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The Role of Human IL-17 Immunity in Fungal Disease

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Abstract

Candida species are major causes of invasive and mucocutaneous fungal infections. Various recognition pathways and effector mechanisms are involved in triggering intrinsic, innate and adaptive host immune responses to these fungi. Invasive candidiasis may involve almost any internal organ or anatomic site and is a significant cause of morbidity and mortality in immunocompromised individuals, including, in particular, those with primary immunodeficiency disorders (PIDs) affecting phagocytic cells. Other PIDs characterized by an impairment of IL-17 T cell-mediated immunity confer predisposition to mucocutaneous Candida infections, with Candida albicans in particular. We discuss here inborn errors of immunity leading to an impairment of IL-17-mediated host defense and the occurrence of mucocutaneous candidiasis.

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References

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

  1. Casanova J-L, Abel L. Inborn errors of immunity to infection: the rule rather than the exception. J Exp Med. 2005;202:197–201.

    Article  PubMed  CAS  Google Scholar 

  2. • Fischer A. Human primary immunodeficiency diseases. Immunity 2007;27:835–45. A comprehensive review on novel primary immunodeficiencies.

    Article  PubMed  CAS  Google Scholar 

  3. • Casanova J-L, Abel L. Primary immunodeficiencies: a field in its infancy. Science 2007;317:617–9. A clear and concised summary of the concept of primary immunodeficiencies as an emerging field of immunology and medicine.

    Article  PubMed  CAS  Google Scholar 

  4. • Maródi L, Notarangelo LD. Immunological and genetic bases of new primary immunodeficiencies. Nat Rev Immunol 2007;7:851–61. A comprehensive review on several novel primary immunodeficiencies.

    Article  PubMed  Google Scholar 

  5. Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2):S182–94.

    Article  PubMed  Google Scholar 

  6. Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8mutations. N Engl J Med. 2009;36:2046–55.

    Article  Google Scholar 

  7. Cypowyj S, Picard C, Maródi L, et al. Immunity to infection in IL-17-deficient mice and humans. Eur J Immunol. 2012;42(9):2246–54.

    Article  PubMed  CAS  Google Scholar 

  8. Puel A, Cypowyj S, Maródi L, et al. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol. 2012;12(6):616–22.

    Article  PubMed  CAS  Google Scholar 

  9. • Maródi L, Cypowyj S, Tóth B, et al. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J Allergy Clin Immunol. 2012;130(5):1019–27. A comprehensive review on the molecular basis of susceptibility to Candida and Staphylococci in humans.

  10. Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19(3):281–6.

    Article  PubMed  CAS  Google Scholar 

  11. Chen Z, Laurence A, O’Shea JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Cytokine Growth Factor Rev. 2007;19(6):400–8.

    CAS  Google Scholar 

  12. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008;28(4):445–53.

    Article  PubMed  CAS  Google Scholar 

  13. Marks BR, Nowyhed HN, Choi JY, et al. Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation. Nat Immunol. 2009;10(10):1125–32.

    Article  PubMed  CAS  Google Scholar 

  14. Zhou L, Littman DR. Transcriptional regulatory networks in Th17 cell differentiation. Curr Opin Immunol. 2009;21(2):146–52.

    Article  PubMed  Google Scholar 

  15. Hirahara K, Ghoreschi K, Laurence A, et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 2010;21(6):425–34.

    Article  PubMed  CAS  Google Scholar 

  16. May MJ. IL-17R signaling: new players get in on the Act1. Nat Immunol. 2011;12(9):813–5.

    Article  PubMed  CAS  Google Scholar 

  17. Sallusto F, Zielinski CE, Lanzavecchia A. Human Th17 subsets. Eur J Immunol. 2012;42:2215–20.

    Article  PubMed  CAS  Google Scholar 

  18. Ness-Schwickerath KJ, Jin C, Morita CT. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells. J Immunol. 2010;184(12):7268–80.

    Article  PubMed  CAS  Google Scholar 

  19. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10(7):479–89.

    Article  PubMed  CAS  Google Scholar 

  20. Gaffen SL. Recent advances in the IL-17 cytokine family. Curr Opin Immunol. 2011;23(5):613–9.

    Article  PubMed  CAS  Google Scholar 

  21. Hardison SE, Brown GD. C-type lectin receptors orchestrate antifungal immunity. Nat Immunol. 2012;13(9):817–22.

    Article  PubMed  CAS  Google Scholar 

  22. Neofytos D, Fishman JA, Horn D, Anaissie E, Chang CH, Olyaei A, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients. Transpl Infect Dis. 2010;12:220–9.

    Article  PubMed  CAS  Google Scholar 

  23. Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36:1–53.

    Article  PubMed  Google Scholar 

  24. Maródi L. Local and systemic host defense mechanisms against Candida: immunopathology of candidal infections. Pediatr Infect Dis J. 1997;16:795–801.

    Article  PubMed  Google Scholar 

  25. Maródi L, Johnston Jr RB. Invasive Candida species disease in infants and children: occurrence, risk factors, management, and innate host defense mechanisms. Curr Opin Pediatr. 2007;19:693–7.

    Article  PubMed  Google Scholar 

  26. Maródi L, Leijh PC, van Furth R. Characteristics and functional capacities of human cord blood granulocytes and monocytes. Pediatr Res. 1984;18:1127–31.

    Article  PubMed  Google Scholar 

  27. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29.

    Article  PubMed  CAS  Google Scholar 

  28. Mc Cormack O, Timlin M, McGowan A, Healy ML, Ravi N, Reynolds JV. Management of squamous cell cancer of the oesophagus in a patient with a polyglandularendocrinopathy (APECED) and achalasia. J Gastro Intest Surg. 2012;16(10):1963–6.

    Article  Google Scholar 

  29. Böckle BC, Wilhelm M, Müller H, Götsch C, Sepp NT. Oral mucous squamous cell carcinoma-an anticipated consequence of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Am Acad Dermatol. 2010;62(5):864–8.

    Article  PubMed  Google Scholar 

  30. • Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17 F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 2010;207:291–7. Refs 30 and 31 are companion papers describing the presence of autoantibobies against IL-17A, IL-17 F and IL-22 inpatients with APECED suggesting a specific role of these cytokines in the susceptipility of patients to Candida.

    Article  PubMed  CAS  Google Scholar 

  31. • Kisand K, Bøe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 2010;207:299–308. Refs 30 and 31 are companion papers describing the presence of autoantibobies against IL-17A, IL-17 F and IL-22 inpatients with APECED suggesting a specific role of these cytokines in the susceptipility of patients to Candida.

    Article  PubMed  CAS  Google Scholar 

  32. Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41:1517–27.

    Article  PubMed  CAS  Google Scholar 

  33. Tóth B, Wolff AS, Halász Z, Tar A, Szüts P, Ilyés I, et al. Novel sequence variation of AIRE and detection of interferon-omega antibodies in early infancy. Clin Endocrinol (Oxf). 2010;72:641–7.

    Article  Google Scholar 

  34. O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol. 2011;11:239–50.

    Article  PubMed  Google Scholar 

  35. • Casanova J-L, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity 2012;36:515–28. A comprehensive review on various mutations of JAKs and STATs causing various clinical phenotypes.

  36. • Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol 2012;(4):364–78. This is a comprehensive description of disease-causing mutations in STAT1.

    Article  Google Scholar 

  37. • Minegishi Y, Saito M, Tsuchiya A, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007;448:1058–62. Refs. 37 and 38 are companion papers describing the genetic etiology of autosomal dominant and sporadic hyper-IgE syndrome.

    Article  PubMed  CAS  Google Scholar 

  38. • Holland SM, De Leo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608–19. Refs. 37 and 38 are companion papers describing the genetic etiology of autosomal dominant and sporadic hyper-IgE syndrome.

    Article  PubMed  CAS  Google Scholar 

  39. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205:1551–7.

    Article  PubMed  CAS  Google Scholar 

  40. • Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008;452:773–6. In this study the authors describe that STAT3 mutations in patients with autosomal dominant and sporadic hyper-IgE syndrome result in severe IL-17 + CD4 T cell depletion.

  41. Jiao H, Tóth B, Erdős M, Fransson I, Rákóczi E, Balogh I, et al. Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. Mol Immunol. 2008;46:202–6.

    Article  PubMed  CAS  Google Scholar 

  42. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008;205:1543–50.

    Article  PubMed  Google Scholar 

  43. • Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, et al. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med 2009;206:1291–301. In this study the authors provide mechanistic data on IL-17 + CD4 T cell depletion in patients with autosomal dominant and sporadic hyper-IgE syndrome.

  44. Chandesris MO, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine. 2012;91(4):1–19.

    Article  Google Scholar 

  45. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25:745–55.

    Article  PubMed  CAS  Google Scholar 

  46. • Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, Kreins AY, Grant AV, Abel L, et al. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 2012;160:1055–7. The authors report here the second Tyk2 deficient patient with phenotypic expression different from that observed in the first patient (Minegishi et al., Immunity 2006;25:745–55).

    Article  PubMed  Google Scholar 

  47. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol. 2006;18(6):347–61.

    Article  PubMed  CAS  Google Scholar 

  48. Al-Muhsen S, Casanova JL. The genetic heterogeneity of Mendelian susceptibility to mycobacterial diseases. J Allergy Clin Immunol. 2008;122:1043–51.

    Article  PubMed  CAS  Google Scholar 

  49. de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, et al. Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries. Medicine (Baltimore). 2010;89:381–402.

    Article  Google Scholar 

  50. • Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011;332:65–8. This is the first report on AR IL-17RA and AD IL-17F deficiencies predisposing patients to chronic mucocutaneous candidiasis disease. The authors clearly demonstrate an essential role of humanIL-17A and/or IL-17 F in host defense against Candida on mucocutaneous surfaces.

    Google Scholar 

  51. • Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011;208:1635–48. This is one of the very first reports on chronic mucocutaneous candidiasis disease caused by dominant mutations in STAT1 in a series of 47 patients. The authors provide mechanistic data suggesting that the mutant alleles are gain-of function due to gain of nuclear phosphorylation of STAT1.

  52. • van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 2011;365:54–61. This is one of the very first reports describing dominant mutations in STAT1 causing chronic mucocutaneous candidiasis disease in a series of 14 patients.

  53. • Tóth B, Méhes L, Taskó S, Szalai Z, Tulassay, Cypowyj S, et al. Herpes in STAT1mutation. The Lancet 2012;379:2500. This study is the first description of two related patients with a STAT1coiled coil domain gain-of-function mutation associated with recurrent herpes virus disease in addition to chronic mucocutaneous candidiasis.

  54. Smeekens SP, Plantinga TS, van de Veerdonk FL, et al. STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS One. 2011;6(12):e29248.

    Article  PubMed  CAS  Google Scholar 

  55. Hori T, Ohnishi H, Teramoto T, et al. Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism. J Clin Immunol. 2012;32(6):1213–20.

    Article  PubMed  CAS  Google Scholar 

  56. Takezaki S, Yamada M, Kato M, et al. Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain. J Immunol. 2012;189(3):1521–6.

    Article  PubMed  CAS  Google Scholar 

  57. Tsumura M, Okada S, Sakai H, Yasunaga S, Ohtsubo M, Murata T, et al. Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. Hum Mutat. 2012;33(9):1377–87.

    Article  PubMed  CAS  Google Scholar 

  58. Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front Immunol. 2011;2:54. doi:10.3389/fimmu.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by a UD Faculty of Medicine Research Fund (Bridging Fund 2012) grant to LM and the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) grant number 8UL1TR000043 from the National Institutes of Health to JLC and SC, and ANR grant number GENCMCD 11-BSV3–005-01 to AP. SC was supported by the AXA Research Fund.

Conflict of Interest

L.Maródi: grant from Bridging Fund 2012; S. Cypowyj: grant from AXA Research Fund; J.-L. Casanova: grants or grants pending from NIH, St. Giles Foundation, Pfizer and Merck, and has provided consultancy to Pfizer, Merck, GSK, Sanofi, and NovImmune; A. Puel: none.

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Authors and Affiliations

  1. Department of Infectious and Pediatric Immunology, University of Debrecen Medical and Health Science Center, Nagyerdei krt. 98, 4032, Debrecen, Hungary

    László Maródi

  2. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University Hospital, The Rockefeller University, New York, NY, USA

    Sophie Cypowyj, Jean-Laurent Casanova & Anne Puel

  3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U980, Paris Sorbonne Cité, Paris, France

    Jean-Laurent Casanova & Anne Puel

  4. Necker Medical School, University Paris Descartes, Paris Sorbonne Cité, Paris, France

    Jean-Laurent Casanova & Anne Puel

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  1. László Maródi
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  2. Sophie Cypowyj
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  3. Jean-Laurent Casanova
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  4. Anne Puel
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Correspondence to László Maródi.

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Maródi, L., Cypowyj, S., Casanova, JL. et al. The Role of Human IL-17 Immunity in Fungal Disease. Curr Fungal Infect Rep 7, 132–137 (2013). https://doi.org/10.1007/s12281-013-0131-4

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