• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Immunol. Author manuscript; available in PMC Sep 12, 2013.
Published in final edited form as:
PMCID: PMC3770911
NIHMSID: NIHMS491438

Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?

Abstract

The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9 the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to Candida albicans. They also suggest that the distinct syndrome of isolated CMC, without autoimmunity or other infections, may be caused by inborn errors of IL-17 immunity.

Introduction

Candidiasis, one of the most frequent fungal diseases in humans, is generally caused by Candida albicans. This fungus is a commensal organism of the oro-gastrointestinal tract and the vulvovaginal cavity. However, in some individuals, C. albicans causes disease, either by infecting mucosal and epidermal surfaces (mucocutaneous candidiasis, which is typically chronic) or, more rarely, by disseminating in the blood (systemic candidiasis, which is typically acute) [1]. Patients with inherited or acquired disorders of granulocytes usually present systemic candidiasis, whereas patients with inherited or acquired disorders of T lymphocytes develop chronic mucocutaneous candidiasis (CMC) [2,3]. Various alterations of the internal (e.g. a central line) or peripheral (e.g. xerostomy) milieu may also predispose to invasive or mucocutaneous CMC. CMC is highly heterogeneous clinically, with recurrent and/or persistent infections of the upper gastro-intestinal mucosa, skin, and nails with C. albicans, which may respond poorly to anti-fungal treatment or relapse upon discontinuation of treatment [1,4]. The mucocutaneous lesions are not themselves life-threatening, but they have been associated with intracranial aneurisms in several patients with CMC, at least in patients with isolated, unexplained CMC [57].

CMC is usually associated with many other, frequently more severe infections, particularly in patients with broad and profound inherited or acquired T-cell immunodeficiencies. Oropharyngeal infections with Candida species are commonly found in HIV-infected individuals [8]. Persistent oral candidiasis and other mucocutaneous fungal infections are also often observed in infants with severe combined immunodeficiency (SCID) [9,10]. T cells therefore play a critical role in protective immunity against mucocutaneous C. albicans infections. By contrast, CMC is a prominent feature of hyper IgE syndrome (HIES), a complex primary immunodeficiency characterized by high levels of serum IgE, severe atopic dermatitis, connective tissue and skeletal abnormalities, recurrent skin and lung infections caused by Staphylococcus aureusand CMC [11]. The typical form of HIES is autosomal dominant (AD) and caused by dominant-negative mutations in STAT3 [12,13]. A related syndrome without developmental features and with very mild CMC has been documented in a patient with autosomal recessive TYK2 deficiency [14].

CMC is also an important infectious phenotype in the rare patients displaying susceptibility to mucocutaneous and systemic fungal infections who carry autosomal recessive mutation in CARD9 [15]. It remains unclear whether Dectin-1 deficiency is the cause of a predisposition to fungal infections, including CMC [16]. CMC may also strike patients not prone to invasive candidiasis and normally resistant to most other infectious agents, including other fungi. Such patients include those with autoimmune polyendocrine type I syndrome (APS-I, also known as autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy, APECED) [17] and patients with CMC and thyroid diseases [18]. APS-I results from autosomal recessive mutations in the autoimmune regulator gene AIRE [19]. In addition, other patients present with a distinct syndrome of isolated CMC, with no other severe infectious or autoimmune disorder [1,20,21]. Abnormalities of T-cell immunity to C. albicans have occasionally been reported in these patients, but no genetic etiology has yet been identified [1,4,2226].

In recent years, the molecular pathogenesis of CMC in patients with primary immunodeficiencies has begun to be deciphered [27]. This process has been facilitated by the development of mouse models for CMC and the discovery of IL-17 cytokines: IL-17A, IL-17F, IL-22 and IL-26 in humans [28,29]. Mouse IL-17 cytokines are essential for mucocutaneous immunity to C. albicans [3,30]. However, these cytokines are also essential for protective immunity to many other pathogens, including Gram-positive and Gram-negative bacteria, such as Staphylococcus, Klebsiella and Salmonella, in various tissues, including the respiratory and gastro-intestinal tracts [3135]. Patients with mutations in STAT3 have been shown to lack IL-17-producing circulating T cells [34,3639], patients with mutation in CARD9 have been shown to have significantly lower than normal proportions of IL-17-producing T cells [15] and patients with mutations in AIRE have high titers of neutralizing auto-Abs against IL-17 cytokines [40,41]. We review here the published studies of inborn errors of immunity conferring CMC, collectively identifying IL-17 cytokines as essential components of human mucocutaneous immunity to C. albicans.

AD-HIES syndrome

Cutaneous and pulmonary staphylococcal diseases affect most, if not all patients with AD-HIES, but CMC is the second most frequent presentation, affecting about 80% of AD-HIES patients [11,42,43]. CMC generally manifests as oral thrush, onychomycosis, and/or vaginal candidiasis [43]. Dermatophytosis has also been described in some patients. In 2007, dominant-negative mutations in the STAT3 gene, encoding signal transducer and activator of transcription 3, were found to be responsible for AD-HIES [12,13]. STAT3 regulates multiple cytokine signaling pathways, including IL-6, IL-21, and IL-23, which are involved in the development of IL-17-producing T cells in mice [28]. Several groups investigated the presence of IL-17-producing T cells in STAT3-deficient patients with AD-HIES, based on the findings that mouse IL-17-producing T cells play a role in immunity to both systemic and mucosal C. albicans infection [30,44,45], these T cells are involved in skin and mucosal host defense [46,47], and mouse STAT3-deficient CD4+ T cells are unable to differentiate into IL-17-producing T cells [48]. From 2008 onwards, five studies documented an almost complete lack of circulating IL-17-producing T cells in patients heterozygous for STAT3 mutations, as assessed ex vivo [34,3639]. T cells from PBMCs or naive CD4+ T cells were unable to differentiate in vitro into memory CD4+/IL-17+ T cells in response to stimulation with various cytokines [3638]. This lack of differentiation was associated with the impaired induction of RORγt mRNA upon stimulation of the patients’ CD4+ T cells, suggesting an intrinsic T-cell defect [36,37]. Three studies reported a concomitant decrease in IL-22 production [34,37,38], whereas a fourth did not [36]. The other IL-17 cytokines, IL-17F and IL-26, were not studied. The strong impairment of T-cell differentiation seemed to be specific to IL-17-producing T cells, although other lymphokines (such as IL-2 and IFN-γ) were also found to be affected, but to a lesser extent [3638]. The proportion of circulating CD4+/CCR6+ T cells among PBMCs is low in AD-HIES patients, consistent with CCR6 being a marker of IL-17-producing T cells [49]. It is still unclear if TYK2 deficiency is associated with CMC, as a very mild form of mucocutaneous candidiasis was reported in the single TYK2-deficient patient described so far. IL-17-producing T cells were not evaluated in this patient [14]. In any event, the identification of the genetic basis of AD-HIES paved the way for cellular and molecular dissection of the pathogenesis of its associated CMC phenotype.

IL-12p40 and IL-12Rβ1 deficiencies

Another study showed that IL-12p40- and IL-12Rβ1-deficient patients, displaying a lack of production and of response, respectively, to both IL-12 and IL-23 have smaller proportions of circulating IL-17-producing T cells than normal individuals, but that this deficiency is much milder than that in patients with AD-HIES [38]. IL-12p40- and IL-12Rβ1-deficient patients typically suffer from the syndrome of Mendelian susceptibility to mycobacterial diseases (MSMD), which has been historically recognized and characterized on the basis of selective predisposition to mycobacteria and Salmonella in otherwise healthy children and adults [50,51]. Nevertheless, it recently became apparent that about 25% of IL-12p40- and IL-12Rβ1-deficient patients also suffer from mild signs of CMC (but not dermatophytosis), even when not clinically ill from other infections or on antibiotic treatment ([52], Carlos Rodriguez-Gallego et al. manuscript in preparation). This mild and surprising phenotype may be partly accounted for by the small proportion of IL-17-producing T cells in these patients, itself probably resulting from the abolition of signaling by IL-23, an important IL-17-inducing cytokine in the mouse model (reviewed in [27]). This is consistent with the apparent lack of CMC in other patients with MSMD and mutations impairing cellular IFN-γ responses [50]. The lack of overt staphylococcal disease in IL-12p40- and IL-12Rβ1-deficient patients, by contrast to the situation observed in AD-HIES patients, may be due to the presence of a sufficiently high proportion of IL-17-producing T cells in IL-12p40- and IL-12Rβ1-deficient patients. The almost complete lack of IL-17-producing T cells in patients heterozygous for STAT3 may therefore account for the susceptibility of these patients to both staphylococcal disease and CMC, the two key infections in such patients. This susceptibility may involved impairment of the recruitment of granulocytes to infected tissues and their activation, and of the induction of antimicrobial peptides in epithelial cells [34]. Consistent with this hypothesis, epithelial cells in the skin and lungs, the organs most frequently affected by staphylococcal disease and CMC in STAT3-deficient patients, have been shown specifically to require IL-17 stimulation for the induction of antimicrobial target genes [34,53].

CARD9 deficiency

Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor acting downstream from C-type lectin receptors, such as Dectin-1 [54,55]. Dectin-1 recruits and activates the spleen tyrosine kinase SYK [56]. The Dectin-1/SYK complex then engages CARD9, promoting pro-inflammatory cytokine production by dendritic cells, thereby inducing the differentiation of T cells into IL-17-producing T cells [57]. Card9-deficient mice are susceptible to systemic C. albicans infection [55] and fail to mount a Candida-specific IL-17-producing T-cell response [57]. In humans, autosomal recessive CARD9 deficiency (Q295X allele) was recently reported in a large multiplex Iranian kindred with CMC (oral and/or vaginal candidiasis), dermatophytosis, and invasive candidiasis, causing the death of at least two, and possibly three of the eight patients with proven or probable CARD9 deficiency [15]. No history of severe bacterial or viral infection was reported. Heterozygous family members were healthy. CARD9 expression was not detected in homozygous patients and the mutant allele was shown to be loss-of-expression when used to transfect bone marrow-derived macrophages from Card9-deficient mice. Moreover, the expression of wild-type but not mutant human CARD9 restored Dectin-1 signaling in Card9-deficient cells. Patients also displayed significantly smaller than normal proportions of IL-17-expressing T cells [15], suggesting that CARD9 is involved in the maturation of T cells for IL-17 cytokine production. The much greater severity of CARD9 deficiency than of Dectin-1 deficiency (see below) suggests that the pathogenesis of mucosal and systemic fungal infections in CARD9 deficiency involves receptors other than Dectin-1, such as Dectin-2, MINCLE, OSCAR, TREM-1 and, possibly, other as yet unknown receptors [5861]. TLRs are unlikely to play a major role, as IRAK4- and MyD88-deficient patients do not present even mild forms of CMC [62,63]. Overall, CARD9 deficiency is essentially an autosomal recessive trait conferring a predisposition to dermatophytosis and candidiasis, including both the mucocutaneous and systemic forms, possibly due, at least partly, to impaired IL-17 cytokine production. The presence of a sufficiently high proportion of IL-17-producing T cells may account for the lack of staphylococcal disease, and invasive candidiasis may involve other mechanisms in these patients. Finally, it is tempting to speculate that the association of CMC with low proportions of IL-17-producing T cells in STAT3-, IL-12Rβ1-, and CARD9-deficient patients may pave the way for treatment of CMC in these and possibly other patients with recombinant IL-17 cytokines.

DECTIN-1 deficiency?

Dectin-1, a C-type lectin cell-surface receptor expressed, in particular, by myeloid and epithelial cells, serves as a receptor for β-glucans, a major component of the yeast cell wall [64]. C. albicans recognition by Dectin-1 induces, via SYK and CARD9, the production of pro-inflammatory cytokines, thereby promoting the differentiation of naive T cells into cells producing IL-17 cytokines [57]. Dectin-1-deficient mice were shown to be susceptible to systemic C. albicans infection in one study [65] but not in another [66]. Recently, three human adult siblings with onychomycosis caused by Trichophyton rubrum (dermatophytosis) and vulvovaginitis caused by C. albicans were reported to be homozygous for a loss-of-expression and loss-of-function DECTIN1 allele (Y238X) [16]. This appears to be a mild form of CMC, as vulvovaginitis caused by Candida is common in the population. The syndrome is apparently dominant or co-dominant, as the heterozygous parents had a milder, but similar clinical phenotype. A causal relationship between the DECTIN1 genotype and both the expression of Dectin-1 and the cellular responses to stimulation of this receptor with β-glucan or C. albicans has been established. In particular, heterozygous cells have a response profile intermediate between those of wild-type and Y238X-homozygous cells. Interestingly, the induction of IL-17-producing T cells is impaired in some experimental conditions, including stimulation with C. albicans. By contrast, the phagocytosis or killing of C. albicans by Dectin-1-deficient monocytes and granulocytes has been shown to be normal. However, no causal relationship between DECTIN1 homozygosity or heterozygosity and the clinical phenotypes of vulvovaginitis and onychomycosis has been demonstrated. Indeed, the Y238X DECTIN1 allele is a common polymorphism, with a frequency of around 7% in European populations and of up to 40% in the San population of South Africa ([16] and http://hapmap.ncbi.nlm.nih.gov/). In the absence of a population-based study, it is therefore premature to attribute any role to this mutant DECTIN1 allele in terms of host defenses against fungi, including C. albicans in particular. Further studies are required to determine whether Dectin-1 deficiency is a genetic etiology of CMC and/or other fungal diseases. In the mean time, it is premature to consider Dectin-1 deficiency as a bona fide primary immunodeficiency. In any event, even if Dectin-1 deficiency could be shown to confer a predisposition to fungal infections, as a dominant, co-dominant, or recessive trait, its clinical penetrance would be low. The available data show that Dectin-1 is largely redundant for protective immunity to fungi in human populations.

APECED/APS-I syndrome

APS-I/APECED is a rare autosomal recessive syndrome characterized by multiple autoimmune polyendocrinopathies, such as hypoparathyroidism and adrenal failure [67,68]. The genetic etiology of APS-I was identified in 1997, with mutations in the autoimmune regulator (AIRE)-encoding gene [69,70]. AIRE governs a T-cell tolerance pathway, by inducing the production, in the thymus and peripheral lymphoid organs, of transcripts encoding proteins normally present in various peripheral tissues [68,71], thereby triggering the deletion of autoreactive T cells. Human AIRE deficiency therefore results in overwhelming auto-immunity. Intriguingly, up to 90% of APECED patients develop early-onset CMC. In 2006, high levels of neutralizing IgG auto-Abs against IFN-α and IFN-ω were found in APS-I patients [72]. These auto-Abs were unlikely to predispose the patients to CMC, as patients with STAT1 deficiency and impaired responses to IFN-α/β and patients with NEMO, UNC-93B or TLR3 deficiencies and impaired production of IFN-α/β [73] do not present CMC. No more than mild manifestations of oral candidiasis were observed in the only known TYK2-deficient patient, whose cellular defects are not restricted to the IFN-α/β pathway [14]. In turn, the lack of severe viral diseases in APS-I patients probably reflects the compensatory role of other anti-viral IFNs. These studies nonetheless led two groups to detect high titers of neutralizing IgG auto-Abs against IL-17A, IL-17F and/or IL-22 (but not IL-26) in the plasma of almost 200 patients tested [40,41]. No such Abs were found in the plasma of the 90 healthy individuals, 54 unaffected heterozygous patients’ relatives and almost 200 other patients with other autoimmune/endocrine disorders tested. Auto-Abs against all other cytokines tested, including those known to cause distinct clinical syndromes, such as IL-6, IFN-γ, and GM-CSF [7478], were undetectable. Remarkably, two patients with thymoma and CMC were found to have auto-Abs against IL-17 cytokines [41], unlike patients with thymoma without CMC, suggesting that the auto-Abs against IL-17 cytokines were responsible for the CMC. Moreover, auto-Abs were found in some patients with APS-I but without CMC, and even before the onset of CMC in some cases, suggesting that these auto-Abs are probably a cause rather than an effect of CMC. However, although correlative [79], the high titers of neutralizing auto-Abs against IL-17 cytokines in APS-I patients are probably sufficient to account for CMC. Clearly, these findings pave the way for the treatment of CMC in these patients with B cell-depleting, CD20-specific monoclonal Abs. Indeed, immunosuppression was used reluctantly in APS-I patients, in part because of the fear to aggravate CMC. The discovery that CMC has an auto-immune basis suggests that immunosuppression, using CD20 mAbs in particular, may actually improve CMC along with other auto-immune phenotypes in these patients. Interestingly, IL-17 cytokines are thought to be key auto-immune cytokines in the mouse model. The multiple and severe auto-immune phenotypes that develop in APS-I patients, despite neutralizing auto-Abs to IL-17 cytokines, indicate paradoxically that at least some of these phenotypes seem to be IL-17-independent. It also implies that neutralization of IL-17 in patients without APS-I and with these or even possibly other auto-immune phenotypes may not be beneficial. Nevertheless, the treatment of APS-I patients with anti-CD20 Abs and the ensuing recovery of IL-17 immunity might reveal new auto-immune phenotypes, which conversely may be IL-17-dependent and good targets for anti-IL-17 therapy in patients without APS-I.

Conclusion

Three human inborn errors of immunity (AD-HIES, CARD9 deficiency, and APS-1) are associated with CMC as a key infectious phenotype. Patients with AD-HIES are also vulnerable to other infections, including staphylococcal disease in particular, and patients with CARD9 deficiency are vulnerable to systemic candidiasis, whereas CMC seems to be the only infection of note in patients with APS-I. In patients with these three disorders, the pathogenesis of CMC seems to involve impaired IL-17 immunity, involving IL-17A, IL-17F, and/or IL-22. This conclusion is strongly correlative, but further human genetic studies are required to document the collective and individual impact of IL-17 cytokines in host defense. The investigation of patients with isolated CMC, with no other autoimmune or infectious phenotype, may be rewarding [26]. No genetic etiology has yet been identified in patients with isolated CMC. Definitive proof of the role of IL-17 cytokines in immunity to C. albicans infection must await the identification of patients with isolated CMC and inherited disorders specifically affecting IL-17 immunity [80].

Figure 1
Inborn errors of mucocutaneous immunity to Candida albicans in humans

Acknowledgments

We would like to thank all the members of the Necker and Rockefeller branches of the Laboratory of Human Genetics of Infectious Diseases. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from The Rockefeller University Center for Clinical and Translational Science grant number 5UL1RR024143-03 and The Rockefeller University.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bibliography

1. Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J. 2001;20:197–206. [PubMed]
2. Hohl TM, Rivera A, Pamer EG. Immunity to fungi. Curr Opin Immunol. 2006;18:465–472. [PubMed] A clear and comprehensive review on immunity to fungi.
3. Pirofski LA, Casadevall A. Rethinking T cell immunity in oropharyngeal candidiasis. J Exp Med. 2009;206:269–273. [PMC free article] [PubMed]
4. Lilic D. New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis. 2002;15:143–147. [PubMed]
5. Grouhi M, Dalal I, Nisbet-Brown E, Roifman CM. Cerebral vasculitis associated with chronic mucocutaneous candidiasis. J Pediatr. 1998;133:571–574. [PubMed]
6. Loeys BL, Van Coster RN, Defreyne LR, Leroy JG. Fungal intracranial aneurysm in a child with familial chronic mucocutaneous candidiasis. Eur J Pediatr. 1999;158:650–652. [PubMed]
7. Marazzi MG, Bondi E, Giannattasio A, Strozzi M, Savioli C. Intracranial aneurysm associated with chronic mucocutaneous candidiasis. Eur J Pediatr. 2008;167:461–463. [PubMed]
8. de Repentigny L, Lewandowski D, Jolicoeur P. Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection. Clin Microbiol Rev. 2004;17:729–759. [PMC free article] [PubMed]
9. Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol. 1999;118(Suppl 1):1–28. [PMC free article] [PubMed]
10. Casanova JL, Abel L. Primary immunodeficiencies: a field in its infancy. Science. 2007;317:617–619. [PubMed]
11. Buckley RH. The hyper-IgE syndrome. Clin Rev Allergy Immunol. 2001;20:139–154. [PubMed]
12. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–1062. [PubMed] Following on from their identification of autosomal recessive TYK2 deficiency, the authors report here the identification of dominant-negative mutations in STAT3 as the first genetic etiology of HIES.
13. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357:1608–1619. [PubMed] This study showed that heterozygous STAT3 mutant alleles accounted for most cases of sporadic and familial forms of autosomal dominant HIES.
14. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25:745–755. [PubMed] This is the first identification of autosomal recessive TYK2 deficiency.
15. Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U, Pfeifer D, Veelken H, Warnatz K, Tahami F, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361:1727–1735. [PubMed] First report of autosomal recessive CARD9 deficiency in a large kindred with susceptibility to multiple fungal infections (Candida albicans and dermatophytes) including invasive and mucocutaneous candidiasis.
16. Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, Elbers CC, Johnson MD, Cambi A, Huysamen C, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361:1760–1767. [PMC free article] [PubMed]
17. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–529. [PubMed] A clear and comprehensive review of the clinical features of APS-I.
18. Atkinson TP, Schaffer AA, Grimbacher B, Schroeder HW, Jr, Woellner C, Zerbe CS, Puck JM. An immune defect causing dominant chronic mucocutaneous candidiasis and thyroid disease maps to chromosome 2p in a single family. Am J Hum Genet. 2001;69:791–803. [PMC free article] [PubMed]
19. Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009;27:287–312. [PubMed] A clear and comprehensive review of the role of AIRE in the induction of T-cell tolerance.
20. Lilic D, Gravenor I. Immunology of chronic mucocutaneous candidiasis. J Clin Pathol. 2001;54:81–83. [PMC free article] [PubMed]
21. Eyerich K, Eyerich S, Hiller J, Behrendt H, Traidl-Hoffmann C. Chronic mucocutaneous candidiasis, from bench to bedside. Eur J Dermatol. 2010 [PubMed]
22. Kobrynski LJ, Tanimune L, Kilpatrick L, Campbell DE, Douglas SD. Production of T-helper cell subsets and cytokines by lymphocytes from patients with chronic mucocutaneous candidiasis. Clin Diagn Lab Immunol. 1996;3:740–745. [PMC free article] [PubMed]
23. Lilic D, Cant AJ, Abinun M, Calvert JE, Spickett GP. Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma (IFN-gamma) production. Clin Exp Immunol. 1996;105:205–212. [PMC free article] [PubMed]
24. de Moraes-Vasconcelos D, Orii NM, Romano CC, Iqueoka RY, Duarte AJ. Characterization of the cellular immune function of patients with chronic mucocutaneous candidiasis. Clin Exp Immunol. 2001;123:247–253. [PMC free article] [PubMed]
25. Lilic D, Gravenor I, Robson N, Lammas DA, Drysdale P, Calvert JE, Cant AJ, Abinun M. Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis. Infect Immun. 2003;71:5690–5699. [PMC free article] [PubMed]
26. Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, Hofmann H, Ring J, Traidl-Hoffmann C. Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol. 2008;128:2640–2645. [PubMed]
27. Conti HR, Gaffen SL. Host responses to Candida albicans: Th17 cells and mucosal candidiasis. Microbes Infect. 2010 [PMC free article] [PubMed] A clear and comprehensive review on host responses to C. albicans.
28. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517. [PubMed]
29. Zhou L, Littman DR. Transcriptional regulatory networks in Th17 cell differentiation. Curr Opin Immunol. 2009;21:146–152. [PubMed] Two clear and comprehensive reviews on the development and functions of IL-17-producing T cells.
30. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206:299–311. [PubMed] This paper describes a mouse model mimicking human CMC and reveals the critical role of IL-17-mediated immunity in protective immunity to C. albicans.
31. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14:275–281. [PMC free article] [PubMed]
32. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, Godinez I, Sankaran S, Paixao TA, Gordon MA, et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med. 2008;14:421–428. [PMC free article] [PubMed]
33. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–289. [PubMed]
34. Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, et al. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med. 2009;206:1291–1301. [PubMed] The authors show that epithelial cells in the lungs and skin need IL-17 to express anti-staphylococcal genes, accounting for the tissue tropism of these infections in AD-HIES patients carrying mutations in STAT3.
35. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, Fujikado N, Tanahashi Y, Akitsu A, Kotaki H, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30:108–119. [PubMed]
36. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. [PMC free article] [PubMed]
37. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205:1551–1557. [PMC free article] [PubMed]
38. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Janniere L, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008;205:1543–1550. [PMC free article] [PubMed]
39. Renner ED, Rylaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, Zhu Q, Jansson AF, Barboza J, Schimke LF, et al. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol. 2008;122:181–187. [PubMed] These four studies demonstrate the impairment of IL-17-producing T-cell generation in patients with AD-HIES carrying mutations in STAT3, suggesting that IL-17 is important for protective immunity to Candida and staphylococci in the lungs, skin, and upper gastro-intestinal tract.
40. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachee-Chardin M, Toulon A, Bustamante J, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291–297. [PMC free article] [PubMed]
41. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207:299–308. [PubMed] These two studies report the presence of high titers of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 in patients with APS-I syndrome. These antibodies may account for the CMC commonly observed in such patients.
42. Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet. 1966;1:1013–1015. [PubMed]
43. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702. [PubMed]
44. Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004;190:624–631. [PubMed]
45. van de Veerdonk FL, Kullberg BJ, Verschueren IC, Hendriks T, van der Meer JW, Joosten LA, Netea MG. Differential effects of IL-17 pathway in disseminated candidiasis and zymosan-induced multiple organ failure. Shock. 2010 [PubMed]
46. Aujla SJ, Kolls JK. IL-22: a critical mediator in mucosal host defense. J Mol Med. 2009;87:451–454. [PubMed]
47. Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009;2:403–411. [PMC free article] [PubMed]
48. Liu X, Lee YS, Yu CR, Egwuagu CE. Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J Immunol. 2008;180:6070–6076. [PMC free article] [PubMed]
49. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8:639–646. [PubMed]
50. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, Jouanguy E, Boisson-Dupuis S, Fieschi C, Picard C, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol. 2006;18:347–361. [PubMed]
51. MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, Sanal O, MacLennan JM, Holland SM, Ottenhoff TH, Casanova JL, et al. Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis. 2004;190:1755–1757. [PubMed]
52. de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, Jannière L, Rose Y, Kong XF, Filipe-Santos O, et al. Revisiting human IL-12Rb1 deficiency: a survey of 141 patients from 30 countries. Medicine. 2010 In press. [PMC free article] [PubMed]
53. Paulson ML, Freeman AF, Holland SM. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr Opin Allergy Clin Immunol. 2008;8:527–533. [PubMed] A clear and comprehensive review on AD-HIES.
54. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22:507–517. [PubMed]
55. Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, Forster I, Ruland J. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442:651–656. [PubMed]
56. Brown GD. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol. 2006;6:33–43. [PubMed]
57. LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, Schweighoffer E, Tybulewicz V, Brown GD, Ruland J, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8:630–638. [PubMed]
58. Sato K, Yang XL, Yudate T, Chung JS, Wu J, Luby-Phelps K, Kimberly RP, Underhill D, Cruz PD, Jr, Ariizumi K. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses. J Biol Chem. 2006;281:38854–38866. [PubMed]
59. Hara H, Ishihara C, Takeuchi A, Imanishi T, Xue L, Morris SW, Inui M, Takai T, Shibuya A, Saijo S, et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol. 2007;8:619–629. [PubMed]
60. Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol. 2008;9:1179–1188. [PubMed]
61. Robinson MJ, Osorio F, Rosas M, Freitas RP, Schweighoffer E, Gross O, Verbeek JS, Ruland J, Tybulewicz V, Brown GD, et al. Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection. J Exp Med. 2009;206:2037–2051. [PMC free article] [PubMed]
62. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204:2407–2422. [PMC free article] [PubMed]
63. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine. 2010 Submitted. [PMC free article] [PubMed]
64. Reid DM, Gow NA, Brown GD. Pattern recognition: recent insights from Dectin-1. Curr Opin Immunol. 2009;21:30–37. [PubMed] A clear and comprehensive review of the role of Dectin-1 in host defense.
65. Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, Haynes K, Steele C, Botto M, Gordon S, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol. 2007;8:31–38. [PMC free article] [PubMed]
66. Saijo S, Fujikado N, Furuta T, Chung SH, Kotaki H, Seki K, Sudo K, Akira S, Adachi Y, Ohno N, et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol. 2007;8:39–46. [PubMed]
67. Peterson P, Pitkanen J, Sillanpaa N, Krohn K. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity. Clin Exp Immunol. 2004;135:348–357. [PMC free article] [PubMed]
68. Notarangelo LD, Gambineri E, Badolato R. Immunodeficiencies with autoimmune consequences. Adv Immunol. 2006;89:321–370. [PubMed]
69. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17:399–403. [PubMed]
70. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393–398. [PubMed]
71. Ramsey C, Hassler S, Marits P, Kampe O, Surh CD, Peltonen L, Winqvist O. Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator. Eur J Immunol. 2006;36:305–317. [PubMed]
72. Meager A, Visvalingam K, Peterson P, Moll K, Murumagi A, Krohn K, Eskelin P, Perheentupa J, Husebye E, Kadota Y, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3:e289. [PMC free article] [PubMed]
73. Zhang SY, Boisson-Dupuis S, Chapgier A, Yang K, Bustamante J, Puel A, Picard C, Abel L, Jouanguy E, Casanova JL. Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-alpha/beta, IFN-gamma, and IFN-lambda in host defense. Immunol Rev. 2008;226:29–40. [PubMed]
74. Puel A, Picard C, Lorrot M, Pons C, Chrabieh M, Lorenzo L, Mamani-Matsuda M, Jouanguy E, Gendrel D, Casanova JL. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J Immunol. 2008;180:647–654. [PubMed]
75. Doffinger R, Helbert MR, Barcenas-Morales G, Yang K, Dupuis S, Ceron-Gutierrez L, Espitia-Pinzon C, Barnes N, Bothamley G, Casanova JL, et al. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin Infect Dis. 2004;38:e10–e14. [PubMed]
76. Kampmann B, Hemingway C, Stephens A, Davidson R, Goodsall A, Anderson S, Nicol M, Scholvinck E, Relman D, Waddell S, et al. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest. 2005;115:2480–2488. [PMC free article] [PubMed]
77. Patel SY, Ding L, Brown MR, Lantz L, Gay T, Cohen S, Martyak LA, Kubak B, Holland SM. Anti-IFN-gamma autoantibodies in disseminated nontuberculous mycobacterial infections. J Immunol. 2005;175:4769–4776. [PubMed]
78. Kitamura T, Tanaka N, Watanabe J, Uchida Kanegasaki S, Yamada Y, Nakata K. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. 1999;190:875–880. [PMC free article] [PubMed]
79. Husebye ES, Anderson MS. Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity. 32:479–487. [PubMed] A clear and comprehensive review of the APS-I syndrome.
80. Alcais A, Abel L, Casanova JL. Human genetics of infectious diseases: between proof of principle and paradigm. J Clin Invest. 2009;119:2506–2514. [PubMed] A clear and comprehensive review of the field of human inborn errors of immunity.
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...