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• W2009013529 abstract "Chronic Candida species infection of the skin and mucosal membranes is viewed as a group of disorders all sharing a similar clinical condition, the susceptibility to localized fungal infections, which can be isolated or as a feature associated with various other entities. Although the pathogenesis underlying such a tendency had previously been poorly understood, the last decade has witnessed significant progress in revealing the molecular and immunologic mechanisms involved in antifungal immunity. TH17 cells and their specific cytokines (IL-17A and IL-17F cytokines and IL-22) are the main players in conferring antifungal protection. Autoimmune polyendocrinopathy and ectodermal dystrophy and hyper-IgE syndrome are 2 entities caused by different genetic mutations affecting distinct immune pathways but eventually share a similar clinical phenotype of Candida species infection. Impaired TH17 responses, although mediated by different mechanisms, seem to underlie this common feature: neutralizing autoantibodies against IL-17A and 1L-22 are involved in patients with autoimmune polyendocrinopathy and ectodermal dystrophy syndrome, whereas abnormal TH17 proliferation and IL-17 production are observed in the latter. Although various degrees of TH17 dysfunction were also observed in most cases of isolated chronic mucocutaneous candidiasis, only in very few families was a distinct mutation detected (caspase recruitment domain family, member 9 [CARD9]), thus indicating certain forms of chronic mucocutaneous candidiasis as monogenic with a Mendelian pattern of inheritance. Hopefully, these data will open the way for further searches for other genes and for introducing new treatment modalities. Chronic Candida species infection of the skin and mucosal membranes is viewed as a group of disorders all sharing a similar clinical condition, the susceptibility to localized fungal infections, which can be isolated or as a feature associated with various other entities. Although the pathogenesis underlying such a tendency had previously been poorly understood, the last decade has witnessed significant progress in revealing the molecular and immunologic mechanisms involved in antifungal immunity. TH17 cells and their specific cytokines (IL-17A and IL-17F cytokines and IL-22) are the main players in conferring antifungal protection. Autoimmune polyendocrinopathy and ectodermal dystrophy and hyper-IgE syndrome are 2 entities caused by different genetic mutations affecting distinct immune pathways but eventually share a similar clinical phenotype of Candida species infection. Impaired TH17 responses, although mediated by different mechanisms, seem to underlie this common feature: neutralizing autoantibodies against IL-17A and 1L-22 are involved in patients with autoimmune polyendocrinopathy and ectodermal dystrophy syndrome, whereas abnormal TH17 proliferation and IL-17 production are observed in the latter. Although various degrees of TH17 dysfunction were also observed in most cases of isolated chronic mucocutaneous candidiasis, only in very few families was a distinct mutation detected (caspase recruitment domain family, member 9 [CARD9]), thus indicating certain forms of chronic mucocutaneous candidiasis as monogenic with a Mendelian pattern of inheritance. Hopefully, these data will open the way for further searches for other genes and for introducing new treatment modalities. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Candida albicans is a dimorphic fungus that can cause a variety of distinct disease forms in human subjects. Normally, this fungus is a commensal organism found in the gastrointestinal and reproductive mucosa. However, in immunocompromised patients C albicans might be responsible for multiple disease states, either systemic or mucosal. Systemic candidiasis usually presents as an acute, disseminated, and invasive form mainly in patients with both inherited and acquired neutrophil disorders or in patients with insertion of central lines. More commonly, C albicans can cause a mucosal and epidermal form of infection, typically presenting with chronic manifestations and thus called chronic mucocutaneous candidiasis (CMC).1Glocker E. Grimbacher B. Chronic mucocutaneous candidiasis and congenital susceptibility to Candida.Curr Opin Allergy Clin Immunol. 2010; 10: 542-550Crossref PubMed Scopus (50) Google Scholar CMC is now viewed as a collection of syndromes with the unifying feature of susceptibility to chronic or recurrent candidiasis localized to the skin, nails, and mucous membranes. The lesions, although not life-threatening, are disfiguring and debilitating, causing a major negative effect on quality of life. As a rule, there is essentially no predisposition to invasive disease, such as sepsis or pneumonia. Because of the diversity of populations of patients with CMC, several clinical syndromes have been defined, differing in their clinical manifestations, severity, distribution, immunologic findings, and genetic features. Cutaneous Candida species infections are more frequently observed secondary to several clinical conditions, such as HIV, diabetes mellitus, intensive care conditions, neoplasia, long-term use of broad-spectrum antibiotics or immunosuppressive agents, and any global T-cell deficiency disorders, such as Di George syndrome or severe combined immunodeficiency.2Conti H.R. Gaffen S.L. Host responses to Candida albicans: Th17 cells and mucosal candidiasis.Microbes Infect. 2010; 12: 518-527Crossref PubMed Scopus (106) Google Scholar All such conditions are characterized by general susceptibility to multiple other pathogens and various severe invasive infectious diseases. In contrast to these entities, more rarely, CMC can be considered a primary condition, either as a prominent clinical feature of several identified primary immunodeficiency syndromes, such as hyper-IgE syndrome (HIES) and autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED), or as an isolated phenomenon with no other overt infection or autoimmune manifestation. These nonsyndromic cases of CMC, first described in 1967, can be sporadic, but multiplex families with both dominant and recessive inheritance have been described.3Puel A. Picard C. Cypowyj S. Lilic D. Abel L. Casanova J.L. Inborn errors of mocucotaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?.Curr Opin Immunol. 2010; 22: 467-474Crossref PubMed Scopus (115) Google Scholar Significant progress has been made regarding the molecular background and pathomechanics of primary CMC since the first published case on primary candidiasis by Thorpe and Handley4Thorpe E.S. Handley H.E. Chronic tetany and chronic mycelial stomatitis in a child aged four and one half years.Am J Dis Child. 1929; 38: 228-238Google Scholar about 8 decades ago. Various investigations conducted recently, both on animal models and in human subjects, have transitioned the description of such cases from idiopathic with an impaired cell-mediated immunity to C albicans to more well-established primary immunodeficiencies. These studies deciphered the specific cells, signal transduction pathways, cytokines, and genes involved. Traditionally, the immune response against Candida species was thought to be mediated by CD4+ TH1 lymphocytes and their major cytokine IFN-γ. Later, Farah et al5Farah C.S. Hu Y. Riminton S. Ashman R.B. Distinct roles for IL-12p40 and TNF in resistance to oral candidiasis defined by gene-targeting.Oral Microbiol Immunol. 2006; 21: 252-255Crossref PubMed Scopus (59) Google Scholar reported that IFN-γ knockout mice were not susceptible to oral candidiasis. The development of murine models for CMC, the availability of numerous knockout and transgenic strains, and the introduction of the relatively newly described CD4+ effector T cells TH17 cells and their related cytokines has facilitated the process of understanding the mucocutaneous immunity against Candida species. In this report we will briefly summarize the pathways for Candida species sensing and signal transduction, TH17 cell development, and their role in cutaneous antifungal immunity and give an overview on the molecular background underlying the several primary genetic disorders associated with susceptibility to peripheral Candida species. During an infection with Candida species, both the innate and adaptive arms of the immune system are involved in mounting a protective response. The first step is the recognition of the fungal pathogen by cell-surface receptors located on professional phagocytes and dendritic cells. Several pathogen-associated molecular patterns (eg, mannans, glucans, and chitin) are recognized by receptors grouped into several families, such as Toll-like receptors (TLRs), the C-type lectin receptors, and others. The detailed Candida species–sensing pathways are beyond the scope of this review, but apparently some of the TLRs seem to be involved in host defense against Candida species. TLR2 and TLR4 are involved in the host interaction with C albicans and play a significant role in the development of host immune response during candidiasis.6Gil M.L. Gozalbo D. Role of Toll-like receptors in systemic Candida albicans infections.Front Biosci. 2009; 14: 570-582Crossref Scopus (43) Google Scholar Recognition of Candida species by TLRs activates intracellular signaling pathways that might contribute to the polarization toward a proinflammatory TH17 response.6Gil M.L. Gozalbo D. Role of Toll-like receptors in systemic Candida albicans infections.Front Biosci. 2009; 14: 570-582Crossref Scopus (43) Google Scholar Furthermore, in a TLR2 knockout murine model increased dissemination of Candida species to the lymph nodes and spleen was observed with decreased neutrophil function.7Tessarolli V. Gasparoto T.H. Lima H.R. Figueira E.A. Garlet T.P. Torres S.A. et al.Absence of TLR2 influences survival of neutrophils after infection with Candida albicans.Med Mycol. 2010; 48: 129-140Crossref PubMed Scopus (29) Google Scholar Still, the C-type lectin receptors, mainly Dectin-1 and Dectin-2, have been demonstrated to be pivotal in the immune response to C albicans.8Drummond R.A. Saijo S. Iwakura Y. Brown G.D. The role of Syk/Card9 coupled C-type lectins in antifungal immunity.Eur J Immunol. 2011; 41: 276-281Crossref PubMed Scopus (155) Google Scholar Dectin-1 recognizes pathogen-associated molecular patterns (β-glucan) and signals through immunoreceptor tyrosine-based activation motif, which becomes phosphorylated by sarcoma kinases. These signaling events are followed by the recruitment and activation of spleen tyrosine kinase (Syk). Dectin-1/Syk then engage caspase recruitment domain family, member 9 (CARD9), the intracellular signaling of which relays fungal recognition through the activation of nuclear factor κB and mitogen-activated protein kinases.9Netea M.G. Marodi L. Innate immune mechanisms for recognition and uptake of Candida species.Trends Immunol. 2010; 31: 346-353Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Dectin-1 seems to also have a role in the innate immune response to fungal infections. For example, it was shown that it was a major initiator of the respiratory burst.8Drummond R.A. Saijo S. Iwakura Y. Brown G.D. The role of Syk/Card9 coupled C-type lectins in antifungal immunity.Eur J Immunol. 2011; 41: 276-281Crossref PubMed Scopus (155) Google Scholar On the other hand, Dectin-2 was shown to be the functional receptor for α-mannans, a known component of fungal structure.10Saijo S. Ikeda S. Yamabe K. Kakuta S. Ushigame H. Akitsu A. et al.Dectin-2 recognition of alfa mannans and induction of Th17 cell differentiation is essential for host defence against Candida albicans.Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar Dectin-2, which is expressed by dendritic cells, was recently shown to be essential in mediating protection against Candida species because survival was significantly decreased in Dectin-2–deficient mice when infected with C albicans. This defect was mainly due to the substantial reduction in cytokine production, especially those involved in TH17 differentiation.10Saijo S. Ikeda S. Yamabe K. Kakuta S. Ushigame H. Akitsu A. et al.Dectin-2 recognition of alfa mannans and induction of Th17 cell differentiation is essential for host defence against Candida albicans.Immunity. 2010; 32: 681-691Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar The Dectin-Syk-CARD9–signaling pathway triggers the production of further cytokines, such as IL-1β, TNF-α, IL-6, and IL-23, which are all contributing to antifungal immunity, including the generation of IL-17– and IL-22–producing T cells, so-called TH17 cells (Fig 1). The TH1 versus TH2 model has dominated T-cell biology for many years. Yet the description of another TH subset, the TH17 lineage, about a decade ago has made a major shift in our understanding of the immune components conferring resistance to Candida species.11Palm N.W. Medzhitov R. Antifungal defence turns 17.Nat Immunol. 2007; 8: 549-551Crossref PubMed Scopus (37) Google Scholar On activation by signaling through the T-cell receptor and costimulatory molecules, naive CD4+ TH precursor cells can differentiate into 3 lineages of effector TH cells (TH1, TH2, and TH17 cells), depending on the local cytokine milieu. Each subset produces different cytokines that mediate distinct effectors mechanisms. TH17 cells develop In the presence of IL-1β, IL-6, and TGF-β. These cytokines act in a signal transducer and activator of transcription 3 (STAT3)–dependent manner to induce the expression of the retinoic acid–related related orphan receptor (ROR) γt, the lineage defining the transcription factor of TH17 cells. In addition, they upregulate the expression of chemokine receptors CCR4 and CCR6, which is required for their migration to the skin and mucosa, respectively. IL-23 is important for TH17 cell maintenance and expansion. Differentiated TH17 cells secrete 1L-17A and IL-17F, IL-21, IL-22, and IL-26 cytokines, which are known to promote cutaneous antifungal immunity by inducing the release of a wide range of proinflammatory danger signals, the expansion of antimicrobial factors, chemokine production at sites of infection, and recruitment of neutrophils. Regulatory T (Treg) cells also play a role in the normal immune response to fungal infections. Treg cells can suppress TH17 function and thus lead to reduced inflammatory responses against Candida species and avoidance of unnecessary inflammatory response.12Kroetz D.N. Deepe G.S. CCR5 dictates the equilibrium of proinflammatory IL-17+ and regulatory Foxp3+ T cells in fungal infection.J Immunol. 2010; 184: 5224-5231Crossref PubMed Scopus (57) Google Scholar Generation of induced Treg and TH17 cells is reciprocally regulated. Depending on the concentration, TGF-β has the ability to induce both RORγt (important for TH17 production) or forkhead box protein 3, which is essential for Treg cells.13Bettelli E. Carrier Y. Gao W. Korn T. Strom B. Oukka M. et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Scopus (5434) Google Scholar The development link between Treg and TH17 cells might suggest that these T-cell subsets exist in equilibrium during inflammation and infection. To summarize, Dectin-mediated fungal recognition preferentially triggers the differentiation of TH17 cells, which produce IL-17A and IL-17F and also IL-22, all of which have a major role in immunity against Candida species (Fig 1).14Gaffen S.L. Structure and signalling in the IL-17 receptor family.Nat Rev Immunol. 2009; 9: 556-567Crossref PubMed Scopus (1018) Google Scholar Although several knockout murine models indeed showed the role of these various components, this review will concentrate on human disorders in which defects in this pathway were found (Fig 1). For more information, see Table I. The most common Candida species infection in human subjects is the oral thrush, which essentially affects most infants around the age of 3 months. This is a self-limited benign condition and usually resolves after several days. Persistent or recurrent oral thrush should raise the possibility of a T-cell primary immunodeficiency, such as severe combined immunodeficiency or Di George syndrome. In adults persistent thrush is common in patients with HIV infection.Table IHuman disease associated with Candida species infectionNameFrequencyCauseOral thrush in infancyVery commonNormal immune responsePersistent oral thrushCommonT-cell deficiency syndromes and HIVSystemic candidiasisCommonImmunocompromised patients and neutrophil dysfunctionHIESRareSTAT3 mutationAPECEDRareAutoantibodies to IL-17A, IL-17F, and IL-22Mendelian susceptibility to mycobacterial diseaseRareMutations in IL12 and IL12RIsolated mucocutaneous candidiasis, autosomal recessive and dominant formsRareIn rare cases there are mutations in CARD9, Dectin-1 (?), and IL17RA; in most cases the cause is still unknown. Open table in a new tab HIES is a rare multisystem disorder characterized by eczema, Staphylococcus aureus–induced skin abscesses, and pneumatocele formation affecting almost all patients. Recurrent mucocutaneous candidiasis is also a common clinical feature described in approximately 80% of these patients. Additional characteristic abnormalities recognized include multiple skeletal and connective tissue abnormalities, such as distinct facial features, hyperextensible joints, pathological bone fractures, scoliosis, craniosynostosis, and retained primary teeth. Among the immunologic abnormalities are markedly increased IgE levels, which lead to the disorder named HIES. Heterozygous mutations of the gene encoding the transcription factor STAT3 have been identified as the cause of this syndrome.15Minegishi Y. Siato M. Tsuchiya S. 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: 1058-1062Crossref PubMed Scopus (776) Google Scholar The mechanism by which mutations in STAT3 cause this unique susceptibility to particular infections has recently begun to be defined. As previously described, STAT3-dependent signaling is crucial for the expression of RORγt, the transcription factor required for TH17 cell line differentiation. Indeed, several studies documented an almost complete lack of circulating IL-17–producing T cells in patients with dominant negative STAT3 mutations.16Milner J. Brenchley J.M. Laurence A. Freeman A.F. Hill B.J. Elias K.M. et al.Impaired Th17 cell differentiation in subjects with autosomal dominant hyper IgE syndrome.Nature. 2008; 452: 773-776Crossref PubMed Scopus (909) Google Scholar Naive T cells were unable to differentiate in vitro into memory CD4+/IL-17 T cells in response to various cytokines, and an impaired induction of ROR mRNA on stimulation was also observed. In patients with autosomal dominant HIES, the proportion of circulating CD4+/CCR6+ cells is low, which is consistent with CCR6 being a marker for IL-17–producing T cells. The levels of other cytokines (eg, IL-2 and IFN-γ) were not affected as much, suggesting TH17-specific differentiation impairment. Recently, it was found that TH17 was also involved in the antifungal activity of saliva,17Conti H.R. Baker O. Freeman A.F. Jang W.S. Holland S.M. Edgerton M. et al.New mechanism of oral immunity to mucosal candidiasis in hyper IgE syndrome.Mucosal Immunol. 2011; ([Epub ahead of print])PubMed Google Scholar which might lead to the commonly observed oral candidiasis seen in patients with HIES. Levels of several antifungal proteins, such as β-defensin 2 and histatins, were markedly decreased in the saliva of patients with HIES, and IL-17 significantly enhanced the expression of histatins.17Conti H.R. Baker O. Freeman A.F. Jang W.S. Holland S.M. Edgerton M. et al.New mechanism of oral immunity to mucosal candidiasis in hyper IgE syndrome.Mucosal Immunol. 2011; ([Epub ahead of print])PubMed Google Scholar APECED syndrome is a rare, autosomal recessive, combined autoimmune and immunodeficiency syndrome arising from mutations in the autoimmune regulator gene (AIRE), leading to aberrant thymic self-tolerance mechanisms and the loss of thymic deletion of autoreactive T cells. It is characterized by multiorgan autoimmunity, mainly hypoparathyroidism and adrenal failure. Another major component of this syndrome is severe CMC, which remains localized to the mucosa and with no susceptibility to other overt infections. Although the basis for the autoimmune disease tendency was clarified with the recognition of AIRE function, its relation to CMC has remained puzzling until the recently described neutralizing autoantibodies to TH17 cytokines. Two articles published concomitantly in 2010 demonstrated high-titer neutralizing autoantibodies to the T-cell cytokines that regulate antifungal activity: IL-17 and IL-22. Puel et al18Puel A. Doffinger R. Natividad A. Chrabieh M. Barcenas-Morales G. Picard C. et al.Autoantibodies against IL17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.J Exp Med. 2010; 207: 291-297Crossref PubMed Scopus (519) Google Scholar and Kisard et al19Kisard K. Boe Wolff A.S. Podkrajsek K.T. Tserel L. Link M. Kisard K.V. et al.Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17 associated cytokines.J Exp Med. 2010; 207: 299-308Crossref PubMed Scopus (458) Google Scholar found high titers of autoantibodies against IL-17A, IL-17F, and/or IL-22 in the sera of almost all patients with APECED and CMC. The neutralizing function of the anti–IL-17A antibody was confirmed by inhibiting IL-6 production from IL-17–responsive fibroblasts. Thus anti-cytokine autoantibodies might be observed in patients with CMC associated with immune dysregulation entities and can inhibit the production of IL-6, IL-23, and TGF-β. A recent third study reported by Ng et al20Ng W.F. von Delwig A. Carmichael A.J. Arkwright P.D. Abinun M. Cant A.J. et al.Impaired Th17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.J Allergy Clin Immunol. 2010; 126: 1006-1015Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar assessing TH17 responses on stimulation of PBMCs from patients with APECED with Candida species has demonstrated normal TH17 cell proliferation and IL-17 production unless exposed to APECED plasma, which inhibited both functions in both the APECED and normal PBMCs. Characterizing anti-cytokine antibodies in patients with APECED might pave the way for new treatment modalities, such as the use of rituximab (anti-CD20). Patients with IL-12p40 and IL-12 receptor β1 deficiencies typically present with Mendelian susceptibility to mycobacterial disease clinically characterized by selective predisposition to mycobacterial and Salmonella species infections. However, around 25% of these patients also display a mild form of CMC. Interestingly, these patients have been shown to have a smaller proportion of circulating IL-17–producing T cells compared with healthy subjects, probably accounting for such susceptibility.21Beaucoudrey L.D. Samarina A. Bustamante J. Cabot A. Boisson-Dupuis S. Feinberg J. et al.Revisiting human IL-12Rbeta1 deficiency.Medicine. 2010; 89: 381-402Crossref PubMed Scopus (291) Google Scholar Nonsyndromic CMC is characterized by an isolated susceptibility to candidiasis limited to the skin, nails, and mucous membranes, with no predisposition to invasive fungal disease or other pathogens and without autoimmune manifestations. Most cases are sporadic, but familial cases with autosomal dominant and recessive inheritance patterns have also been described. Several hundred patients worldwide have been reported. Various defects in T-cell function were reported, but none could explain the unique susceptibility to Candida species infections in these patients. Until recently, the genetic background to such cases has remained elusive. In 2009, the first autosomal recessive form of susceptibility to isolated CMC was reported.22Glocker E.O. Hennigs A. Nabavi M. Schaffer A.A. Woellner C. Salzer U. et al.A homozygous CARD9 mutation in a family with susceptibility to fungal infections.N Engl J Med. 2009; 361: 1727-1735Crossref PubMed Scopus (605) Google Scholar A homozygous point mutation in CARD9 that results in a loss-of-function mutation caused by a premature termination codon (Q295X) was reported in a large, consanguineous, 5-generation Iranian family. Multiple members had recurrent peripheral fungal infections and all had a homozygous point mutation in CARD9 and lacked wild-type expression of CARD9 protein, whereas healthy family members had normal gene and protein expression. The CARD9-deficient patients also displayed a significantly smaller proportion of IL-17–expressing T cells and almost a complete defect in the generation of a TH17 response. Experiments in the murine CARD9−/− model showed that only wild-type CARD9 and not the mutated human CARD9 gene found, could restore cytokine production in response to the triggering of Dectin-1. In line with the critical role for Dectin/Syk/CARD9-signaling pathway in promoting proinflammatory cytokine production by dendritic cells, thereby inducing TH17 cell line differentiation, these data again strengthen the evidence for a crucial role of TH17 responses for host defense against mucosal Candida species infections. As previously described, Dectin-1 plays a role in the immune response to C albicans, and Dectin-1 knockout mice display a higher susceptibility to this fungus. An early stop codon polymorphism in Dectin-1 has been defined in a family with several members with mild CMC.23Ferwerda B. Ferwerda G. Plantinga T.S. Willment J.A. van Spriel A.B. Venselaar H. et al.Human Dectin 1 deficiency and mucocutaneous fungal infections.N Engl J Med. 2009; 361: 1760-1767Crossref PubMed Scopus (581) Google Scholar Macrophages of affected patients demonstrated a significantly lower fungal sensing capacity, but in vitro phagocytosis and intracellular killing were normal. Still, there is some doubt regarding Dectin-1 as a bona fide primary immunodeficiency: the family displayed a mild form of CMC, and Dectin-2 was found recently to be more important than Dectin-1.6Gil M.L. Gozalbo D. Role of Toll-like receptors in systemic Candida albicans infections.Front Biosci. 2009; 14: 570-582Crossref Scopus (43) Google Scholar Furthermore, in the family described, both members with homozygous and heterozygous mutations had candidiasis, and finally, this polymorphism has been observed frequently in healthy donors from different ethnic populations, but the data regarding the prevalence of Candida species in these groups are not available. To summarize, the role of Dectin-1 deficiency in human subjects remains controversial. Most likely it constitutes a risk factor for mild forms of CMC. Recently, Puel et al24Puel A. Cyppowyj S. Bustamante J. Wright J.F. Liu L. Kyung Lim H. et al.Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.Science. 2011; 332: 65-68Crossref PubMed Scopus (747) Google Scholar described 2 families with primary CMC, one of which had a homozygous mutation in IL17RA, with the other having an autosomal dominant defect in IL17F. We have investigated another family with an autosomal dominant form of CMC who lacked IL-17 and TH17 cells while the expression of IL17 mRNA was completely normal (manuscript in preparation), pointing to a posttranscriptional defect. Still, it should be noted that these are rare cases of CMC in which the specific mutations were found, whereas in most cases, although an abnormal TH17 production or function was observed,25Eyerich K. Foerster S. Rombold S. Seidl H.P. Behrendt H. Hofmann H. et al.Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th-17 associated cytokines Il-17 and IL-22.J Invest Dermatol. 2008; 128: 2640-2645Crossref PubMed Scopus (202) Google Scholar the primary defect or defects leading to autosomal and recessive forms of isolated CMC are still unknown. CorrectionJournal of Allergy and Clinical ImmunologyVol. 128Issue 2PreviewIn the June 2011 Current Perspectives article entitled “New host defense mechanisms against Candida species clarify the basis of clinical phenotypes” by Hanna and Etzioni (J Allergy Clin Immunol 2011;127:1433-7), the surname of senior author Amos Etzioni is misspelled. Full-Text PDF" @default.
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