Clinical Reviews in Allergy & Immunology

, Volume 38, Issue 1, pp 11–19 | Cite as

The Role of Toll-Like Receptor Signaling in Human Immunodeficiencies

Article

Abstract

Through the last decade, clinical immunology has witnessed a considerable progress in understanding the role of the innate immunity in human host defense, with Toll-like receptors (TLRs) being the most extensively innate immune receptors investigated. Growing literature documents the relevance of TLR signaling pathways to human disease, revealing a small, but expanding, group of new monogenic primary immunodeficiencies, in patients with various infectious diseases, previously considered as of unexplained “idiopathic” origin. Herein, we review these recently described deficiencies. Autosomal recessive IRAK-4 and myeloid differentiation factor 88 deficiencies were reported in 2003 and 2008, respectively, conferring predisposition to pyogenic bacterial infections, and autosomal recessive UNC93B1 and autosomal dominant TLR3 deficiencies were reported in 2006 and 2007, respectively, conferring predisposition to herpes simplex encephalitis. Furthermore, we highlight the published data associating TLR polymorphism with an altered susceptibility to infectious diseases.

Keywords

TLR Immunodeficiences TIR domain 

References

  1. 1.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216CrossRefPubMedGoogle Scholar
  2. 2.
    Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5(10):987–995CrossRefPubMedGoogle Scholar
  3. 3.
    Lemaitre B, Nicolas E, Michaut L et al (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86(6):973–983CrossRefPubMedGoogle Scholar
  4. 4.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376CrossRefPubMedGoogle Scholar
  5. 5.
    Kawai T, Akira S (2005) Pathogen recognition with Toll-like receptors. Curr Opin Immunol 17(4):338–344CrossRefPubMedGoogle Scholar
  6. 6.
    O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signaling. Nat Rev Immunol 7(5):353–364CrossRefPubMedGoogle Scholar
  7. 7.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124(4):783–801CrossRefPubMedGoogle Scholar
  8. 8.
    Turvey SE, Hawn TR (2006) Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections. Clin Immunol 120(1):1–9CrossRefPubMedGoogle Scholar
  9. 9.
    Akira S, Takeda K (2004) Toll-like receptor signaling. Nat Rev Immunol 4(7):499–511CrossRefPubMedGoogle Scholar
  10. 10.
    Kawia T, Akira S (2006) TLR signaling. Cell Death Differ 13(5):816–825CrossRefGoogle Scholar
  11. 11.
    Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signaling. Nature 430(6996):257–63CrossRefPubMedGoogle Scholar
  12. 12.
    Yamamoto M et al (2002) Essential role for TIRAP in activation of the signaling cascade shared by TLR2 and TLR4. Nature 420(6913):324–329CrossRefPubMedGoogle Scholar
  13. 13.
    Horng T et al (2002) The adaptor molecule TIRAP provides signaling specificity for Toll-like receptors. Nature 420(6913):329–333CrossRefPubMedGoogle Scholar
  14. 14.
    Yamamoto M et al (2003) Role of adaptor TRIF in the Myd88-independent Toll-like receptor signaling pathway. Science 301(5633):640–643CrossRefPubMedGoogle Scholar
  15. 15.
    Yamamoto M et al (2003) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4(11):1144–1150CrossRefPubMedGoogle Scholar
  16. 16.
    Kawai T et al (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5(10):1061–1068CrossRefPubMedGoogle Scholar
  17. 17.
    Doffinger R, Smahi A, Bessia C et al (2001) X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by NF-kappaB signaling. Nat Genet 27(3):277–285CrossRefPubMedGoogle Scholar
  18. 18.
    Jain A, Ma CA, Liu S et al (2001) Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia. Nat Immunol 2(3):223–228CrossRefPubMedGoogle Scholar
  19. 19.
    Zonana J, Elder ME, Schneider LC et al (2000) A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinenta pigmenti and due to mutations in IKK-gamma (NEMO). AM J hum Genet 67(6):1555–1562CrossRefPubMedGoogle Scholar
  20. 20.
    Courtois G, Smahi A, Reichenbach J et al (2003) A hypomorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest 112(7):1108–1115PubMedGoogle Scholar
  21. 21.
    Picard C, Puel A, Bonnet M et al (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299(5615):2076–2079CrossRefPubMedGoogle Scholar
  22. 22.
    Casrouge A, Zhang SY, Eidenschenk C et al (2006) Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314(5797):308–312CrossRefPubMedGoogle Scholar
  23. 23.
    Zhang SY, Jouanguy E, Ugolini S et al (2007) TLR3 deficiency in patients with herpes simplex encephalitis. Science 317(5844):1522–1527CrossRefPubMedGoogle Scholar
  24. 24.
    von Bernuth H, Picard C, Jin Z et al (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321(5889):691–696CrossRefGoogle Scholar
  25. 25.
    Li S, Strelow A, Fontana EJ et al (2002) IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 99(8):5567–5572CrossRefPubMedGoogle Scholar
  26. 26.
    Suzuki N, Suzuki S, Duncan GS et al (2002) Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4. Nature 416(6882):750–756CrossRefPubMedGoogle Scholar
  27. 27.
    Kuglstatter A, Villasenor AG, Shaw D et al (2007) Cutting edge: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations. J Immunol 178(5):2641–2645PubMedGoogle Scholar
  28. 28.
    Medvedev AE, Lentschat A, Kuhns DB et al (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198(4):521–531CrossRefPubMedGoogle Scholar
  29. 29.
    Picard C, von Bernuth H, Ku CL et al (2007) Inherited human IRAK-4 deficiency: an update. Immunol Res 38(1–3):347–352CrossRefPubMedGoogle Scholar
  30. 30.
    Day N, Tangsinmankong N, Ochs H et al (2004) IRAK-4 deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr 144(4):524–526CrossRefPubMedGoogle Scholar
  31. 31.
    Ku CL, Picard C, Erdos M et al (2007) IRAK-4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 44(1):16–23CrossRefPubMedGoogle Scholar
  32. 32.
    Ku CL, von Bernuth H, Picard C et al (2007) Human IRAK-4 deficiency: a selective predisposition to life-threatening pyogenic bacterial infections during childhood reveals an otherwise redundant role for TLRs in protective immunity. J Exp Med 204(10):2407–2422CrossRefPubMedGoogle Scholar
  33. 33.
    Yang K, Puel A, Zhang S et al (2005) Human TLR-7, -8 and -9 mediated induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23(5):465–478CrossRefPubMedGoogle Scholar
  34. 34.
    Von Bernuth H, Ku CL, Rodriguez-Gallego C et al (2006) A fast procedure for the detection of defects in early Toll-like receptor signaling. Pediatrics 118(6):2498–2503CrossRefGoogle Scholar
  35. 35.
    Gavin AL, Hoebe K, Betal D et al (2006) Adjuvant-enhanced antibody responses in the absence of TLR signaling. Science 314(5807):1936–1938CrossRefPubMedGoogle Scholar
  36. 36.
    Pham LN, Dionne MS, Shirasu-Hiza M, Schneider DS (2007) A specific primed immune response in Drosophila is dependent on phagocytes. PLoS Pathog 3:e26CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang SY, Jouanguy E, Sancho-Shimizu V et al (2007) Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol Rev 220(1):225–236CrossRefPubMedGoogle Scholar
  38. 38.
    Muller U, Steinhoff U, Reis LF et al (1994) Functional role of type 1 and type II interferons in antiviral defense. Science 264(5167):1918–1921CrossRefPubMedGoogle Scholar
  39. 39.
    Jouanguy E, Zhang SY, Chapgier A et al (2007) Human primary immunodeficiencies of type I interferons. Biochimie 89(6–7):878–883CrossRefPubMedGoogle Scholar
  40. 40.
    Vollstedt S, Arnold S, Schwerdel C et al (2004) Interplay between alpha/beta and gamma interferons with B, T, and natural killer cells in the defense against herpes aimplex virus type 1. J Virol 78(8):3846–3850CrossRefPubMedGoogle Scholar
  41. 41.
    Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7(2):131–137CrossRefPubMedGoogle Scholar
  42. 42.
    Nahmias AJ, Lee FK (2006) The natural history and epidemiology of herpes simplex viruses. In: Studahl M, Bergstrom T (eds) Herpes simplex viruses. Taylor & Francis, New York, pp 55–98Google Scholar
  43. 43.
    Najioullah F, Bosshard S, Thouvenot D et al (2000) Diagnosis and surveillance of herpes simplex virus infection of the central nervous system. J Med Virol 61(4):468–473CrossRefPubMedGoogle Scholar
  44. 44.
    Whitley RJ, Roizman B (2001) Herpes simplex virus infections. Lancet 357(9267):1513–1518CrossRefPubMedGoogle Scholar
  45. 45.
    Sancho-Shimizu V, Zhang SY, Abel L et al (2007) Genetic susceptibility to herpes simplex virus 1 encephalitis in mice and humans. Curr Opin Clin Immunol 7(6):495–505CrossRefGoogle Scholar
  46. 46.
    Tabeta K, Hoebe K, Jansen EM et al (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 7(2):156–164CrossRefPubMedGoogle Scholar
  47. 47.
    Brinkmann MM, Spooner E, Hoebe K et al (2007) The interaction between the ER membrane protein UNC93B and TLR3, 7 and 9 is crucial for TLR signaling. J Cell Biol 177(2):265–275CrossRefPubMedGoogle Scholar
  48. 48.
    Kim YM, Brinkmann MM, Paquet ME et al (2008) UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452(7184):234–240CrossRefPubMedGoogle Scholar
  49. 49.
    Wintergerst U, Gangemi JD, Whitley S et al (1999) Effects of recombinant human IFN alpha in combination with acyclovir in experimental HSV-1 encephalitis. Antiviral Res 44(1):75–78CrossRefPubMedGoogle Scholar
  50. 50.
    Casanova JL, Abel L (2002) Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 20:581–620CrossRefPubMedGoogle Scholar
  51. 51.
    Casanova JL, Abel L (2004) The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol 4(1):55–66CrossRefPubMedGoogle Scholar
  52. 52.
    Quintana-Murci L, Alcais A, Abel L et al (2007) Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat Immunol 8(11):1165–1170CrossRefPubMedGoogle Scholar
  53. 53.
    Goldstein DB, Cavalleri GL (2005) Genomics: understanding human diversity. Nature 437(7063):1241–1242CrossRefPubMedGoogle Scholar
  54. 54.
    Arbour NC, Lorenz E, Schutte BC et al (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25(2):187–191CrossRefPubMedGoogle Scholar
  55. 55.
    Lorenz E, Mira JP, Frees KL et al (2002) Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch Intern Med 162(9):1028–1032CrossRefPubMedGoogle Scholar
  56. 56.
    Agnese DM, Calvano JE, Hahm SJ et al (2002) Human Toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of Gram-negative infections. J Infec Dis 186(10):1522–1525CrossRefGoogle Scholar
  57. 57.
    Bochud PY, Chien JW, Marr KA et al (2008) Toll-like receptor 4 polymorphisms and aspergillosis is stem cell transplantation. N Engl J Med 359(17):1766–1777CrossRefPubMedGoogle Scholar
  58. 58.
    Eric G, Pamer (2008) TLR polymorphisms and the risk of invasive fungal infections. N Engl J Med 359(17):1836–1838CrossRefGoogle Scholar
  59. 59.
    Tal G, Mandelberg A, Dalal I et al (2004) Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus. J Infect Dis 189(11):2057–2063CrossRefPubMedGoogle Scholar
  60. 60.
    Faber J, Meyer CU, Gemmer C et al (2006) Human Toll-like receptor 4 mutations are associated with susceptibility to invasive meningococcal disease in infancy. Peadiart Infect Dis J 25(1):80–81CrossRefGoogle Scholar
  61. 61.
    Hawn TR, Verbon A, Janer M et al (2005) Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaire’s disease. Proc Natl Acad Sci USA 102(7):2487–2489CrossRefPubMedGoogle Scholar
  62. 62.
    Cooke GS, Segal S, Hill AV et al (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347(24):1978–1980CrossRefPubMedGoogle Scholar
  63. 63.
    Feterowski C, Emmanuilidis K, Miethke T et al (2003) Effects of functional Toll-like receptor 4 mutations on the immune response to human and experimental sepsis. Immunology 109(3):426–431CrossRefPubMedGoogle Scholar
  64. 64.
    Ogus AC, Yoldas B, Ozdemir T et al (2004) The Arg753Gln polymorphism of the human Toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23(2):219–223CrossRefPubMedGoogle Scholar
  65. 65.
    Schroder NW, Diterich I, Zinke A et al (2005) Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia Burgdorferi and protects from late stage Lyme disease. J Immunol 175(4):2534–2540PubMedGoogle Scholar
  66. 66.
    Moore CE, Segal S, Berendt AR et al (2004) Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by staphylococcus aureus. Clin Diagn Lab Imunol 11(6):1194–1197Google Scholar
  67. 67.
    Yim JJ, Lee HW, Lee HS et al (2006) The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans. Genes Immunol 7(2):150–155CrossRefGoogle Scholar
  68. 68.
    Hawn TR, Verbon A, Lettinga KD et al (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaire’s disease. J Exp Med 198(10):1563–1572CrossRefPubMedGoogle Scholar
  69. 69.
    Dunstan SJ, Hawn TR, Hue NT et al (2005) Host susceptibility and clinical outcomes in Toll-like receptor 5 deficient patients with typhoid fever in Vietnam. J Infect Dis 191(7):1068–1071CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Meyer’s Children Hospital, HaifaThe Rappaport School of Medicine, TechnionHaifaIsrael

Personalised recommendations