes simplex virus detection by polymerase chain reaction in intestinal ulcer of patients with Behçet’s disease. The 7th international conference on Behçet’s disease. Tunis, Revue de rheumatism. 1996;63:531.Google Scholar
  58. 58.
    Bang D, Cho YH, Choi HJ, Lee S, Sohn S. Herpes simplex virus detection by polymerase chain reaction in genital ulcer of patients with Behçet’s disease. The 7th international conference on Behçet’s disease. Tunis, Revue de rheumatism. 1996;63:532.Google Scholar
  59. 59.
    Studd M, McCance DJ, Lehner T. Detection of HSV-1 DNA in patients with Behcet’s syndrome and in patients with recurrent oral ulcers by the polymerase chain reaction. J Med Microbiol. 1991;34(1):39–43.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Nomura Y, Kitteringham N, Shiba K, Goseki M, Kimura A, Mineshita S. Use of the highly sensitive PCR method to detect the Herpes simplex virus type 1 genome and its expression in samples from Behcet disease patients. J Med Dent Sci. 1998;45(1):51–8.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Young C, Lehner T, Barnes CG. CD4 and CD8 cell responses to herpes simplex virus in Behcet’s disease. Clin Exp Immunol. 1988;73(1):6–10.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Aksu K, Kabasakal Y, Sayıner A, Keser G, Oksel F, Bilgiç A, et al. Prevalences of hepatitis A, B, C and E viruses in Behçet’s disease. Rheumatology. 1999;38:1279–81.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Hamuryudan V, Sonsuz A, Yurdakul S. More on hepatitis C virus and Behcet’s syndrome. N Engl J Med. 1995;333(5):322.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    BenEzra D. More on hepatitis C virus and Behcet’s syndrome. N Engl J Med. 1995;333(5):322.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Oguz A, Sametoglu F, Erdogan S. More on hepatitis C virus and Behcet’s syndrome. N Engl J Med. 1995;333(5):322.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Akaogi J, Yotsuyanagi H, Sugata F, Matsuda T, Hino K. Hepatitis viral infection in Behçet’s disease. Hepatol Res. 2000;17:126–38.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Kiraz S, Ertenli I, Benekli M, Çalgüneri M. Parvovirus B19 infection in Behçet’s disease. Clin Exp Rheumatol. 1996;14:71–3.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Fujiwara N, Tsuruda K, Iwamoto Y, Kato F, Odaki T, Yamane N, et al. Significant increase of oral bacteria in the early pregnancy period in Japanese women. J Investig Clin Dent. 2017;8(1).CrossRefGoogle Scholar
  69. 69.
    Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6(237):237ra65.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Perez-Muñoz ME, Arrieta MC, Ramer-Tait AE, Walter J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome. 2017;5(1):48.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Maes M, Kubera M, Leunis JC, Berk M. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012;141:55–62.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Ismail AS, Severson KM, Vaishnava S, et al. Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A. 2011;108(21):8743–8.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Fortune F. Can you catch Behçet’s disease? J Lab Clin Med. 2003;141(1):5–6.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Bank I, Duvdevani M, Livneh A. Expansion of gammadelta T-cells in Behçet’s disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med. 2003;141(1):33–40.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Yasuoka H, Yamaguchi Y, Mizuki N, Nishida T, Kawakami Y, Kuwana M. Preferential activation of circulating CD8+ and gammadelta T cells in patients with active Behcet’s disease and HLA-B51. Clin Exp Rheumatol. 2008;26(4suppl 50):S59–63.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Trost B, Kusalik A, Lucchese G, Kanduc D. Bacterial peptides are intensively present throughout the human proteome. Self Nonself. 2010;1:1–4.CrossRefGoogle Scholar
  77. 77.
    Hasan A, Fortune F, Wilson A, et al. Role of γδ T cells in pathogenesis and diagnosis of Behçet’s disease. Lancet. 1996;347(9004):789–94.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Hasan MS, Bergmeier LA, Petrushkin H, Fortune F. Gamma delta (γδ) T cells and their involvement in Behçet’s disease. J Immunol Res. 2015;2015:705831.PubMedPubMedCentralCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Queen Mary University of London- Barts and The London School of Medicine and Dentistry, London Behçet’s CentreLondonUK
  2. 2.Department of Internal Medicine, Division of RheumatologyIstanbul University-Cerrahpasa, School of MedicineIstanbulTurkey

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