Chronic Mucocutaneous Candidiasis Disease Research Articles

IL-17 serum level in patients with chronic mucocutaneous candidiasis disease.

BackgroundChronic mucocutaneous candidiasis (CMC) is defined by recurrent or persistent superficial infections involving nails, skin, and/or oral and genital mucosae. IL‐17 promotes the recruitment, chemotaxis, and expansion of neutrophils and acts directly on keratinocytes and epithelial cells, driving the production of antimicrobial peptides, essential for the immune response against Candida.AimTo evaluate the serum level of IL‐17 in a family affected by CMC restricted to the nails of the hands and feet.MethodsSerum IL‐17 was assayed on 16 patients (aged 21 ± 3.1 years) suffering from persistent onychomycosis caused by Candida and 18 healthy controls (aged 19 ± 2.7 years). Comparisons between groups were performed by Student's unpaired t‐test. The level of significance was set at 0.05.ResultsThe mean serum IL‐17 level in patients was 74 ± 1.42 pg/ml, whereas the control group showed a significantly lower level of 25.6 ± 6.7 pg/ml (p < 0.05).ConclusionsWe showed a potential defect in the IL‐17 signaling pathway in a family affected by CMC restricted to the nails of the hands and feet. Further research is needed to clarify the immunological mechanisms and the genetic etiology at the basis of the unusual clinical presentation in this family.

A naturally-occurring mutation in IL-17F reveals a protective role for the IL-17AF heterodimer in oropharyngeal candidiasis (OPC)

Abstract IL-17A is the original member of the IL-17 family of cytokines. Among the IL-17 family, IL-17F shares the most homology with IL-17A at the amino acid level. IL-17A and IL-17F exist as homodimers and also form a heterodimer (IL-17AF). All of these cytokine dimers signal through the same IL-17RA:IL-17RC receptor complex, but the ligands exhibit different signaling strengths (IL-17A &amp;gt; IL-17AF &amp;gt; IL-17F). We previously showed that IL-17 signaling is critical for immunity against oropharyngeal candidiasis (OPC), an opportunistic infection of the oral mucosa caused by the commensal fungus C. albicans. Mice lacking IL-17RA, IL-17RC, or the adaptor ACT1 all have higher oral fungal burdens than wild type (WT) following oral infection with C. albicans. IL-17A deficient mice are also mildly susceptible to C. albicans oral infection, but blockade of IL-17F does not cause disease susceptibility. Furthermore, double blockade of IL-17A and IL-17F during OPC reveals a cooperative antifungal activity of IL-17A and IL-17F. However, the role of the IL-17AF heterodimer still remains poorly understood. Here, we took advantage of a dominant-negative mutation (IL-17F.S65L) that was previously identified in chronic mucocutaneous candidiasis disease (CMCD) patients. This mutation blocks the signals of IL-17F and IL-17AF but not IL-17A. Using CRISPR/Cas9 technology, we created mice with the analogous IL-17F S65L mutation. These IL-17FS65L/S65L mice showed a similar degree of susceptibility as IL-17A−/− mice though less than IL-17RA−/− mice upon C. albicans oral infection. This result suggests that IL-17AF contributes to protection against OPC.

Progress in mechanisms and immunological treatment of chronic mucocutaneous candidiasis associat-ed with congenital IL-17 pathway deficiency

Chronic mucocutaneous candidiasis (CMC) is a rare, persistent and recurrent infection affecting skin, nails, and oral and genital mucosae. It is mainly caused by Candida albicans and hard to be cured with routine antifungal therapy. Usually, CMC is a primary immunodeficiency disease and can be divided into two categories. The most common one is CMC disease (CMCD), which defined as Candida infection confined to the surface of the skin and mucous membranes and not complicated by systemic Candida albicans infection or other clinical symptoms. The other category is systemic CMC (SCMC) complicated by infections caused by other pathogens, systemic invasive fungal infections, or other clinical symptoms apart from the symptoms of CMCD. It is currently believed that both CMCD and SCMC are related to immunodeficiency caused by gene mutations related to IL-17 signal pathway. The inhibited Th17 proliferation, decreased secretion of IL-17 or IL-22 cytokine, or increased IL-17 or IL-22 neutralizing antibody induced by the mutations promoted the susceptibility to Candida or other pathogens. In the treatment of CMC, in addition to the traditional antifungal drugs such as azoles, polyenes and echinocandins, biological agents and target gene therapy offer potential new therapeutic strategies. This article reviewed the association between congenital immunodeficiency in the IL-17 signaling pathway and CMC, and the possible immunological therapeutic approaches and new therapeutic targets. Key words: Chronic mucocutaneous candidiasis; Candidia albicans; IL-17

The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies

Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA-binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss-of-function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain-of-function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.

Novel Regulatory Mechanism of STAT1 through Redox Post-translational Modification of Cysteines

STAT1 plays a central role in the immune system, in which it mediates signaling induced by different cytokines, including type I (α/β) and type II Interferon (IFN), and regulates expression of genes involved in many physiological processes, including antiviral and antibacterial defense, immune tolerance, suppression of cell proliferation, and induction of apoptosis. Dysregulation or mutation of STAT1 causes life threatening conditions resulting from inefficient defense against pathogens, autoimmunity or cancer development. Single nucleotide polymorphisms of STAT1 Cys residues are associated with chronic mucocutaneous candidiasis disease (CMCD), suggesting a role of Cys in the capacity of STAT1 to drive an appropriate anti-pathogen response. Regulation of STAT1 activity through different post-translational modifications is well-characterized. However, the role of Reactive Oxygen species (ROS) and Cys reversible oxidative post-translational modifications (ox-PTMs) on STAT1 function remained to be investigated. Using maleimide-derivative switch methods to label Cys ox-PTMs, we found that Diamide, a thiol-oxidizing agent, and the myeloperoxidase-generated HOCl induce ox-PTMs of STAT1 Cys in epithelial cells (A549), monocytes (THP-1) and ectopically expressed STAT1 in STAT1 deficient fibroblasts (U3A). Analysis of Cys/Ala (C/A) mutants of STAT1 in response to IFNγ and IFNβ revealed gain of function phenotype of mutations in two different functional domains of STAT1. Altogether, our data supports a model in which previously unrecognized ox-PTMs of STAT1 Cys residues are essential to dampen STAT1 activity. Current studies are aimed at further characterizing the specific Cys ox-PTMs and their consequences on STAT1-dependent transcriptional program induction and antiviral immune response.

Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases.

Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs. Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood. Multicolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X-HIGM, AT, WAS, HIES, and CMCD. Immunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs.

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

Gain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of signal transducer and activator of transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease. This condition is characterized by fungal and bacterial infections caused by impaired generation of TH17cells; meanwhile, some patients with chronic mucocutaneous candidiasis disease might also have viral or intracellular pathogen infections. We sought to investigate the effect of STAT1 GOF mutations on the functioning of natural killer (NK) cells. Because STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in 8 patients with STAT1 GOF mutations. Functional analysis of NK cells shows a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF mutations. Moreover, NK cells from these patients display lower production of IFN-γ in response to IL-15 and reduced proliferation after stimulation with IL-2 or IL-15, suggesting that STAT5 signaling is affected. In addition, signaling studies demonstrate that the increased phosphorylation of STAT1 in response to IFN-α is associated with detectable activation of STAT1 and increased STAT1 binding to the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) promoter in response to IL-15, whereas STAT5 phosphorylation and DNA binding to IL-2 receptor α (IL2RA) are reduced or not affected in response to the same cytokine. These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.

CMCD: Chronic Mucocutaneous Candidiasis Disease.

Chronic mucocutaneous candidiasis (CMC) is an infectious phenotype which is characterized by recurrent or persistent infections affecting the nails, skin, and oral and genital mucosae caused by Candida species. Th17 cells produce interleukin-17 (IL-17) and play an important role in host mucosal immunity to Candida. Recent studies revealed that an impairment of IL-17 immunity underlies development of CMC. CMC disease (CMCD) is a primary immunodeficiency disease which is defined as CMC in patients in the absence of other prominent clinical signs. However, this definition is not strict. Thus, CMCD is currently used to refer to patients presenting with CMC as the main clinical phenotype. As well as CMCD, CMC is a major infectious phenotype in syndromic CMC. However, patients with syndromic CMC also present other clinical and infectious manifestations in addition to CMC. The genetic defects which affect development and/or proliferation of Th17 cells have been identified in patients with syndromic CMC. In contrast, germline mutations in the genes which directly involved in IL-17 signaling have been identified in patients with CMCD. Here, we review current knowledge of IL-17-signaling defects and the genetic etiologies of CMCD and syndromic CMC.

Clinical and immunological data of nine patients with chronic mucocutaneous candidiasis disease.

This paper describes the heterogeneous clinical phenotype of a cohort of nine patients diagnosed with heterozygous mutations in STAT1. We report data of extended immunophenotyping over time and we show lung damage in four patients. The increased phosphorylation of STAT1 in response to IFNγ and IFNα stimulation proves the gain-of-function nature of the defects. The data are supplemental to our original article concurrently published “Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease” [1], where additional results and interpretation of our research can be found.

Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease

In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Genetics of Candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by chronic or recurring infection with Candida albicans and, to a lesser extent, with Staphylococcus aureus . The underlying cause of CMCD is unknown. Puel et al. (p. [65][1], published online 24 February; see the Perspective by [ Dominguez-Villar and Hafler ][2]) now report two genetic etiologies associated with CMCD. The first is an autosomal recessive mutation in interleukin 17 (IL-17) receptor A, which prevents its expression. The second is an autosomal dominant mutation in the cytokine IL-17F, which partially reduces its activity. Thus, human IL-17–mediated immunity is required for protection against these mucocutaneous infections. [1]: /lookup/doi/10.1126/science.1200439 [2]: /lookup/doi/10.1126/science.1205311