Mucocutaneous Candidiasis Research Articles

Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. In this study, we performed Sanger sequencing ofAIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1. After analyzing 14AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE, including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients. According to our results, sequencing analysis ofAIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1.

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.

Autoimmune Polyglandular Syndrome Type 1: a case report

BackgroundMutations of the autoimmune regulator gene (AIRE), located on chromosome 21q22.3, are recognized as the cause of a rare monogenic organ-specific autoimmune disorder called autoimmune polyglandular syndrome type 1 (APS-1). Three major components of this syndrome include chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenocortical failure.Case presentationWe report a 19-year-old girl, who was born in an Iranian Muslim family with a clinical diagnosis of APS-1. To identify the causative mutation, a direct sequencing of the entire AIRE gene sequence was performed by Sanger sequencing method.Three distinct variants were discovered, including c.1095 + 2 T > A, c.1197 T > C (rs1800521) and c.1578 T > C (rs1133779), in intron 9, exons 10 and 14 of the AIRE gene, respectively.ConclusionsTo the best of our knowledge, this is the first report of an Iranian Muslim APS-1 patient with combination of these variations. In addition, the effect of c.1095 + 2 T > A mutation on AIRE mRNA expression was reported for the first time. This study expands the diversity of variants that could cause APS-1. More genetic studies are required to determine the exact frequency of these variants and their diagnostic significance.

Multiple Nail Candidosis in a Child with APECED Syndrome

The APECED syndrome (autoimmune polyendocrinopathy, candidosis, ectodermal dystrophy) is a rare autosomal recessive disorder that develops in early childhood and results in tissue-specific multiorgan autoimmunity, leading to the hypofunction of multiple glands. Is clinically defined as the presence of at least two components of the classic triad of hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis. We report a case in a child, illustrating the importance of dermatological disorders.

Identification of a distinct subset of disease-associated gain-of-function missense mutations in the STAT1 coiled-coil domain as system mutants

Heterozygous gain-of-function (GOF) mutations in the cytokine-regulated transcription factor STAT1 (signal transducer and activator of transcription 1) lead to chronic mucocutaneous candidiasis (CMC). However, the molecular basis of these pathogenic missense mutations is largely unknown. In this study, we characterized in more detail the CMC-associated GOF substitution mutation of arginine-to-tryptophan at position 274 (R274W) and, in addition, the adjacent glutamine-to-alanine mutation at position 275 (Q275A). Both mutants displayed elevated tyrosine phosphorylation levels, prolonged nuclear accumulation, and increased transcriptional responses to interferon-γ (IFNγ) stimulation. No difference was observed between wild-type (WT) and mutant STAT1 in DNA sequence-specificity or dissociation kinetics from high-affinity DNA-binding elements known as gamma-activated sites (GAS). Furthermore, all variants exhibited similar cooperative DNA binding. Unexpectedly, in vitro dephosphorylation rates using the recombinant STAT1-inactivating Tc45 phosphatase in both the absence and presence of double-stranded GAS elements were similar in all STAT1 variants. Likewise, the rate of tyrosine phosphorylation by Janus kinase 2 (JAK2) was unaltered as compared to the WT molecule, excluding that the phenotype of these mutants is caused by either defective Tc45-catalyzed dephosphorylation or JAK2-induced hyper-activation. Interestingly, within 10 min of IFNγ exposure, the majority of R274W and Q275A molecules had entered the nucleus, whereas the wild-type protein remained predominantly cytosolic. Thus, the exchange of critical residues located at the binding interface in the antiparallel dimer conformer led to a premature accumulation of phospho-STAT1 in the nuclear compartment. In summary, our data show that the hyper-activity of the GOF mutations results, at least in part, from the premature nuclear import of the tyrosine-phosphorylated molecules and not from alterations in their phosphorylation or dephosphorylation rates.

Superficial candidosis by Candida duobushaemulonii: An emerging microorganism

The Candida haemulonii species complex and other phylogenetically related species, such as Candida auris, are emerging pathogens. The C. haemulonii complex comprises C. haemulonii, C. haemulonii var. vulnera, and Candida duobushaemulonii species. The correct identification of this fungal complex is clinically and epidemiologically relevant; however, conventional identification methods are currently inadequate. In this study, we report the molecular reidentification of two clinical isolates: isolate 553 that was recovered from a patient with total dystrophic onychomycosis and isolate 77–18 from a patient with mucocutaneous candidiasis. Both patients had diabetes mellitus as baseline disease. These isolates were initially identified as C. haemulonii by the VITEK® 2 system but were later determined to be C. duobushaemulonii based on the amplification and sequencing of a 115-bp fragment of the region of 26S rDNA. The isolates were resistant to fluconazole, and only isolate 553 was resistant to amphotericin B. Patients showed clinical and mycological cure after treatment with itraconazole. The clinical and microbiological data of these two cases of superficial candidiasis caused by C. duobushaemulonii, along with previous reports about infections with the C. haemulonii complex species, suggest that patients with diabetes mellitus are highly susceptible to infection with these fungi. Therefore, for diagnosing candidiasis in patients with diabetes mellitus, yeasts must be identified at the species level, and antifungal susceptibility testing must be carried out for adequate treatment.

A case of double cancer involving the mandibular gingiva and esophagus in a patient with chronic mucocutaneous candidiasis

A case of double cancer involving the mandibular gingiva and esophagus in a patient with chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis associated with a novel frameshift mutation in IL-17 receptor alpha

Background: Chronic mucocutaneous candidiasis (CMCC) has traditionally encompassed endocrinopathy, autoimmunity, and infection of the skin, nails, oral and genital mucosa. It is typically caused by Candida albicans, an organism that is found to be commensal in healthy individuals. To date, most patients with CMCC have mutations in AIRE or STAT1. While chronic Candida spp. infection is a feature of multiple profound T cell deficiencies, it has also been identified in rare cases involving selective immune defects, including interleukin-17 receptor A (IL-17RA) deficiency. An association between Staphylococcus aureus infections and candidiasis due to IL-17RA deficiency has recently been proposed. Aim: We sought to identify the genetic defect in a patient presenting with recurrent oral thrush and S. aureus infections, but otherwise unremarkable immune workup. Methods: Whole exome sequencing and Sanger confirmation was performed, and protein expression analysis utilized to assess the impact of the genetic aberration. A comprehensive immune workup was completed to characterize any possible deficits in his immune system. Results: Next generation sequencing techniques identified a homozygous mutation in IL17RA, c.1696insAG, resulting in the frameshift mutation p.Q566fs. Western blot analysis confirmed the loss of IL-17RA expression. Conclusion: We describe here a novel frameshift mutation in IL17RA. Clinically, the patient was a diagnostic challenge as he did not present with a classic CMCC phenotype. This case emphasizes the importance of genetic analysis in patients presenting with recurrent infections. Statement of novelty: We identify a novel frameshift mutation in IL17RA in a patient presenting with recurrent bacterial and fungal mucocutaneous infections.

K21 Compound, a Potent Antifungal Agent: Implications for the Treatment of Fluconazole-Resistant HIV-Associated Candida Species.

Background/Objectives: With mucocutaneous candidiasis being highly prevalent in HIV patients, the emergence of fluconazole-resistant Candida species forms a major challenge in treating and eradicating these infections. The objective of this study was to establish the antifungal activity of K21, a membrane-rupturing antimicrobial compound derived from a silica quaternary ammonium compound (SiQAC) with tetraethoxysilane (TEOS).Methods: The study sample included 81 Candida species of which 9 were type strains and 72 were clinical isolates. Minimum inhibitory concentrations, synergy, fractional inhibitory concentration index (FICI), and time kill assays were determined by broth microdilution. Electron microscopy (EM) was used to determine the qualitative changes brought about after treatment with K21.Results: K21 inhibited the growth of all fluconazole-resistant and susceptible Candida strains with only 2 h of exposure required to effectively kill 99.9% of the inoculum, and a definite synergistic effect was observed with a combination of K21 and fluconazole. EM demonstrated the presence of two forms of extracellular vesicles indicative of biofilm formation and cell lysis.Conclusion: The study established the efficacy of K21 as an antifungal agent and with fluconazole-resistant candidiasis on the increase, the development of K21 can provide a promising alternative to combat acquired drug resistance.

SAT-242 Pigmented Paravenous Retinochorodial Atrophy: A Novel Manifestation of Autoimmune Polyglandular Syndrome Type 1

Autoimmune polyglandular Syndrome Type 1 (APS-1) is an autoimmune disease due to defects in the AIRE gene. It is characterized by a triad of hypoparathyroidism, mucocutaneous candidiasis, and Addison’s disease. We present a case of pigmented paravenous retinochoroidal atrophy associated with APS-1. Case description: A 14 year old female who was admitted for cramps in her hands secondary to hypocalcemia. Past medical history is significant for recurrent vaginal candidiasis and panic attacks. Laboratory assessment revealed low parathyroid hormone and hypocalcemia confirming the diagnosis of hypoparathyroidism. After 4 months she presented with vomiting, and dizziness. Serum cortisol levels were low consistent with the diagnosis of adrenal insufficiency. Further evaluation revealed a mutation in the APS-1 gene. At 28 years she presented with complaints of blurred vision and blind spots for a year. Initial ophthalmologic evaluation revealed a visual acuity of 20/60 in the right eye and 20/50 in the left eye. Anterior segment assessment was normal. Fundoscopy revealed presence of speculated pigment and atrophy of the macula long with attenuated retinal vessels. Optical coherence tomography did not show any macular edema. Visual field assessment was normal. She was diagnosed with pigmented paravenous chorioretinal atrophy. Anti-retinal antibodies were positive for 30-kDa, 36-kDa, 40-kDa, and 46-kDa confirming the autoimmune etiology of the disorder. Over the next 2 years, her visual acuity decreased to 20/400 in the right eye and 20/80 in the left eye. Conclusion: APS-1 is a rare disease associated with numerous autoimmune disorders, beyond the classic clinical triad. Pigmented paravenous chorioretinal atrophy is a previously unreported manifestation of APS-1. Unfortunately no definitive treatment exists for retinal degeneration.

SAT-241 Hyposplenism and Autoimmune Hepatitis: Rare Complications of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dystrophy (APECED)

Background: APECED is a rare monogenic autosomal recessive syndrome caused by mutation in the AIRE gene located on chromosome 21q22.3. Phenotypic expression is variable but classically includes chronic mucocutaneous candidiasis, chronic hypoparathyroidism and hypoadrenalism. Studies demonstrate prevalence of autoimmune hepatitis (AIH) is 12%, and hyposplenism is approximately 20%. (Peterson P, Pitkänen J, Sillanpää N,2004; Capalbo D, De Martino L, Giardino G, 2012) Clinical Case: A 29 year old man was diagnosed with autoimmune hepatitis (AIH) at 6 years. He presented with symptomatic hypocalcaemia secondary to autoimmune hypoparathyroidism at 11 years. At 12 years he developed primary adrenal insufficiency. He also had nail dystrophy and mucocutaneous candidiasis. Genetic analysis revealed he was homozygous for for a 13bp deletion in Exon 8 of the AIRE gene consistent with diagnosis of APECED. His sister, who presented with hypoparathyroidism, was also AIRE gene positive. He transitioned from paediatric to adult care age at 16 years and subsequently defaulted from care. Following re-engagement with adult services at age 19 years, he was diagnosed with cirrhosis and portal hypertension and has had an oesophageal variceal bleed. Regular dental review has not revealed an oral mucocutaneous malignancy. At age 24, during an admission with decompensated liver disease, an elevated LDH 384 I.U. /l (120 - 220) and bilirubin (total) 121 μmol/l (5-24) were noted. A blood film demonstrated Howell Jolly bodies, target cells, polychromasia, target cells and anisopoikilocytosis consistent with hyposplenism. In 2011 a CT abdomen reported the spleen as severely shrunken. On review of previous abdominal ultrasounds reports in dating back to 2012 the spleen was undetectable. He was therefore diagnosed with functional hyposplenism. Hyposplenism was complicated by streptococcal sepsis. He was treated as per guidelines with pneumococcus, haemophilus, meningitis C, influenza vaccinations and penicillin prophylaxis. The pathogenesis underlying functional hyposplenism in APECED is unknown however it is hypothesized that it occurs secondary to local AIRE gene dysfunction in the spleen.(Starzyk J, Kumorowicz-Kopiec M, Kowalczyk M, 2001). Another possible contributory factor in this gentleman is his liver cirrhosis. Discussion: This case highlights the multifaceted nature of this rare disease as well as the associated morbidity and need for a multidisciplinary approach to a complex multi-organ condition. It is important to be cognisant of its many associations in order to avoid missing life threatening diagnoses. Patients with APECED should be evaluated for hyposplenia and appropriate vaccination schedule initiated.

SUN-040 Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) Syndrome: Prospective Screening of Asplenism and Pneumonitis in a Cohort of 25 Patients

Background: APECED syndrome is a rare monogenic disease caused by homozygous mutation of AIRE gene. It classically presents with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency with an early onset in childhood. Non-endocrine manifestations as ectodermic dystrophy, asplenism and pneumonitis are also observed but their incidence remains unknown and their mechanisms not well understood. APECED has been poorly reported in France although it is widely described in several European countries. The aim of this study was to report on rare manifestations of APECED syndrome in a French cohort. Patients and methods: We performed a multicentric prospective observational study in France in order to collect clinical, biological, immunological and genetic data, after written informed consent in the frame of a PHRC (Hospital Project of Clinical Research #1927). Bronchiolitis, splenic atrophy and ocular manifestations were systematically investigated. Results We enrolled 25 patients between 2009 and 2016. Clinically, the median age at diagnosis was 12 while the median age of the first manifestation was 6, so there was diagnostic delay. The median number of manifestations was seven. 76 % of patients presented with the classical triad. Reduction of lung function was observed in 62% of patients, asplenism in 26%, and ocular manifestation in 33%. Genetically, eleven mutations of the AIRE gene were identified, two of which never previously reported: an intronic variation c.653-70G>A (intron 5) in a patient with hypoparathyroidism as unique manifestation , and c.1066del (p.Arg356GlyfsX22) (exon 9) in a patient from Guadeloupe with composite heterozygous mutations (c.967_979del13; exon 8). The most common AIRE mutation was the mutation R257X. Median age was 26 and sex ratio was 1.1. Biologically, 100% of tested sera were positive for anti-IFNα-antibodies, 15/18 for anti-IL-22, and 13/18 for anti-IL-17F antibodies. Conclusion: This series shows a high genotypic and phenotypic variability of APECED in France, that could be explained by different ethnic origins. The systematic screening for non-classic manifestations shows a more frequent occurrence than in other series. Systematic screening of asplenism and bronchiolitis could be a useful strategy to make an earlier diagnosis, to prevent infections by vaccination and to treat earlier pulmonary involvement. Lastly, antibodies against Th17 cytokines appear as good soluble markers for diagnosis of non-classical presentation of the syndrome.

MON-364 Autoimmune Polyendocrinopathy Syndrome Type I Presented with Adrenal Insuffiency and Nail Fungal Infection Confirmed by Homozygous Pathogenic Variant in the AIRE Gene

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder. APS-1 diagnosed when patient have at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. We report a7 years old boy with history of fungal infections since early childhood affecting nails and skin. Also he has alopecia . recurrent abdominal pain,lethargy and vomiting. At diagnosis his skin was hyper pigmented at gums and palms and nail dystrophy. His laboratory shows high ACTH 1251 pmol/l and low aldosterone 57 pg/ml. he has positive candida culture in the nail. We send genetic study Whole Exome Sequencing and came to be positive for A homozygous pathogenic variant in the AIRE gene. c.205_208dup p.(Asp70Alafs*148). The child was treated with hydrocortisone and fludrocortisone. We report a rare case of a homozygous pathogenic variant in the AIRE gene that illustrate the typical presentation of APS type 1

MON-123 Atypical Diabetes Mellitus or Type 1 Diabetes Mellitus?

Introduction: Autoimmune (AI) polyglandular syndromes (APS) share common susceptibility gene variants and therefore have strong genetic predisposition. Type 1 APS includes chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. Type 2 APS includes adrenal insufficiency and at least one of following: AI thyroiditis or type 1 diabetes (T1DM). Type 3 APS variant is AI thyroiditis and T1DM without adrenal insufficiency. Furthermore, no single diagnostic test can consistently distinguish T1DM from type 2 diabetes (T2DM). In clinical practice it is important to recognize APS, so that the correct diagnosis can be made. Case: A 44 year old African American female with AI hypothyroidism, and orthostatic hypotension presented with the complaint of blurry vision. She had a strong family history of DM and was concerned about developing diabetes herself. [(BMI= 30.3 kg/m²), (Fasting blood glucose (BG) =111 mg/dL), (Hba1c level of 6.3%), (glutamic acid decarboxylase (GAD-65) antibodies >30; normal=0-1.01 U/mL), (C-peptide= 1.28; normal = 0.81-3.85 ng/mL)]. Continuous glucose monitor testing showed normal pre-prandial levels with post-prandial elevated BG to 178 mg/dL. Due to elevated BG, elevated GAD-65, and family history of DM, a diagnosis of T1 DM was made. She was started with low dose insulin (detemir 1 units daily), and increased slowly to 6 unit daily. During this time, Hba1c ranged from 6-6.4%. Over the next few years, she made drastic lifestyle changes (strict diet and increased physical activity). She then developed an eating disorder and lost 86 lbs. (BMI=17.5 kg/m²). She started to have hypoglycemic episodes (HYPO), more so from exercise. The insulin dose was decreased to 2 units daily on days of no exercise, due to HYPO. Hba1c dropped to 5.2%. She continued to have recurrent HYPO (BG in 40’s with Hba1c= 4.3%). Therefore, insulin therapy was discontinued. She has not taken exogenous insulin for the past three years (most recent Hba1c=6.6%). GAD-65 continues to be elevated (>250 U/mL) and she continues to have a normal C-peptide level of 2.67ng/mL. She no longer has HYPO. Discussion: The clinical case presented describes atypical DM that depicts slowly progressive autoimmune diabetes. The patient had phenotypical features that could be suggestive of T2DM with insulin resistance - obese at initial presentation, ethnicity, family history of DM, post-prandial hyperglycemia, and not requiring insulin for many years. However, it is important to assess all the patient’s clinical conditions and consider possibility of APS. It is also important not to assume a patient has T2DM and consider atypical diabetes in a patient with features suggestive of APS. Studies have shown that up to 30% of individuals with the classical appearance and presentation of T2DM have positive autoantibodies, and may have slowly progressive type of autoimmune diabetes.

Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined.

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development andchronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

The Skin as a Window into Primary Immune Deficiency Diseases: Atopic Dermatitis and Chronic Mucocutaneous Candidiasis

Primary immune deficiency diseases characteristically present with recurrent, severe, or unusual infections. These infections may often involve the skin, with mucocutaneous candidal infections seen in a variety of different primary immune deficiencies. Primary immune deficiencies may also present with noninfectious cutaneous complications, of which eczema is the most common. In a patient with suspected primary immune deficiency, the presence of eczema or candidal skin infections offers critical information about the underlying immune defect, either the presence of atopy or defect in the TH17 pathway, respectively. These skin manifestations also are often early or heralding findings of the underlying immunologic disease. Therefore, awareness of associations between these skin findings and specific immune deficiencies may aide in the early detection and treatment of serious or life-threatening immunologic defects. This review specifically will focus on the primary immune deficiencies commonly associated with eczema or mucocutaneous candidiasis.

CME Exam: The Skin as a Window into Primary Immune Deficiency Disease: Atopic Dermatitis and Chronic Mucocutaneous Candidiasis

CME Exam: The Skin as a Window into Primary Immune Deficiency Disease: Atopic Dermatitis and Chronic Mucocutaneous Candidiasis

Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guérin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-γ-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-γ, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8months and 3.7years. The remaining patients were alive at the last follow-up and were aged between 2 and 13years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12Rβ1 deficiency, meaning their cells produced low levels of IFN-γ. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-γ. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. We found low levels of IFN-γ production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.

IRF and STAT Transcription Factors - From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies.

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

First Korean case of a STAT1 gene mutation: chronic mucocutaneous candidiasis, hypothyroidism, chronic hepatitis and systemic lupus erythematosus

First Korean case of a <i>STAT1</i> gene mutation: chronic mucocutaneous candidiasis, hypothyroidism, chronic hepatitis and systemic lupus erythematosus