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TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children

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Abstract

The recently described family of toll-like receptors (TLRs) is a key player in host immunity by mediating inflammatory reactions against a wide range of pathogens. Mutations and polymorphisms in TLRs have revealed the importance of TLRs in human defence against diseases. TLR-2 is reported to interact with different bacterial structures, including lipoproteins, peptidoglycan and lipoteichoic acid. To assess the role of TLR-2 gene polymorphism in acute rheumatic fever (ARF) etiopathology, 61 independent Caucasian Turkish patients and 91 child and 116 adult controls were studied. Antistreptolycin O, C-reactive protein, sedimentation and white blood cell counts were studied to evaluate the clinical characteristics of the patients. Genomic DNA was extracted from peripheral blood using a standard column extraction technique. The Arg753Gln and Arg677Trp polymorphisms were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products for the TLR-2 gene were analysed on 1.5% agarose gel pre-stained with ethidium bromide. Compared with healthy adult controls, the Arg753Arg genotype was significantly decreased in the entire group of ARF cases [odds ratio (OR) 0.01, 95% confidence interval (95% CI) 0.0034–0.031, p<0.0001]. Significantly, ARF patients were just 16 times more frequent with Gln allele (OR 15.6, 95% CI 7.87–30.8, p<0.0001). Moreover, evidence for an intensifying effect of the Gln allele was noteworthy when patients with Arg753Gln genotype were compared with healthy controls (OR 97.1, 95% CI 32.5–290, p<0.0001). However, no Arg677Trp polymorphism was detected in either patients or controls. Our data suggest that there is strong evidence for the biological role of TLR-2 in ARF. The common TLR-2 Arg to Gln polymorphism at position 753 significantly contributes to the pathogenesis of ARF. These results will allow the construction of a profile of individuals prone to ARF and may assist in developing new therapies.

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Abbreviations

ARF:

Acute rheumatic fever

RHD:

Rheumatic heart disease

TLR:

Toll-like receptor

PCR:

Polymerase chain reaction

RFLP:

Restriction fragment length polymorphism

ASO:

Antistreptolysin O

CRP:

C-reactive protein

ESR:

Erythrocyte sedimentation rate

WBC:

White blood cells count

NF-κB:

Nuclear transcription factor kappa B

References

  1. Kaplan E (1996) Recent epidemiology of group A streptococcal infections in North America and abroad: an overview. Pediatrics 97:S945–S948

    Google Scholar 

  2. Krishna Kumar R et al (1999) Epidemiology of streptococcal pharyngitis, rheumatic fever and rheumatic heart disease. In: Narula J et al (eds) Rheumatic fever. American Registry of Pathology, Washington, D.C., pp 41–78

    Google Scholar 

  3. Bisno AL (1996) Acute pharyngitis: etiology and diagnosis. Pediatrics 97:S949–S954

    Google Scholar 

  4. Shulman ST et al (2000) Streptococcal infections. In: Stevens D, Kaplan E (eds) Clinical aspects, microbiology, and molecular pathogenesis. Oxford University Press, New York, pp 76–101

    Google Scholar 

  5. World Health Organization (2004) Rheumatic fever and rheumatic heart disease: report of a WHO expert consultation. Geneva, 20 October–1 November 2001. World Health Organization, Albany, NY, USA

    Google Scholar 

  6. Stollerman GH (1997) Rheumatic fever. Lancet 349:935–942

    Article  CAS  PubMed  Google Scholar 

  7. Kaplan EL (1980) The group A streptococcal upper respiratory tract carrier state: an enigma. J Pediatr 97:337–345

    CAS  PubMed  Google Scholar 

  8. Stollerman GH (2001) Rheumatic fever in the 21st century. Clin Infect Dis 33:806–814

    Article  CAS  PubMed  Google Scholar 

  9. Karaaslan S, Oran B, Reisli I, Erkul I (2000) Acute rheumatic fever in Konya, Turkey. Pediatr Int 42:71–75

    Article  CAS  PubMed  Google Scholar 

  10. Olgunturk R, Aydin GB, Tunaoglu FS, Akalin N (1999) Rheumatic heart disease prevalence among schoolchildren in Ankara, Turkey. Turk J Pediatr 41:201–206

    CAS  PubMed  Google Scholar 

  11. Guilherme L, Kalil J (2002) Rheumatic fever: the T cell response leading to autoimmune aggression in the heart. Autoimmun Rev 1:261–266

    Google Scholar 

  12. Brewerton DA, Joseph J (1976) Bunim memorial lecture. HLA-B27 and the inheritance of susceptibility to rheumatic disease. Arthritis Rheum 19:656–668

    CAS  PubMed  Google Scholar 

  13. Ebringer A, Wilson C (2000) HLA molecules, bacteria and autoimmunity. J Med Microbiol 49:305–311

    Google Scholar 

  14. Senitzer D, Freimer EH (1984) Autoimmune mechanisms in the pathogenesis of rheumatic fever. Rev Infect Dis 6:832–839

    CAS  PubMed  Google Scholar 

  15. Weidebach W, Goldberg AC, Chiarella JM, Guilherme L, Snitcowsky R, Pileggi F, Kalil J (1994) HLA class II antigens in rheumatic fever. Analysis of the DR locus by restriction fragment-length polymorphism and oligotyping. Hum Immunol 40:253–258

    Article  CAS  PubMed  Google Scholar 

  16. Yoshinoya S, Pope RM (1980) Detection of immune complexes in acute rheumatic fever and their relationship to HLA-B5. J Clin Invest 65:136–145

    CAS  PubMed  Google Scholar 

  17. Zwillich SH, Lipsky PE (1987) Molecular mimicry in the pathogenesis of rheumatic diseases. Rheum Dis Clin North Am 13:339–352

    CAS  PubMed  Google Scholar 

  18. Chou HT, Chen CH, Tsai CH, Tsai FJ (2004) Association between transforming growth factor-beta 1 gene C-509T and T869C polymorphisms and rheumatic heart disease. Am Heart J 148:181–186

    Article  CAS  PubMed  Google Scholar 

  19. Berdeli A, Celik HA, Ozyurek R, Aydin HH (2004) Involvement of immunoglobulin FcgammaRIIA and FcgammaRIIIB gene polymorphisms in susceptibility to rheumatic fever. Clin Biochem 37:925–929

    Article  CAS  PubMed  Google Scholar 

  20. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT (2003) Recognition of pneumolysin by toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci U S A 100:1966–1971

    Article  CAS  PubMed  Google Scholar 

  21. Knapp S, Wieland CW, Van Veer C, Takeuchi O, Akira S, Florquin S, van der Poll T (2004) Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J Immunol 172:3132–3138

    CAS  PubMed  Google Scholar 

  22. O’Neill LA (2004) TLRs: Professor Mechnikov, sit on your hat. Trends Immunol 25:687–693

    Google Scholar 

  23. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191

    Article  CAS  PubMed  Google Scholar 

  24. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Willeit J, Schwartz DA (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:185–192

    Article  CAS  PubMed  Google Scholar 

  25. Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O’Neill LA (2001) Mal (MyD88-adapter-like) is required for toll-like receptor 4 signal transduction. Nature 413:78–83

    Article  CAS  PubMed  Google Scholar 

  26. Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the toll signaling pathway. Nat Immunol 2:835–841

    Google Scholar 

  27. Schroder NW, Schumann RR (2005) Single nucleotide polymorphisms of toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5:156–164

    PubMed  Google Scholar 

  28. Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA (2000) A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68:6398–6401

    Article  CAS  PubMed  Google Scholar 

  29. Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, Skerrett SJ, Beutler B, Schroeder L, Nachman A, Ozinsky A, Smith KD, Aderem A (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires’ disease. J Exp Med 198:1563–1572

    Article  CAS  PubMed  Google Scholar 

  30. Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198:521–531

    Article  CAS  PubMed  Google Scholar 

  31. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079

    Article  CAS  PubMed  Google Scholar 

  32. Committee on Rheumatic Fever and Bacterial Endocarditis of the American Heart Association (1982) Jones criteria (revised) for guidance in the diagnosis of rheumatic fever. American Heart Association, Dallas, TX, USA

    Google Scholar 

  33. Schröder NW, Hermann C, Hamann L, Göbel UB, Hartung T, Schumann RR (2003) High frequency of polymorphism Arg753Gln of the toll-like receptor 2 gene detected by a novel allele-specific PCR. J Mol Med 81:368–372

    PubMed  Google Scholar 

  34. World Health Organization (1988) Rheumatic fever and rheumatic heart disease. Report of a WHO Study Group. World Health Organization, Geneva (Technical Report Series No. 764)

  35. Taranta A, Markowitz M (1989) Rheumatic fever. Kluwer, Boston, pp 19–25

    Google Scholar 

  36. Stevens D, Kaplan E (2000) Streptococcal infections. Clinical aspects, microbiology and molecular pathogenesis. Oxford University Press, New York, pp 102–132

    Google Scholar 

  37. Simpson WA, Courtney HS, Ofek I (1987) Interactions of fibronectin with streptococci: the role of fibronectin as a receptor for Streptococcus pyogenes. Rev Infect Dis 9:S351–S359

    Google Scholar 

  38. Kotb M, Watanabe-Ohnishi R, Wang B (1993) Analysis of the TCR V beta specificities of bacterial superantigens using PCR. ImmunoMethods 2:33–40

    Article  CAS  Google Scholar 

  39. Underhill DM (2004) Toll-like receptors and microbes take aim at each other. Curr Opin Immunol 16:483–487

    Article  CAS  PubMed  Google Scholar 

  40. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ (1999) Peptidoglycan and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 274:17406–17409

    Article  CAS  PubMed  Google Scholar 

  41. Schröder NW, Opitz B, Lamping N, Michelsen KS, Zähringer U, Göbel UB, Schumann RR (2000) Involvement of lipopolysaccharide binding protein, CD14, and toll-like receptors in the initiation of innate immune responses by Treponema glycolipids. J Immunol 165:2683–2693

    PubMed  Google Scholar 

  42. Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, Weis JJ (1999) Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoprotein is mediated by toll-like receptor 2. J Immunol 163:2382–2386

    CAS  PubMed  Google Scholar 

  43. Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, Mühlradt PF, Akira S (2000) Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2 and MYD88-dependent signaling pathway. J Immunol 164:554–557

    CAS  PubMed  Google Scholar 

  44. Takeuchi O, Akira S (2002) Genetic approaches to the study of toll-like receptor function. Microbes Infect 4:887–895

    Article  CAS  PubMed  Google Scholar 

  45. Kang TJ, Chae GT (2001) Detection of toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol 31:53–58

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Afig Berdeli.

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Berdeli, A., Celik, H.A., Özyürek, R. et al. TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children. J Mol Med 83, 535–541 (2005). https://doi.org/10.1007/s00109-005-0677-x

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