Mucocutaneous Candidiasis Research Articles

Autosomal dominant hyper IgE syndrome from a single centre in Chongqing, China (2009-2018).

Autosomal dominant hyper IgE syndrome (AD-HIES) caused by STAT3 gene mutation is a rare primary immunodeficiency disease. To better understand the disease, we described the clinical characteristics of 20 AD-HIES patients in Chongqing, China and explored the effect of mutations in different domains of STAT3 gene on the function of STAT3 protein by Western blot and confocal microscopy. The mean age at onset was 0.12years. The mean age at diagnosis was 5.31years. The most common presentation was eczema, pneumonia, skin abscesses and chronic mucocutaneous candidiasis. Seven patients suffered from BCG complications. R382W/Q were identified in 12 patients, V637M mutation in three patients. Three patients have died. The phosphorylated STAT3 was expressed more in wild-type(WT) and R382W mutant STAT3 in the cytoplasm of COS7 cells with epidermal growth factor(EGF) stimulation, less in the V637M mutation and T620S mutation. Dynamic observation showed that STAT3 cytoplasmic accumulation and nuclear translocation occurred rapidly after EGF stimulation in WT-STAT3-GFP, the time of accumulation and nuclear translocation was later and the expression was less in R382W-STAT3-GFP compared with WT-STAT3-GFP, followed by V637M and T620S mutation. These results suggested that our patients had earlier onset, diagnostic age and higher rate of BCG complications. However, our patients had higher incidence of mortality though the earlier diagnostic age. We did not find a significant genotype/phenotype correlation, but Src homology 2 domain mutations (V637M and T620S) had a greater effect on STAT3 phosphorylation and nuclear translocation than DNA-binding domain mutation (R382W) in vitro.

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Humaninborn errors of immunity underlying superficial or invasive candidiasis.

Candida species, including C. albicans in particular, can cause superficial or invasive disease, often in patients with known acquired immunodeficiencies or iatrogenic conditions. The molecular and cellular basis of these infections in patients with such risk factors remained largely elusive, until the study of inborn errors of immunity clarified the basis of the corresponding inherited and "idiopathic" infections. Superficial candidiasis, also known as chronic mucocutaneous candidiasis (CMC), can be caused by inborn errors of IL-17 immunity. Invasive candidiasis can be caused by inborn errors of CARD9 immunity. In this chapter, we review both groups of inborn errors of immunity, and discuss the contribution of these studies to the deciphering of the critical mechanisms of anti-Candida immunity in patients with other conditions.

The safety of brodalumab for the treatment of psoriasis

ABSTRACTIntroduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.

Molecular mechanism of azoles resistant Candida albicans in a patient with chronic mucocutaneous candidiasis

BackgroundMore and more azole-resistant strains emerged through the development of acquired resistance and an epidemiological shift towards inherently less susceptible species. The mechanisms of azoles resistance of Candida albicans is very complicated. In this study, we aim to investigate the mechanism of azole-resistant C. albicans isolated from the oral cavity of a patient with chronic mucocutaneous candidiasis (CMC).Case presentationCMC diagnosis was given based on clinical manifestations, laboratory test findings and gene sequencing technique. Minimum inhibitory concentration (MIC) of the fungal isolate, obtained from oral cavity termed as CA-R, was obtained by in vitro anti-fungal drugs susceptibility test. To further investigate the resistant mechanisms, we verified the mutations of drug target genes (i.e. ERG11 and ERG3) by Sanger sequencing, and verified the over-expression of ERG11 and drug efflux genes (i.e. CDR1 and CDR2) by RT-PCR. A heterozygous mutation of c.1162A > G resulting in p.K388E was detected in STAT1 of the patient. The expression of CDR1 and CDR2 in CA-R was 4.28-fold and 5.25-fold higher than that of type strain SC5314, respectively.ConclusionsUp-regulation of CDR1 and CDR2 was mainly responsible for the resistance of CA-R. For CMC or other immunodeficiency patients, drug resistance monitoring is necessary.

Primary Immunodeficiency Diagnoses seen in Patients with Chronic Lung Disease: Findings from the USIDNET Registry

In patients with chronic lung disease (CLD), a diagnosis of underlying primary immunodeficiency (PID) can have unique implications on evaluation and management. It is important to recognize the full spectrum of PID diagnoses that can present with CLD. The USIDNET Registry was queried for patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Demographics, diagnoses, diagnosis dates, infections, immunology tests, and treatments were extracted. There were 116 patients (median age 22 years, range 0-81) with reported ILD (90.5%, 105/116) and COPD (20.7%, 24/116). Both ILD and COPD were reported in 11.2% (13/116). PIDs most commonly reported with ILD were common variable immunodeficiency (CVID) (56.2%, 59/105), severe combined immunodeficiency (11.4%, 12/105), and chronic granulomatous disease (CGD) (7.6%, 8/105). Chronic mucocutaneous candidiasis (CMC), Hyper-IgE Syndrome (HIES), and PIK3CD disorder were reported in 2.9% (3/105); autoimmune lymphoproliferative syndrome, GATA2 deficiency, hypogammaglobulinemia, IL-10 mutation, X-linked agammaglobulinemia in 1.9% (2/105); and ataxia-telangiectasia, CTLA4 deficiency, DiGeorge Syndrome, Hyper-IgM syndrome in 1.0% (1/105). ILD diagnosis preceded or coincided with PID diagnosis in 29.5% (31/105). PIDs commonly reported with COPD were CVID (37.5%, 9/24), HIES (16.7%, 4/24), and PIK3CD disorder (8.3%, 2/24). CGD, CMC, combined immunodeficiency, GATA2 deficiency, and hypogammaglobulinemia were reported in 4.2% (1/24). COPD diagnosis preceded or coincided with PID diagnosis in 25.0% (6/24). CLD was associated with a range of PID diagnoses. Importantly, PID was diagnosed after or at time of CLD diagnosis in 29.3% (34/116) of patients, providing support that immune evaluation may be prudent in CLD patients with frequent infections.

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

Chinese consensus on the diagnosis and management of adult candidiasis

In this consensus we mainly present the etiology, epidemiology, risk factors, microbiology, clinical diagnosis and general principles of treatment, as well as the detailed diagnosis and treatment of common candidiasis. Though mucocutaneous candidiasis such as oral, esophageal and vulvovaginal infections are known as non-invasive diseases, they are included in this consensus, considering their high prevalence and the potential to be the source of systematic infections.In order to be accordant with the practical situation in China, new technologies and drugs that have not been well developed or routinely applied are not recommended in this consensus. As to the differences from foreign guidelines, we address the explanations. Individualized treatment and management should be administrated based on the specific underlying conditions, organism distribution and drug resistance profile of Candida species.

Persistence of Clonal Azole-Resistant Isolates of Candida albicans from a Patient with Chronic Mucocutaneous Candidiasis in Colombia.

Purpose:The present article describes retrospectively a case of a patient with chronic mucocutaneous candidiasis (CMC) who presented recurrent Candida albicans infection since he was 6 months old. We obtained 16 isolates recovered during a 4-year period. Our purpose was to determinate the susceptibility, genotyping, and the pathogenicity profile in all the isolates.Methods:Sixteen C. albicans were isolated from a 25-year-old male with several recurrent fungal infections admitted to Hospital. The isolates were recovered during 4 years from a different anatomical origin. We typified them by multilocus sequence typing, also we evaluated susceptibility to fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, caspofungin, and amphotericin B by microdilution method and we also test the pathogenic capacity in the Galleria mellonella model.Results:Genotyping of all clinical isolates showed the persistence of the same diploid sequence type (DST). Isolates changed their susceptibility profile over time, but there were no significant statistical differences in pathogenicity.Conclusion:Herein, a persistent clonal isolates of C. albicans (DST 918) in a patient with CMC, showed changes in its susceptibility profile after several antifungal treatments acquiring gradual resistance to the azole drugs, which did not affect their pathogenicity.

New STAT1 gene mutation associated with chronic mucocutaneous candidiasis

New STAT1 gene mutation associated with chronic mucocutaneous candidiasis

Chronic primary mucocutaneous candidiasis in a child

Chronic primary mucocutaneous candidiasis in a child

AAV9-mediated AIRE gene delivery clears circulating antibodies and tissue T-cell infiltration in a mouse model of autoimmune polyglandular syndrome type-1.

ObjectivesAutoimmune polyglandular syndrome type‐1 (APS‐1) is a monogenic recessive disorder characterised by multiple endocrine abnormalities, chronic mucocutaneous candidiasis and high titres of serum autoantibodies. To date, no curative treatment is available; current therapies manage the symptoms rather than treating the cause and have major side effects. APS‐1 is caused by mutations in the autoimmune regulator (AIRE) gene. AIRE mediates central tolerance by directing the ectopic expression of tissue‐specific antigens (TSAs) in medullary thymic epithelial cells, causing the deletion of self‐reactive thymocytes. Therefore, loss‐of‐function mutations in AIRE result in a multisystem autoimmune disease. Because of the monogenic aetiology of APS‐1 and availability of an APS‐1 mouse model, we have explored the option of restoring functional AIRE using adeno‐associated virus serotype 9 (AAV9).MethodsThe efficacy of AAV9‐AIRE (AAV9 carrying AIRE cDNA) gene therapy was assessed in an APS‐1 mouse model. We performed intrathymic injection of AAV9‐AIRE into APS‐1 mouse model using ultrasound imaging technique to accurately locating the thymus. We evaluated the efficiency of this approach alongside measures of autoimmunity and histology of target tissues.ResultsIntrathymic injection of AAV9‐AIRE demonstrated high transduction efficiency and restored AIRE expression in the thymus. AIRE gene delivery led to a significant increase in TSA expression, and importantly a significant reduction of serum autoantibodies in treated versus control mice, which fell to near‐undetectable levels by 4 weeks post‐treatment. Furthermore, histological analysis of treated animals showed near‐normal tissue morphology with no lymphocytic infiltrations, a hallmark of untreated Aire‐deficient mice.ConclusionThis study has demonstrated the feasibility of AAV9‐AIRE as a vehicle for gene therapy for APS‐1.

Treatment of autoimmune polyglandular syndrome type 1 in children. Hypoparathyroidism: traditional approaches and perspectives

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disease, defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis. In total, more than 30 manifestations of APS1 are described, while the patient can have up to 20 autoimmune diseases. Therefore, the management of patients with APS1 requires a multidisciplinary approach. The article presents a literature review on the treatment of one of APS1 classic endocrinopathy — hypoparathyroidism. Standard therapy of hypoparathyroidism is oral calcium and active vitamin D supplementation.Biological effects and metabolism of parathyroid hormone, vitamin D, calcium and magnesium are closely linked. Calcitriol doesn’t produce all the functions of the parathyroid hormone. Conventional treatment has several disadvantages: kidney damage; hyperphosphatemia that contributes to calcification in tissues; impaired bone remodeling. Patients with coexisting hypoparathyroidism and malabsorption syndrome are less responsive to conventional therapy, since it contributes to the normalization of calcium levels in the blood mainly by increasing of its absorption in the gastrointestinal tract. In recent decades, recombinant parathyroid hormone drugs have been successfully introduced into clinical practice. Use of a pump devicesis a particularly promising way of its delivery. Pump therapy has shown good results in the treatment of congenital and acquired hypoparathyroidism in adults and children. Development of new technologies of drug administrationwill make replacement therapy in APS1 closer to the physiological hormone secretion and improve the quality of life of patients.

Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice.

Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4+ T cells, those with 'normal' or 'high' level of basal STAT1 protein in Stat1R274Q/R274Q mice. Upon IFN-γ stimulation, the 'normal' level CD4+ T cells were more efficiently phosphorylated than those from WT mice, whereas the 'high' level CD4+ T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/R274Q mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4+ T cells. GOF-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder.

Delayed Diagnosis of Good Syndrome

An 82-year-old man presented with worsening vision in his left eye for 2 weeks. He was found to have cytomegalovirus (CMV) retinitis and was treated with intravenous valganciclovir. He has a history of blindness in his right eye thought to be due to an undiagnosed infectious retinitis in the past. His medical history is otherwise notable for a “mass in his chest,” which was incidentally found on imaging more than a decade prior when he was treated for pneumonia. Records obtained from the outside hospital showed biopsy results consistent with thymoma type AB, a noninvasive tumor with low risk of metastasis. A chest x-ray revealed an anterior mediastinal mass, as shown in Figure 1. Because CMV retinitis is an opportunistic infection that occurs mainly in immunocompromised patients, an immunologic workup was initiated. An HIV test was negative. Lymphocyte subsets revealed normal CD3+ T cells (1754; 84%; ref 760-2130; 58% to 85%), a reduction of CD4+ T-cell subsets (373; 17%; ref 430-1185; 31% to 62%), an elevation of CD8+ T cells (1250; 57%; 180-865; 15% to 36%) with an inverted CD4:CD8 ratio of 0.3 (ref 0.9-3.0), and CD19+ B-cell count of zero (ref 25-285; 1% to 21%). He had normal CD16+CD56+ natural killer cells. Immunoglobulin levels were uniformly low: IgG 183 mg/dL (ref 700-1600 mg/dL), IgA 54 mg/dL (ref 70-400 mg/dL), IgM 13 mg/dL (ref 46-304 mg/dL). The patient was diagnosed with Good syndrome (GS) and started on immunoglobulin replacement, prophylactic antibiotics, and after completion of his CMV retinitis treatment, antiviral prophylaxis. GS is a rare syndrome defined by the presence of thymoma and immunodeficiency. It was first described in 1955 by Robert Good who played a crucial role in identifying the thymus' role in the immune system. Patients with GS usually present after the fourth decade of life. Presenting symptoms may be related to the thymoma, either due to its mechanical effects such as cough, dysphagia, and superior vena cava syndrome, or secondary entities such as myasthenia gravis and pure red cell aplasia. Patients have an antibody deficiency and differ from patients with common variable immunodeficiency (CVID) in that they have very few or absent B cells. GS is also characterized by CD4 lymphopenia, inversion of the CD4:CD8 ratio, and reduced T-cell mitogen proliferation. Similar to patients with CVID, patients with GS may present with recurrent sinopulmonary infections. However, their CD4 lymphopenia also leads to opportunistic infections normally not seen in patients with CVID. Notably, opportunistic infections in GS differ from patients with HIV in several ways: (1) they occur at significantly higher CD4 counts compared with HIV (CMV retinitis is documented in patients with HIV with CD4 counts <50, but occurs in patients with GS at CD4 counts >300), (2) the most common opportunistic infections include CMV retinitis and colitis, and mucocutaneous candidiasis, and (3) there have been no documented cases of cryptococcus or systemic fungal infections, and toxoplasmosis and disseminated tuberculosis are rare in patients with GS. Thymectomy is recommended for patients in whom a margin-negative resection is feasible. However, the immunologic abnormalities leading to immunodeficiency do not correct after thymectomy, and we recommend an immunological evaluation for all patients found to have a thymoma. Treatment of the immunodeficiency consists of immunoglobulin replacement, targeted antimicrobial prophylaxis, and appropriate vaccination with avoidance of live vaccines.1Malphettes M. Gérard L. Galicier L. Boutboul D. Asli B. Szalat R. et al.Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications.Clin Infect Dis. 2015; 61: e13-e19Crossref PubMed Scopus (54) Google Scholar,2Multani A. Gomez C.A. Montoya J.G. Prevention of infectious diseases in patients with Good syndrome.Curr Opin Infect Dis. 2018; 31: 267-277Crossref PubMed Scopus (8) Google Scholar

Putting JNK1 on the immunodeficiency map

Immunodeficiencies Impaired T helper 17 cell immunity is the shared element among a group of inherited immunodeficiencies that are associated with chronic mucocutaneous candidiasis (CMC). Li et al. studied three patients from a single family who had a combination of CMC and an atypical form of connective tissue disorder that had some features of Ehlers-Danlos syndrome. Whole-exome sequencing identified a loss-of-function splice-site mutation in the MAPK8 gene encoding c-Jun N-terminal kinase 1 (JNK1) that causes JNK1 haploinsufficiency with autosomal dominant inheritance. The complex clinic al phenotype in these patients results from defects in signaling downstream of both interleukin-17 and transforming growth factor–β (TGF-β) cytokines. Thus, JNK1-mediated signaling plays a critical role in maintaining normal immunity to Candida , and TGF-β promotes homeostasis of connective tissues. Sci. Immunol. 4 , eaax7965 (2019).

Jakinibs for the Treatment of Immune Dysregulation in Patients With Gain–of–Function Signal Transducer and Activator of Transcription 1 (STAT1) or STAT3 Mutations

To investigate the efficacy of jakinib therapy in patients with gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) or signal transducer and activator of transcription 3 (STAT3) mutations.The study included 17 total patients with either a STAT1 GOF (n = 11) or STAT3 GOF (n = 6) mutation who were treated with jakinibs (ruxolitinib or tofacitinib). Patients came from 11 international centers.This was a retrospective study to describe disease-related clinical manifestations and determine indication for treatment, dosage, length of treatment, treatment response, and treatment-associated complications. All subjects underwent thorough pre- and posttreatment clinical and laboratory evaluations and follow-up (follow-up period: 1–34 months).Fourteen patients (82%) responded favorably with clinical improvement to jakinib treatment. Observed clinical improvements included resolution of enteropathy leading to total parenteral nutrition independence, better lung function, improved autoimmune cytopenias, decreased arthritis symptoms, and remission of hemophagocytic lymphohistiocytosis. All patients with STAT1 GOF had resolved chronic mucocutaneous candidiasis with treatment. Most patients tolerated the jakinibs well with minimal or transient adverse effects. An increase in herpes zoster infections (none systemic and all cleared with antiviral agents) was observed in some patients. Four patients died despite treatment with a jakinib. The majority of these patients were critically ill with severe invasive infection or progressive lung disease. One patient died due to posttransplant complications.Jakinibs are both safe and effective in the treatment of patients with STAT1 or STAT3 GOF mutations with clinical manifestations of autoimmunity and/or immune dysregulation.Patients with STAT1 and STAT3 GOF mutations often present in early childhood with severe and/or refractory infections, lymphoproliferation, autoinflammation, and autoimmunity. Jakinibs allow for a targeted therapeutic approach to block the cytokine-induced JAK activation in STAT1 and STAT3 GOF diseases. This is the first study to evaluate the use and clinical impact of jakinibs in STAT1 and STAT3 GOF. The results are overwhelmingly encouraging, with the majority of patients having clinical improvement and reduction or resolution of autoimmune manifestations after treatment with a jakinib. Use of jakinibs late in disease progression or when critically ill was associated with mortality, suggesting early initiation may improve efficacy. This study has significant clinical impact in the treatment of STAT1 and STAT3 GOF and reinforces the notion that early genetic diagnosis of primary immunodeficiency diseases may lead to targeted therapeutic options and improved clinical outcomes.

Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β.

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues.

Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran

ABSTRACTAutoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Chronic mucocutaneous candidiasis with STAT1 gain-of-function variant: a case report and review of the literature

Background: Chronic mucocutaneous candidiasis (CMC) is a rare clinically heterogeneous disease characterized by susceptibility to chronic or recurrent superficial Candida infection of the skin, nails and mucous membranes.