Mucocutaneous Candidiasis Research Articles

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.

Chronic mucocutaneous candidiasis: characterization of a family with STAT-1 gain-of-function and development of an ex-vivo assay for Th17 deficiency of diagnostic utility.

SummaryChronic mucocutaneous candidiasis (CMC) is characterized by recurrent and persistent superficial infections, with Candida albicans affecting the mucous membranes, skin and nails. It can be acquired or caused by primary immune deficiencies, particularly those that impair interleukin (IL)−17 and IL‐22 immunity. We describe a single kindred with CMC and the identification of a STAT1 GOF mutation by whole exome sequencing (WES). We show how detailed clinical and immunological phenotyping of this family in the context of WES has enabled revision of disease status and clinical management. Together with analysis of other CMC cases within our cohort of patients, we used knowledge arising from the characterization of this family to develop a rapid ex‐vivo screening assay for the detection of T helper type 17 (Th17) deficiency better suited to the routine diagnostic setting than established in‐vitro techniques, such as intracellular cytokine staining and enzyme‐linked immunosorbent assay (ELISA) using cell culture supernatants. We demonstrate that cell surface staining of unstimulated whole blood for CCR6+CXCR3–CCR4+CD161+ T helper cells generates results that correlate with intracellular cytokine staining for IL‐17A, and is able to discriminate between patients with molecularly defined CMC and healthy controls with 100% sensitivity and specificity within the cohort tested. Furthermore, removal of CCR4 and CD161 from the antibody staining panel did not affect assay performance, suggesting that the enumeration of CCR6+CXCR3–CD4+ T cells is sufficient for screening for Th17 deficiency in patients with CMC and could be used to guide further investigation aimed at identifying the underlying molecular cause.

Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients.

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder characterised by susceptibility to chronic Candida and fungal dermatophyte infections of the skin, nails and mucous membranes. Molecular epidemiology studies of CMC infection are limited in number and scope and it is not clear whether single or multiple strains inducing CMC persist stably or are exchanged and replaced. We subjected 42 C. albicans individual single colony isolates from 6 unrelated CMC patients to multilocus sequence typing (MLST). Multiple colonies were typed from swabs taken from multiple body sites across multiple time points over a 17-month period. Among isolates from each individual patient, our data show clonal and persistent diploid sequence types (DSTs) that were stable over time, identical between multiple infection sites and exhibit azole resistant phenotypes. No shared origin or common source of infection was identified among isolates from these patients. Additionally, we performed C. albicans MLST SNP genotype frequency analysis to identify signatures of past loss of heterozygosity (LOH) events among persistent and azole resistant isolates retrieved from patients with autoimmune disorders including CMC.

Anticytokine Autoantibodies: Association with Infection and Immune Dysregulation.

The association of autoantibodies to cytokines with immune deficiency, autoimmunity and/or immune dysregulation is increasingly being recognized. For example, autoantibodies to interferon gamma have been found to be associated with chronic, treatment refractory infections with intracellular organisms such as mycobacteria, autoantibodies to interleukin 17 with chronic mucocutaneous candidiasis, and anti-interferon alpha autoantibodies with systemic lupus erythematosus. While low titer autoantibodies to these and other cytokines may be detected in normal individuals, patients with infectious or autoimmune manifestations tend to have high titer autoantibodies that may block or potentiate the function of the respective cytokine. Recognition of these autoantibodies is important because it may direct treatment toward a combination of adjunctive immunotherapy to modulate the autoantibody level while continuing with appropriate anti-microbial therapy. This review focuses on the anti-cytokine autoantibodies documented to date, their autoimmune, immune dysregulation and infectious disease associations, methods for detection of these antibodies and potential treatment options.

A case of autoimmune polyendocrine syndrome type 1 with ocular findings and unique AIRE gene defect

Autoimmune polyendocrine syndrome type 1 (APS 1) is a rare autosomal recessive disorder that is characterized by autoimmunity against endocrine and ectodermal tissues. Clinical manifestations usually appear in childhood and consist of hypoparathyroidism, oral candidiasis, and adrenocortical insufficiency. Ocular complications include keratoconjunctivitis, dry eye, iridocyclitis, cataract, retinitis pigmentosa, and optic atrophy. We report a 9-year-old girl with APS 1 who had polar cataract in her left eye (LE), retinal changes with retinal pigment atrophy, and a new autoimmune regulator (AIRE) gene defect on chromosome 21. When a pediatric patient presents with decreased visual acuity with a history of chronic mucocutaneous candidiasis, ectodermal dysplasias, or hypoparathyroidism, we should consider the diagnosis of APS type 1 and arrange a pediatric endocrinological evaluation. The gene studied in this case may contribute to the characterization of the molecular pathology of the AIRE gene and may allow preclinical diagnosis in families at risk.

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.

Impairment of IL-17 Immunity to Candida and IFN-g Immunity to Mycobacterium in Humans with Bi-Allelic Rorc mutations

Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis (CMC), which is characterized by infections of the skin, nails, oral and genital mucosae with Candida albicans. Inborn errors of human IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital disorder characterized by susceptibility to infections by poorly virulent intracellular pathogens such as Mycobacterium bovis Bacille Calmette-Guérin vaccines (BCG) and non-tuberculosis Mycobacterium. Rarely, patients may be affected by both candidiasis and mycobacteriosis, including some patients with IL-12p40 and IL-12Rβ1 deficiencies that impair IFN-γ immunity and IL-17 immunity. We studied seven patients from three unrelated consanguineous kindreds with this unusual combination of infectious diseases without known genetic disorder. We combined whole exome sequencing and genome wide linkage analysis, and discovered bi-allelic loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. All of the seven patients suffered from severe mycobacterial infections, and six also exhibited mild CMC. RORγT is the key transcription factor of Th17 cells, which produce IL-17 and IL-22. Therefore, as predicted by the mouse model, RORγT deficiency prevented the development of IL-17-producing T cells, which accounts for the patients' CMC. Consistent with the phenotype of Rorc-/- mice, these patients presented with mild T cell lymphopenia, small thymus, lack of palpable axillary and cervical lymph nodes, and absence of MAIT and iNKT cells.The patients' severe infections with mycobacteria were not predicted by previous studies of Rorc-/- mice. To explain this unexpected phenotype, we focused on IFN-γ immunity. Leukocytes from RORC-/- patients showed impaired IFN-γ production in response to a mycobacterial challenge, and this defect is probably attributable to the functional impairment of CD4+ CCR6+ CXCR3+ αβ T cells, γδT cells, or both. These findings also suggested that IFN-γ treatment may be beneficial for RORC-/- patients. Moreover, this phenotype does not seem to be human-specific, as we also found that Rorc-/- mice deficient were susceptible to mycobacterial infection. We thus discovered that human RORC is essential not only for the development of IL-17-producing lymphocytes protecting the mucocutaneous barriers against Candida, but also for the activation of IFN-g-producing T cells, and for systemic protection against Mycobacterium. DisclosuresNo relevant conflicts of interest to declare.

Successful Therapy of a Patient with a Novel STAT1 Gain of Function Mutation and Life-Threatening Cytopenias with Janus Kinase Inhibitor Ruxolitinib

Monoallelic gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity. The immunodeficiency is caused by impaired IL-17 immunity and typically presents with chronic mucocutaneous candidiasis, variably associated with other opportunistic infections. The autoimmune manifestations due to exaggerated responsiveness to interferon are more diverse and include SLE, thyroiditis, hepatitis, and alopecia areata. The phenotypic spectrum of STAT1 GOF mutations is extremely wide, ranging from intermittent localized disease to chronic systemic illness and fatality. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor, leaving a void for alternate long-term strategies to control the disease and maintain remission. Recently, we diagnosed a patient suffering from chronic mucocutaneous candidiasis and life-threatening autoimmune cytopenias with a novel monoallelic mutation in the linker domain of STAT1 (c.1633G>A; p.E545K). The mutation caused a profound increase in STAT1 phosphorylation in response to type 1 and 2 interferon without affecting dephosphorylation kinetics, which is mechanistically distinct from all reported STAT1 GOF mutations to date. The potential of naïve patient CD4+ T cells to become IFN- γ or IL-17 producing cells was investigated under TH0 (anti-CD3/28), TH1 (anti-CD3/28, IL-12) and TH17 (anti-CD3/28, IL6, IL-23, TGF-β1) conditions and revealed that patient CD4+ T cells are biased to produce IFN-γ irrespective of polarizing conditions, and resistant to TH17 induction upon stimulation with IL6, IL-23 and TGF-β1. In addition, the patient's proportion of T follicular helper cells (TFH) relative to regulatory T cells (Treg) was increased. Treatment with the Janus Kinase (JAK) 1/2 inhibitor Ruxolitinib reduced the hyperresponsiveness to interferon, normalized the TH1 response, enabled naïve T cells to differentiate into TH17 cells and decreased the TFH to Treg ratio. Under therapeutic dose Ruxolitinib the patient maintained clinical remission with respect to both autoimmunity and mucocutaneous candidiasis.Conclusion: Clinical vigilance for an underlying immune dysregulation syndrome due to abnormal JAK-STAT signaling is critical when evaluating patients with autoimmunity combined with opportunistic infections as JAK-inhibitors represents an effective targeted therapy for long-term disease control even in severely affected patients for whom hematopoietic stem cell transplantation is not available. DisclosuresOff Label Use: Ruxolitinib use for STAT1 GOF mutation.

Novel Treatments for Thymoma and Thymic Carcinoma.

Novel Treatments for Thymoma and Thymic Carcinoma.

The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1.

PurposeGain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.MethodsSTAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients’ peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.ResultsHeterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.ConclusionSTAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.

IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1β and TNF-α, which is consistent with the persistent systemic inflammation. This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.

Autosomal dominant transmission of signal transduction and activator of transcription 1 (STAT1) mutation (Thr385Met) and extended lifespan

Introduction: Heterozygous mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with selective deficiencies to mycobacterial or fungal infections. Recent reports revealed that patients found to carry de novo heterozygous mutations in STAT1 encoding specific amino acid substitutions can go on to develop progressive combined immunodeficiency, distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. Objectives: We present a case of a mother and her son with chronic mucocutaneous candidiasis and T-cell dysfunction, both of whom lived longer than projected life expectancy with a heterozygous STAT1 mutation. The son lived to the age of 20 years and the mother to the age of 32 years. Methods: The son's blood sequencing of STAT1 was performed on a pure T-cell lineage at The Hospital for Sick Children and the Canadian Center for Primary Immunodeficiency, Toronto, Ontario. Results: STAT1 analysis revealed a heterozygous DNA binding domain mutation at Thr385Met. The patient proceeded to develop fulminant progressive multifocal leukoencephalopathy that ultimately led to his death. The patient's mother, although never confirmed to have STAT1 mutation with formal blood sequencing, had multiple comorbidities including progressive lymphopenia, hypogammaglobulinemia, recurrent Pseudomonas pneumonias with associated bronchiectasis, end-stage kidney disease requiring hemodialysis, and ultimately death due to multiple end organ failure associated sepsis. Conclusion: This is the first autosomal dominant transmission of the STAT1 DNA binding domain Thr385Met mutation with an extended lifespan. Statement of Novelty: Previous patients found to have heterozygous mutations of STAT1 that were associated with progressive combined immunodeficiency, arose de novo in each case. Presumed autosomal dominant transmission of a heterozygous STAT1 DNA binding domain Thr385Met mutation has not been reported.

Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis.

Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC) we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs) present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte-derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity.

Chronic Granulomatous Disease Complicated With Dissemination of BCG Vaccine

SESSION TITLE: Tuberculosis Global Case Reports SESSION TYPE: Global Case Report Poster PRESENTED ON: Tuesday, October 27, 2015 at 01:30 PM - 02:30 PM INTRODUCTION: Chronic granulomatous disease is caused by a deficiency of phagocyte microbicidal function, due to the inability to produce hydrogen peroxide and superoxide anion. The most common form is X-linked and presented with recurrent pulmonary infections. CASE PRESENTATION: A male patient a one year and nine months old, presented with febriles syndrome treated with multiple antibiotics such as clabulanic amoxicillin due to reoccurrent infection in the whole respiratory system; anemia, axillary adenopathy, without symptoms of recovery. For this reason he was referred to our hospital for diagnosis and treatment. At admission, his general condition was bad, with the following BM16.5 kg/m2, the patient is between 50-25 percentile growth. Presented: asthenia, decreased appetite, fever syndrome with records of 38 °, oxygen desaturation, with a 92 % to 21 % FiO2, respiratory rate of 36 per minute. Physical examination presented: right axillary lymphadenopathy, mobile, painless, hard elastic 1cm diameter, crepitant widespread rales and rhonchi in both lung fields and Other symptoms such as, increased rate of breathing, breathlessness and wheezing. Treatment was initiated with Clarithromycin and Amoxicillin clavulanic. TB empirical first-line treatment is added. He continued, febrile with records of 38-39 ° C, with antipyretics and physical means. Added access nonproductive cough and increased respiratory compromise adding retractions, and tachypnea. Background: Fully vaccinated. From month of life was treated for recurrent respiratory tract infections. Five months olds requiring hospitalization for acute pneumonia record. Laboratory results: anemia, increased erythrocyte sedimentation rate, hyperglycemia, and mild oxygen desaturation. Serological tests, toxoplasmosis, HIV, EBV, parvovirus, CMV, Mycoplasma, Bartonella, Brucella, Leptosipirosis, all negative. Dosage IgA and IgG slightly above its normal value, IgE 541.6 Ul/ml. Elevation of gamma globulin. DNA- antibody, ANCAs, and Rheumatoid Factor negative. Thorax CT: multiple images of lymph nodes in the mediastinum Observed in lung parenchyma patchy areas of airspace occupation distributed in both lungs and cavitated images in the lower lobes. Axillary lymphadenopathy. Upper abdomen no abnormalities. Normal Echocardiogram. Ocular Fundus, right eye net edges whitish lesions without macular involvement Faced with suspected diagnosis of TB specific studies are requested: Gastric Lavage, Lymph Node and Cerebrospinal Fluid: Negative smear and culture. Blood cultures for mycobacteria: Negatives. Tuberculin Skin Test: Negative. DISCUSSION: Were raised various differential diagnosis: Infectious diseases such as tuberculosis, toxoplasmosis, aspergillosis, staphylococci sepsis, tuberculosis being the entity that most compatible with the characteristics presented by the patient, although the bacillus was not found by the methods referred. Immunological diseases: Wiskott Aldrich immunodeficiency. Severe combined immunodeficiency disease is a group with deficiency of humoral and cellular immunity caused by various genetic mutations and associated enzyme deficiencies. The most common form is X-linked early onset in the first months of life, and is presented as severe mucocutaneous candidiasis, dissemination of BCG vaccine, persistent diarrhea, lung infections, meningitis, septicemia. Complement deficiency can start at different ages. C3 deficiencies present with sino-pulmonary infections by encapsulated bacteria, pneumococcus, Neisseria meningitidis, Haemophilus influenza. Autoimmune disease Systemic lupus erythematosus, polyangiitis, Wegener's granulomatosis. CONCLUSIONS: The patient remained febrile despite therapy instituted and showed no improvement in respiratory symptoms so it is referred to a specialist center for studies to detect diseases of the immune system. Resulting poor response in nitroblue tetrazolium (NBT) test, it was assumed as a chronic granulomatous disease complicated with dissemination of BCG (Bacille Calmette-Guerin) vaccine, given that the child was vaccinated at birth. Treatment was started with interferon gamma, TB drugs, Trimethoprim-sulfamethoxazole and Itraconazol, and showed significant improvement 40 days after starting treatment. Reference #1: Chronic granulomatous disease, Current Opinion in Immunology, Volume 15, October 2003, Pages 578-584, P G Heyworth, and col. DISCLOSURE: The following authors have nothing to disclose: Gabriela Manonelles, Vanina Martin No Product/Research Disclosure Information

Intracranial Calcifications in Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) Syndrome: A Case Report and Literature Review

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED [MIM 240300]), also known as autoimmune polyglandular syndrome type I (APS I), is a rare, debilitating autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. The clinical spectrum of the disease is variable and includes several autoimmune endocrine and non-endocrine manifestations, which may lead to acute metabolic alterations and eventually life-threatening events. The clinical diagnosis requires the presence of two out of three major criteria; chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and autoimmune adrenal failure. Brain calcifications secondary to hypoparathyroidism have been reported in many patients with APECED. These tend to be extensive, bilateral and symmetrical and have characteristic predilection to the basal ganglia. The calcifications may extend to affect the cerebellum and subcortical white matter. The aim of this work is to describe intracranial calcifications in APECED and to report a new feature of pontine calcification expanding the phenotype of this rare condition.

Cardiovascular abnormalities in primary immunodeficiency diseases

In recent years, increasing numbers of patients with primary immune deficiency (PID) are being recognized as also suffering from cardiovascular system (CVS) abnormalities. These CVS defects might be explained by infectious or autoimmune etiologies, as well as by the role of specific genes and the immune system in the development and function of CVS tissues. Here, we provide the first comprehensive review of the clinical, potentially pathogenic mechanisms, and the management of PID, as well as the associated immune and CVS defects. In addition to some well-known associations of PID with CVS abnormalities, such as DiGeorge syndrome and CHARGE anomaly, we describe the cardiac defects associated with Omenn syndrome, calcium channel deficiencies, DNA repair defects, common variable immunodeficiency, Roifman syndrome, various neutrophil/macrophage defects, FADD deficiency, and HOIL1 deficiency. Moreover, we detail the vascular abnormalities recognized in chronic mucocutaneous candidiasis, chronic granulomatous disease, Wiskott–Aldrich syndrome, Schimke immuno-osseus dysplasia, hyper-IgE syndrome, MonoMAC syndrome, and X-linked lymphoproliferative disease. In conclusion, the expanding spectrum of PID requires increased alertness to the possibility of CVS involvement as an important contributor to the diagnosis and management of these patients.

English

Chronic mucocutaneous candidiasis (CMC) is a rare group of overlapping syndromes that have in common a clinical pattern of persistent and diffuse cutaneous or mucosal candidal infections. It is usually associated with multiple endocrine dysfunctions and autoimmune disorders therefore patient needs a complete systemic evaluation. Patients of CMC are also susceptible to other fungal and viral infections due to impaired cell mediated immunity. We report a case of CMC wherein the cutaneous and mucosal lesions were not associated with any systemic disorder. The patient responded to topical clotrimazole and oral fluconazole.

Interleukin 17-Mediated Host Defense against Candida albicans.

Candida albicans is part of the normal microbiota in most healthy individuals. However, it can cause opportunistic infections if host defenses are breached, with symptoms ranging from superficial lesions to severe systemic disease. The study of rare congenital defects in patients with chronic mucocutaneous candidiasis led to the identification of interleukin-17 (IL-17) as a key factor in host defense against mucosal fungal infection. Experimental infections in mice confirmed the critical role of IL-17 in mucocutaneous immunity against C. albicans. Research on mouse models has also contributed importantly to our current understanding of the regulation of IL-17 production by different cellular sources and its effector functions in distinct tissues. In this review, we highlight recent findings on IL-17-mediated immunity against C. albicans in mouse and man.

Immunological and histopathological characterization of cutaneous candidiasis.

Chronic mucocutaneous candidiasis constitutes a heterogeneous group of syndromes, characterized by non-invasive infection of the skin, nails and mucosal membranes by the fungus Candida spp. Although symptoms are heterogeneous, in all cases there is a reduction in protective cytokines, favouring the development of disease. The normal role of cytokines in skin lesions is not well understood. The present study aimed to investigate the progression of disease, understand specific cellular and molecular components involved in immunity to Candida albicans and determine the balance between pro- and anti-inflammatory cytokines over the course of cutaneous infection in immunocompetent mice. BALB/c mice (five per group) were inoculated with 5 × 10(6)C. albicans pseudohyphae in the deep dermis of the paw and analysed over 1-14 days post-infection. The contralateral paws were used for negative controls. Haematoxylin and eosin staining of skin sections during C. albicans infection was performed to analyse structural modifications to the epidermis such as hyperplasia, and infiltration of neutrophils and fibroblasts in the dermis. The cytokine populations were determined by capture ELISA using popliteal lymph node tissue. Pro-inflammatory cytokines (IL-6, TNF-α, IL-12, IFN-γ and IL-17) were detected at significant levels during the initial phase of cutaneous infection and correlated with the rapid elimination of C. albicans. Anti-inflammatory cytokines (IL-13, IL-4, IL-10 and transforming growth factor-β) were detected on day 4 post-infection, and prevented exacerbation of inflammation and participated in healing of lesions. Thus, a balance between pro- and anti-inflammatory cytokines was fundamental for the resolution of infection. Importantly, these findings broaden our understanding of the immune mechanisms involved in chronic cutaneous candidiasis.

IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.