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2009, Number 2

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Bioquimia 2009; 34 (2)

Toll-like receptors gene polymorphisms, their role in diseases and transplantation

Martínez-Córdova Z, Calzadilla-Lugo F, Artiles-Valor A

Language: Spanish
References: 107
Page: 83-94
PDF size: 185.66 Kb.


ABSTRACT

The innate immunity plays a critical role in host protection against pathogens and the pattern recognition receptors such as the Toll-like receptors (TLRs), are key mediators of the activation and regulation of this immune response. The function of TLRs in several human diseases has been investigated by comparing the incidence of disease among persons with different polymorphisms in the genes of TLRs suggesting that some of these polymorphisms are associated with susceptibility to a spectrum of diseases. In this review we summarize studies of TLRs polymorphisms in human infectious and non-infectious diseases, allograft rejection and graft versus host disease because these findings have resulted in new opportunities to study the pathogenesis of disease, the events implicated in the allograft rejection, graft versus host disease and the development of novel therapeutic products specifically tailored to individuals.


REFERENCES

  1. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007; 449: 819-26.

  2. Akira S. Toll-like receptor signaling. J Biol Chem. 2003; 278: 38105-8.

  3. Casanova JL, Abel L. Genetic dissection of immunity to Mycobacteria: the human model. Annu Rev Immunol. 2002; 20: 581-620.

  4. Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat Rev Genet. 2001; 2: 967-77.

  5. Hill AV. The genomics and genetics of human infectious disease susceptibility Annu Rev Genomics Hum Genet. 2001; 2: 373-400.

  6. Misch EA, Hawn TR. Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci. 2008; 114: 347-60.

  7. Molvig J, Baek L, Christensen P, Manogue KR, Vlassara H, Platz P, et al. Endotoxin-stimulated human monocyte secretion of interleukin 1, tumour necrosis factor alpha, and prostaglandin E2 shows stable interindividual differences. Scand J Immunol. 1988; 27: 705-16.

  8. Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet. 1997; 349: 170-3.

  9. Wurfel MM, Park WY, Radella F, Ruzinski J, Sandstrom A, Strout J, et al. Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity. J Immunol. 2005; 175: 2570-8.

  10. Yaqoob P, Newsholme EA, Calder PC. Comparison of cytokine production in cultures of whole human blood and purified mononuclear cells. Cytokine. 1999; 11: 600-5.

  11. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002; 20: 197-216.

  12. Ameziane N, Beillat T, Verpillat P, Chollet-Martin S, Aumont MC, Seknadji P, et al. Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol. 2003; 23: 61-4.

  13. Hill AV. Aspects of genetic susceptibility to human infectious diseases. Annu Rev Genet. 2006; 40: 469-86.

  14. Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med. 2002.13; 162: 1028-32.

  15. Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, et al. Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci USA. 2003; 100: 6075-80.

  16. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the DrosophilaToll protein signals activation of adaptive immunity. Nature. 1997; 388(6640): 394-7.

  17. Tesar BM, Goldstein DR. Toll-like receptors and their role in transplantation. Front Biosci. 2007; 12: 4221-38.

  18. Akira S. TLR signaling. Curr Top Microbiol Immunol. 2006; 311: 1-16.

  19. Kawai T, Akira S. TLR signaling. Cell Death Differ 2006; 13: 816-25.

  20. Albiger B, Dahlberg S, Henriques-Normark B, Normark. Role of the innate immune system in host defense against bacterial infections: focus on the Toll-like receptors. J Intern Med. 2007; 261: 511-28.

  21. Adachi K, Tsutsui H, Kashiwamura S, Seki E, Nakano H, Takeuchi O, et al. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol. 2001; 167: 5928-34.

  22. Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med. 2006; 84: 712-25.

  23. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124: 783-801.

  24. Beutler B, Eidenschenk C, Crozat K, Imler JL, Takeuchi O, Hoffmann JA, et al. Genetic analysis of resistance to viral infection. Nat Rev Immunol. 2007; 7: 753-66.

  25. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature. 2002; 420: 324-9.

  26. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301: 640-3.

  27. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol. 2003; 4: 1144-50.

  28. Orange JS, Geha RS. Finding NEMO: genetic disorders of NF-[kappa]B activation. J Clin Invest. 2003; 112: 983-5.

  29. Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004; 16: 34-41.

  30. Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol 2004; 5: 975-799.

  31. Schröder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005; 5: 156-64.

  32. Schwartz DA, Cook DN. Polymorphisms of the Toll-like receptors and human disease. Clin Infect Dis. 2005; 41(Suppl 7): S403-7.

  33. Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis. 2002; 186: 1522-5.

  34. Barber RC, Chang LY, Arnoldo BD, Purdue GF, Hunt JL, Horton JW, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006; 4: 250-5.

  35. Child NJ, Yang IA, Pulletz MC, de Courcy-Golder K, Andrews AL, Pappachan VJ, et al. Polymorphisms in Toll-like receptor 4 and the systemic inflammatory response syndrome. Biochem Soc Trans. 2003; 31(Pt 3): 652-3.

  36. Feterowski C, Emmanuilidis K, Miethke T, Gerauer K, Rump M, Ulm K, et al. Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology. 2003; 109: 426-31.

  37. Allen A, Obaro S, Bojang K, Awomoyi AA, Greenwood BM, Whittle H, et al. Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children. Pediatr Infect Dis J. 2003; 22: 1018-19.

  38. Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, et al. A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis. 2001; 184: 640-2.

  39. Faber J, Meyer CU, Gemmer C, Russo A, Finn A, Murdoch C, et al. Human toll-like receptor 4 mutations are associated with susceptibility to invasive meningococcal disease in infancy. Pediatr Infect Dis J. 2006; 25: 80-1.

  40. Hawn TR, Verbon A, Janer M, Zhao LP, Beutler B, Aderem A. Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci USA. 2005; 102: 2487-9.

  41. Kurt-Jones EA, Chan M, Zhou S, Wang J, Reed G, Bronson R, et al. Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc Natl Acad Sci USA. 2004; 101: 1315-20.

  42. Paulus SC, Hirschfeld AF, Víctor RE, Brunstein J, Thomas E, Turvey SE. Common human Toll-like receptor 4 polymorphisms-role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin Immunol. 2007; 123: 252-7.

  43. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, et al. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001; 103: 1064-70.

  44. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002; 347: 185-92.

  45. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, Reitsma PH, et al. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation. 2003; 107: 2416-21.

  46. Edfeldt K, Bennet AM, Eriksson P, Frostegård J, Wiman B, Hamsten A, et al. Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004; 25: 1447-53.

  47. Kilding R, Akil M, Till S, Amos R, Winfield J, Iles MM, et al. A biologically important single nucleotide polymorphism within the toll-like receptor-4 gene is not associated with rheumatoid arthritis. Clin Exp Rheumatol. 2003; 21: 340-2.

  48. Sánchez E, Orozco G, López-Nevot MA, Jiménez-Alonso J, Martín J. Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus. Tissue Antigens. 2004; 63: 54-7.

  49. Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, et al. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J. 2004; 23: 219-23.

  50. Bochud PY, Hawn TR, Aderem A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol. 2003; 170: 3451-4.

  51. Kang TJ, Chae GT, Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol. 2001; 31: 53-8.

  52. Kang TJ, Lee SB, Chae GT. A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine. 2002; 20: 56-62.

  53. Ben-Ali M, Barbouche MR, Bousnina S, Chabbou A, Dellagi K. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol. 2004; 11: 625-6.

  54. Bochud PY, Hawn TR, Siddiqui MR, Saunderson P, Britton S, Abraham I, et al. Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. J Infect Dis. 2008; 197: 253-61.

  55. Thuong NT, Hawn TR, Thwaites GE, Chau TT, Lan NT, Quy HT, et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun. 2007; 8: 422-8.

  56. Berdeli A, Celik HA, Ozyürek R, Dogrusoz B, Aydin HH. TLR1 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children. J Mol Med 2005; 83: 535-41.

  57. Lee EY, Yim JJ, Lee HS, Lee YJ, Lee EB, Song YW. Dinucleotide repeat polymorphism in intron II of human Toll-like receptor 2 gene and susceptibility to rheumatoid arthritis. Int J Immunogenet. 2006; 33: 211-15.

  58. Boraska Jelavic´ T, Barisic´ M, Drmic Hofman I, Boraska V, Vrdoljak E, Peruzovic´ M, et al. Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. Clin Genet. 2006; 70: 156-160.

  59. Omueti KO, Beyer JM, Johnson CM, Lyle EA, Tapping RI. Domain exchange between human toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. J Biol Chem. 2005; 280: 36616-25.

  60. Hawn TR, Misch EA, Dunstan SJ, Thwaites GE, Lan NT, Quy HT, et al. A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. Eur J Immunol. 2007; 37: 2059-62.

  61. Sun J, Wiklund F, Hsu FC, Bälter K, Zheng SL, Johansson JE, et al. Interactions of sequence variants in interleukin-1 receptor-associated kinase4 and the toll-like receptor 6-1-10 gene cluster increase prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2006; 15: 480-5.

  62. Tantisira K, Klimecki WT, Lazarus R, Palmer LJ, Raby BA, Kwiatkowski DJ, et al. Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun. 2004; 5: 343-6.

  63. Zhou XX, Jia WH, Shen GP, Qin HD, Yu XJ, Chen LZ, et al. Sequence variants in toll-like receptor 10 are associated with nasopharyngeal carcinoma risk. Cancer Epidemiol Biomarkers Prev. 2006; 15: 862-6.

  64. Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires Disease. J Exp Med. 2003; 198: 1563-72.

  65. Dunstan SJ, Hawn TR, Hue NT, Parry CP, Ho VA, Vinh H, et al. Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam. J Infect Dis. 2005; 191: 1068-71.

  66. Gewirtz AT, Vijay-Kumar M, Brant SR, Duerr RH, Nicolae DL, Cho JH. Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn’s disease. Am J Physiol Gastrointest Liver Physiol. 2006; 290: G1157-63.

  67. Demirci FY, Manzi S, Ramsey-Goldman R, Kenney M, Shaw PS, Dunlop-Thomas CM, et al. Association study of Toll-like receptor 5 (TLR5) and Toll-like receptor 9 (TLR9) polymorphisms in systemic lupus erythematosus. J Rheumatol. 2007; 34: 1708-11.

  68. Hidaka F, Matsuo S, Muta T, Takeshige K, Mizukami T, Nunoi H. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol. 2006; 119: 188-94.

  69. Ranjith-Kumar CT, Miller W, Sun J, Xiong J, Santos J, Yarbrough I, et al. Effects of single nucleotide polymorphisms on Toll-like receptor 3 activity and expression in cultured cells. J Biol Chem. 2007; 282: 17696-705.

  70. Ueta M, Hamuro J, Kiyono H, Kinoshita S. Triggering of TLR3 by polyI: C in human corneal epithelial cells to induce inflammatory cytokines. Biochem Biophys Res Commun. 2005; 331: 285-94.

  71. Bochud PY, Hersberger M, Taffé P, Bochud M, Stein CM, Rodrigues SD, et al. Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. AIDS. 2007; 21: 441-6.

  72. Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, et al. Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis. 2006; 194: 184-8.

  73. Lazarus R, Klimecki WT, Raby BA, Vercelli D, Palmer LJ, Kwiatkowski DJ, et al. Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics. 2003; 81: 85-91.

  74. Noguchi E, Nishimura F, Fukai H, Kim J, Ichikawa K, Shibasaki M, et al. An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population. Clin Exp Allerg. 2004; 34: 177-83.

  75. Tao K, Fujii M, Tsukumo S, Maekawa Y, Kishihara K, Kimoto Y, et al. Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis. 2007; 66: 905-9.

  76. De Jager PL, Richardson A, Vyse TJ, Rioux JD. Genetic variation in toll-like receptor 9 and susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2006; 54: 1279-82.

  77. Hur JW, Shin HD, Park BL, Kim LH, Kim SY, Bae SC. Association study of Toll-like receptor 9 gene polymorphism in Korean patients with systemic lupus erythematosus. Tissue Antigens. 2005; 65: 266-70.

  78. Ng MW, Lau CS, Chan TM, Wong WH, Lau YL. Polymorphisms of the toll-like receptor 9 (TLR9) gene with systemic lupus erythematosus in Chinese. Rheumatology. 2005; 44: 1456-7.

  79. Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet. 1996; 14: 199-202.

  80. Ohashi K, Burkart V, Flohé S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol. 2000; 164: 558-61.

  81. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem. 2002; 277: 15107-12.

  82. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol. 2002; 168: 5233-9.

  83. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M. Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J Immunol. 2002; 168: 5989-92.

  84. Oyama J, Blais C Jr, Liu X, Pu M, Kobzik L, Kelly RA, et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation. 2004; 109: 784-9.

  85. Shishido T, Nozaki N, Yamaguchi S, Shibata Y, Nitobe J, Miyamoto T, et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation. 2003; 108: 2905-10.

  86. Zhai Y, Shen XD, O’Connell R, Gao F, Lassman C, Busuttil RW, et al. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol. 2004; 173: 7115-9.

  87. Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005; 175: 7661-8.

  88. Leemans JC, Stokman G, Claessen N, Rouschop KM, Teske GJ, Kirschning CJ, et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest. 2005; 115: 2894-903.

  89. Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R. Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001; 2: 947-50.

  90. Luster AD. The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol. 2002; 14: 129-135.

  91. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay CR, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998; 28: 2760-9.

  92. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Aït-Yahia S, et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med. 1998; 188: 373-86.

  93. Pockley AG. Heat shock proteins, anti-heat shock protein reactivity and allograft rejection. Transplantation. 2001; 71: 1503-7.

  94. Goldstein DR, Tesar BM, Akira S, Lakkis FG. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J Clin Invest. 2003; 111: 1571-8.

  95. Lin T, Zhou W, Sacks SH. The role of complement and Toll-like receptors in organ transplantation. Transpl Int. 2007; 20: 481-9.

  96. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature. 2003; 424: 743-8.

  97. Weighardt H, Jusek G, Mages J, Lang R, Hoebe K, Beutler B, et al. Identification of a TLR4- and TRIF-dependent activation program of dendritic cells. Eur J Immunol. 2004; 34: 558-64.

  98. McKay D, Shigeoka A, Rubinstein M, Surh C, Sprent J. Simultaneous deletion of MyD88 and TRIF delays major histocompatibility and minor antigen mismatch allograft rejection. Eur J Immunol. 2006; 36: 1994-2002.

  99. Palmer SM, Burch LH, Davis RD, Herczyk WF, Howell DN, Reinsmoen NL, et al. The role of innate immunity in acute allograft rejection after lung transplantation. Am J Respir Crit Care Med. 2003; 168: 628-32.

  100. Ducloux D, Deschamps M, Yannaraki M, Ferrand C, Bamoulid J, Saas P, et al. Relevance of Toll-like receptor-4 polymorphisms in renal transplantation. Kidney Int. 2005; 67: 2454-61.

  101. Palmer SM, Burch LH, Mir S, Smith SR, Kuo PC, Herczyk WF, et al. Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin Transplant. 2006; 20: 30-6.

  102. Elmaagacli AH, Koldehoff M, Hindahl H, Steckel NK, Trenschel R, Peceny R, et al. Mutations in innate immune system NOD2/CARD 15 and TLR4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation. 2006; 81: 247-54.

  103. Lorenz E, Schwartz DA, Martin PJ, Gooley T, Lin MT, Chien JW, et al. Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001; 7: 384-7.

  104. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, et al. Effect of the Toll-like receptor 4 (TLR4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med. 2005; 258: 21-7.

  105. Kesh S, Mensah NY, Peterlongo P, Jaffe D, Hsu K, Van Den Brink M, et al. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann N Y Acad Sci. 2005; 1062: 95-103.

  106. Mullighan CG, Bardy PG. New directions in the genomics of allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13: 127-44.

  107. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK. A high-resolution survey of deletion polymorphism in the human genome. Nat Genet. 2006; 38: 75-81.




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