Mucocutaneous Candidiasis Research Articles

Innate immunodeficiencies: a group of primary immunodeficiencies predisposing exclusively to common diseases

Abstract Background Innate immune deficiencies can impair both cellular and humoral immune responses. In contrast, other immune functions may appear normal, leading to increased susceptibility to specific pathogens, such as severe viral infections or Mendelian Susceptibility to Mycobacterial Disease (MSMD). Studying these deficiencies is essential for understanding the pathophysiology of these infectious diseases. Main body While primary immunodeficiencies (PIDs) generally cause vulnerability to multiple infections, innate immunodeficiencies increase susceptibility to specific pathogens, despite normal immune responses to others. Patients with these deficiencies show normal immunoglobulins and lymphocyte subpopulations, complicating diagnosis. This review highlights genetic susceptibility to mycobacteria, pneumococci, herpes simplex virus, and candidiasis, emphasizing recognizing this subset of PIDs. Conclusion This review highlights the diverse spectrum of genetic mutations contributing to defects in innate and intrinsic immunity, including Mendelian susceptibility to mycobacterial disease (MSMD), chronic mucocutaneous candidiasis, and predispositions to invasive bacterial and viral infections. Identifying key mutations in pathprovideh such as TLR3, IFN signaling, and IL-17A/F immunity provides valuable insights into the pathogenesis of these conditions. Our findings underscore the need for early genetic diagnosis and targeted interventions, particularly in regions with high undiagnosed cases, to reduce the morbidity and mortality associated with defects in innate and intrinsic immunity.

The outcome of haematopoietic stem cell transplantation in a patient with STAT1 gain-of-function: a case report

Background: The human signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor and one of seven members of the STAT family. Autosomal dominant (AD) STAT1 gain-of-function (GOF), characterized by enhanced phosphorylation of the tyrosine-701 residue and STAT1 activation, is commonly associated with chronic mucocutaneous candidiasis (CMCC), immunodeficiency, aneurysms, malignancies, and autoimmune phenomena. The best management strategies for patients with STAT1 GOF remain unclear. Typically, the standard care includes supportive treatments such as antimicrobial prophylaxis, either alone or combined with immunoglobulin replacement therapy. Biological therapies such as JAK inhibitors have been shown to alleviate symptoms of infection and autoimmune disorders in patients with STAT1 GOF mutations. However, there is a lack of long-term outcome data for JAK inhibition. Hematopoietic stem cell transplantation (HSCT) is an alternative treatment option for a subset who experience a persistent disease course despite conventional therapy. However, the effectiveness of HSCT for this condition is not yet well established. Methods: Our patient’s medical records were analyzed retrospectively, including her medical history. Results: We present the outcome of HSCT performed on a 27-year-old female with STAT1 GOF, conducted as a treatment for acute myeloid leukemia (AML). Conclusion: HSCT may serve as an alternative and potentially curative treatment for certain STAT1 GOF patients with progressive, life-threatening conditions that do not respond to conventional therapies. Additional research is needed to improve the management of these patients. Statement of Novelty: We present a novel case study of HSCT as a treatment for AML in a 27-year-old patient with STAT1 GOF, highlighting the potential for curative outcomes in progressive, life-threatening conditions unresponsive to conventional therapies. This case contributes to the limited body of evidence supporting the efficacy and challenges of HSCT in STAT1 GOF patients.

Bimekizumab-bkzx for the Treatment of Plaque Psoriasis: A Drug Review.

Bimekizumab is a biologic targeting interleukin (IL)-17A/17F, approved by the Food and Drug Administration (FDA) for moderate-to-severe plaque psoriasis in 2023. A PubMed search was performed using the keywords "bimekizumab," "plaque psoriasis," and "bimekizumab clinical trials," from origin to August 1, 2024. We included phase I to III trials of bimekizumab for plaque psoriasis, studies published post-FDA approval, and information from the package insert. We summarized 1 phase I, 4 phase II, and 4 phase III trials, and 3 real-world studies published post-FDA approval. Bimekizumab was effective; >85% and 70% of patients achieved PASI90 and PASI100, respectively, in phase III trials. Head-to-head, 85% of bimekizumab patients achieved PASI90 versus 50% of ustekinumab patients. The most frequent adverse event was oral candidiasis (4%-10%); serious adverse events were rare (<1%). Long-term studies confirmed sustained efficacy and consistent safety profile. Bimekizumab was more efficacious than other IL-17 inhibitors, ustekinumab, and adalimumab. Real-world data corroborate bimekizumab's efficacy. Bimekizumab had a safety profile like other IL-17 inhibitors, with higher rates of mucocutaneous candidiasis. Many patients who failed other IL-17 inhibitors and switched to bimekizumab experienced clearance. The efficacy of bimekizumab in patients who failed other IL-17 blockers may be attributable to bimekizumab's ability to block multiple IL-17 isoforms. Bimekizumab also outperformed tumor necrosis factor (TNF)-alpha inhibitors. There may be patients who fail previously available drugs, for reasons including nonadherence, antidrug antibodies, or adverse effects; bimekizumab, which targets additional cytokines, may bridge that gap.

STAT1 and STAT3 gain of function: clinically heterogenous immune regulatory disorders.

The identification of STAT1 gain-of-function (GOF) in 2011 and STAT3 GOF in 2014 has advanced our understanding of the host immunity along the JAK/STAT pathway and allowed targeted treatment approaches. We review the clinical features and pathogenesis of STAT1 and STAT3 GOF and how this has shaped new approaches to therapy. STAT1 GOF, initially described in patients with chronic mucocutaneous candidiasis (CMC) and autoimmune thyroid disease, is now recognized to cause early-onset multisystem autoimmunity and a range of infections. STAT3 GOF comprises mostly lymphoproliferation and autoimmunity but also with varying severity, including some with life threatening organ dysfunction. Treatment has evolved along with the understanding of the pathogenesis, with patients now receiving JAK inhibition to block upstream of the STAT defect with good response in autoimmunity and CMC in STAT1 GOF. Blockade of IL-6 signaling has also been used in STAT3 GOF. Hematopoietic cell transplantation had initial poor outcomes, but outcomes are now improving with focus on the control of inflammation pretransplant. Understanding the pathogenesis of STAT1 and STAT3 GOF has allowed great recent advancements in therapy, but many questions remain as to the best approach to therapy for each patient's clinical presentation as well as the durability of these therapies.

Phenotypes of 126 Moroccan HIES patients according to NIH Score.

Hyper-IgE syndrome is a group of inborn errors of immunity, some of which are syndromic, characterized clinically by the classic triad of chronic eczema, cutaneous and/or pulmonary staphylococcal infections and high serum IgE concentrations (> 2000 IU/ml or > 10 x normal for age). We report here the clinical and immunological aspects of Moroccan patients presenting probable or possible HIES according to NIH-HIES score. This retrospective study covers the period from 1998 to 2023 and includes Moroccan patients with a clinical presentation suggestive of HIES (skin and/or pulmonary infections, eczema, high IgE levels) and an NIH score ≥ 20. We attempted to classify the patients phenotypically according to the 2022 IUIS IEI Expert Committee classification. Median age at symptom onset was 0.5 years and median age at diagnosis was 5.5 years. The main clinical signs were eczema (66%), skin abscesses (32.5%), pneumonia (32.5%), otitis (20%), mucocutaneous candidiasis (19%), diarrhea (12%), facial dysmorphism (10.3%), lymphadenopathy (9.5%), bronchial dilation (8%), pneumatoceles (8%), conjunctivitis (7.1%), rhinitis (6.3%), psychomotor delay (5.6%), pathological fractures (4%), retention of deciduous teeth (4%), cognitive delay (3.2%). This is the first clinical description of a cohort of Moroccan patients presenting HIES according to NIH criteria. Phenotype can sometimes orient towards identification of the mutated gene, but the overlapping clinical signs make molecular analysis necessary for genetic counseling and appropriate treatment.

8131 A Rare Case of Autoimmune Polyendocrine Syndrome; a Menopause Despite Replacement Therapy

Abstract Disclosure: M.E. Chacon Cruz: None. M. Sanchez Cordero: None. R.M. Roman Torres: None. G. Guerra Velazquez: None. Polyendocrinopathy is a heterogeneous group of disorders leading to dysfunction of multiple endocrine glands and other tissues. The syndromes can occur in patients from early infancy to old age and new components of a given syndrome can appear throughout life. APS can be classified into APS type 1 and APS2-4. APS-1 is a rare monogenic autosomal recessive autoimmune disorder consisting of the triad of chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. APS2 require presence of Addison disease, autoimmune thyroid disorder and type 1 diabetes. APS 3 requires presence of Thyroid autoimmune disease associated with other autoimmune diseases. APS4 is a combination of organ specific autoimmune disease non included in a previous group. Autoimmune oophoritis is found in approximately 4 percent of females who presented with spontaneous primary ovarian insufficiency and may occur in type I and II syndromes of polyglandular autoimmune failure. This is the case of 44 year old female patient with history of hypertension, hypoparathyroidism diagnose at the age of 9 year old, vitiligo and premature ovarian failure diagnose at the age of 16 year old. Patient reported that started with multiple episodes of watery non bloody diarrhea and arthralgia. Patient went to her Pediatrician and they found hypocalcemia hyperphospathemia. Patient mineral was replaced with medication and then followed by pediatric endocrinologist. Patient continues with normal life, but menstrual periods had not started even at age 16th. Laboratory work up was done and premature ovarian failure was diagnosed after that, patient started with progesterone and estrogen to induce menstrual periods. Menstrual periods began regularly and monthly. Patient continues taking medication regularly, phoslo, calcitriol, progestin and estradiol without problem until this year that despite regular medication, started with signs and symptoms of menopause with irregular menstrual periods, palpitations hot flashes, sweating, anxiety and sleep problems. Patient met criteria for APS4 due to combination of organ specific autoimmune disease such premature ovarian failure, vitiligo and hypoparathryroidism. This case is extremely important since despite the fact that there is no family history of either endocrinological or autoimmune diseases, our patient debuts throughout her life with several autoimmune diseases, such as premature ovarian failure and vitiligo. Patient had Schedule appointment with gynecologist who increased the dose of progestin and estradiol. This case highlights the importance of being vigilant about new components of a syndrome developing at different times though a patient's life. As described, autoimmune diseases commonly are related to other diseases, but without a good clinical history and physical examination could be misdiagnosed affecting the quality of life of those patients. Presentation: 6/2/2024

Whitaker syndrome: A case report of autoimmune polyendocrine syndrome type 1 with dilated cardiomyopathy.

This case report highlights dilated cardiomyopathy as a cardiovascular complication in autoimmune polyendocrine syndrome type 1 (APS-1), emphasizing the need for early recognition and a multidisciplinary approach. Comprehensive care and regular follow-up are crucial in managing these atypical presentations to optimize patient outcomes. APS-1, also known as Whitaker syndrome, is characterized by a triad of mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. This rare autosomal recessive disorder results from mutations in the autoimmune regulator (AIRE) gene. Cardiovascular and pulmonary manifestations in APS-1 are infrequently reported in the literature. We present a case of a 28-year-old male who presented with shortness of breath and pedal edema. Physical examination revealed alopecia, absence of eyebrows, hyperpigmentation on joints, oral candidiasis, and nail dystrophy. Echocardiography demonstrated dilated cardiomyopathy (DCM) and pericardial effusion. Chest x-ray showed left-sided pleural effusion. Laboratory investigations revealed hypocalcemia, hyperphosphatemia, low parathyroid hormone (PTH), low cortisol, and high adrenocorticotropic hormone (ACTH) levels. The combination of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency confirmed the diagnosis of APS-1. To the best of our knowledge, this is the first Pakistani and second worldwide reported case of APS-1 presenting with such a combination of manifestations. Early recognition and multidisciplinary management are crucial for improving outcomes in these patients.

Reduction in mucosal-associated invariant T cells (MAIT) in APECED patients is associated with elevated serum IFN-γ concentration.

Mucosal-associated invariant T cells (MAIT) are innate-like lymphocytes enriched in mucosal organs where they contribute to antimicrobial defense. APECED is an inborn error of immunity characterized by immune dysregulation and chronic mucocutaneous candidiasis. Reduction in the frequency of circulating MAITs has been reported in many inborn errors of immunity, but only in a few of them, the functional competence of MAITs has been assessed. Here, we show in a cohort of 24 patients with APECED, that the proportion of circulating MAITs was reduced compared with healthy age and sex-matched controls (1.1% vs. 2.6% of CD3+ T cells; p < 0.001) and the MAIT cell immunophenotype was more activated. Functionally the IFN-γ secretion of patient MAITs after stimulation was comparable to healthy controls. We observed in the patients elevated serum IFN-γ (46.0 vs. 21.1 pg/mL; p = 0.01) and IL-18 (42.6 vs. 13.7 pg/mL; p < 0.001) concentrations. Lower MAIT proportion did not associate with the levels of neutralizing anti-IL-22 or anti-IL-12/23 antibodies but had a clear negative correlation with serum concentrations of IFN-γ, IL-18, and protein C-reactive protein. Our data suggest that reduction of circulating MAITs in patients with APECED correlates with chronic type 1 inflammation but the remaining MAITs are functionally competent.

Clinical diagnosis of chronic mucocutaneous candidiasis in a patient with recurrent staphylococcal infections

Chronic mucocutaneous candidiasis is a primary immunodeficiency characterized by persistent or recurrent candidal infections of the skin, nails, or mucous membranes. It can be associated with endocrinopathies and autoimmune diseases. A 37-years-old male patient is presented who attended an immunology consultation referred from the dermatology service due to recurrent pyodermitis of several years of evolution; the physical examination also revealed signs of candidiasis in the oral mucosa and lip corners, in the eyelids of both eyes and skin in the abdominal region, which were recurrent, as well as onychomycosis in all toenails. The microbiological study of the pyodermitis lesions showed infection by staphylococcus aureus, and the lesions of the mouth, eyes, abdominal skin and nails showed the presence of Candida albicans. Delayed intradermal skin testing was performed with no T cell response to Candida and Trichophyton antigens. Complementary drugs were indicated to rule out any associated endocrine disorder

Immunophenotyping and Therapeutic Insights from Chronic Mucocutaneous Candidiasis Cases with STAT1 Gain-of-Function Mutations.

Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.

Clinical and Biological Perspectives on Noncanonical Esophageal Squamous Cell Carcinoma in Rare Subtypes.

Esophageal squamous cell carcinoma (ESCC) remains the most common malignancy of the esophagus worldwide. Environmental and lifestyle exposures such as alcohol and tobacco have been well defined in the pathogenesis of ESCC, acting in concert with cell intrinsic epigenomic, genomic and transcriptomic changes. However, a variety of nonenvironmental etiologies including Fanconi anemia, lichen planus, chronic mucocutaneous candidiasis, esophageal epidermoid metaplasia, epidermolysis bullosa, tylosis, esophageal atresia, and achalasia receive minimal attention despite a high risk of ESCC in these diseases. The goal of this review was to promote clinical recognition and suggest a diagnostic framework for earlier detection of ESCC in patients with these rare diseases. In all the discussed conditions, a change in symptoms should trigger a prompt endoscopic evaluation, and endoscopic surveillance programs with advanced imaging techniques and chromoendoscopy should be considered. Moreover, we leverage the convergence of these diseases on ESCC to identify common mechanisms underlying malignant transformation including aberrant proliferation, mucosal barrier dysfunction, increased inflammation, and genome instability. In this study, we summarize the clinical presentation, pathologic findings, potential screening strategies, and common mechanisms of malignant transformation associated with these rare diseases that drive ESCC.

Retrospective identification of the first cord blood-transplanted severe aplastic anemia in a STAT1-associated chronic mucocutaneous candidiasis family: case report, review of literature and pathophysiologic background.

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood-transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1-mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases.

Chronic mucocutaneous candidiasis due to signal transducer and activator of transcription 1 mutation in a Saudi patient: a case report

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency condition caused by a genetic abnormality that increases the risk of recurrent and persistent skin, nail and mucous membrane infections with Candida species, typically Candida albicans. Signal transducer and activator of transcription 1 (STAT 1) gene mutation is a genetic trigger that causes CMC, which increases the risk of infections, multisystem disorders and cancer susceptibility. We describe the first case of a Saudi female patient with clinical features of CMC with an underlying (STAT 1) gene mutation.

Late-Onset Concurrent Infection of Vaccine Strain VZV and HSV-1 after Varicella Vaccination in a Child with Natural killer T Cell Deficiency

AbstractWe describe a case with natural killer cell deficiency of late-onset Oka vaccine varicella zoster virus (VZV) strain and Herpes simplex virus-1 (HSV-1) dual infection resulting in fatal clinical course. An 18-month-old boy presented with a papulovesicular rash, mucocutaneous candidiasis, encephalopathy, and severe respiratory distress 6 months after receiving varicella vaccine. VZV and HSV-1 were analysed by real-time reverse-transcriptase polymerase chain reaction (RT-qPCR) and Oka vaccine strain of VZV by gene sequencing. HSV-1 and VZV dual infection was detected in the blood and skin samples by RT-qPCR. Gene sequencing of VZV isolated from vesicular lesions was compatible with the Oka vaccine strain. Flow cytometry revealed a natural killer deficiency, but whole exome analysis failed to identify an associated genetic defect. Vesicular rashes in immunocompromised patients who were inadvertently vaccinated should be taken seriously, and antiviral therapy should be prompt and aggressive.

A rare incidence of severe dermatological toxicities triggered by concomitant administration of all-trans retinoic acid and triazole antifungal in patients with acute promyelocytic leukemia: a case series and review of the literature

BackgroundAll-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450.Case presentationThree Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients.ConclusionBy highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.

Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.

STAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy. Eleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity. All patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts. STAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

A novel mutation site in STAT in a chronic mucocutaneous candidiasis pediatric patient with disseminated cryptococcosis: Case report and review of the literature

A novel mutation site in STAT in a chronic mucocutaneous candidiasis pediatric patient with disseminated cryptococcosis: Case report and review of the literature

The ouroboros of autoimmunity.

Human autoimmunity against elements conferring protective immunity can be symbolized by the 'ouroboros', a snake eating its own tail. Underlying infection is autoimmunity against three immunological targets: neutrophils, complement and cytokines. Autoantibodies against neutrophils can cause peripheral neutropenia underlying mild pyogenic bacterial infections. The pathogenic contribution of autoantibodies against molecules of the complement system is often unclear, but autoantibodies specific for C3 convertase can enhance its activity, lowering complement levels and underlying severe bacterial infections. Autoantibodies neutralizing granulocyte-macrophage colony-stimulating factor impair alveolar macrophages, thereby underlying pulmonary proteinosis and airborne infections, type I interferon viral diseases, type II interferon intra-macrophagic infections, interleukin-6 pyogenic bacterial diseases and interleukin-17A/F mucocutaneous candidiasis. Each of these five cytokine autoantibodies underlies a specific range of infectious diseases, phenocopying infections that occur in patients with the corresponding inborn errors. In this Review, we analyze this ouroboros of immunity against immunity and posit that it should be considered as a factor in patients with unexplained infection.

STAT1 Mutations in Chronic Mucocutaneous Candidiasis Diagnosed in an Adult.

A 30-year-old man presented with oral candidiasis and a history of lung abscess. He experienced recurring oral and skin candidiasis in childhood but spent long periods without any infections. Therefore, immunodeficiency was suspected. T and B lymphocyte and natural killer cell counts as well as immunoglobulin levels were normal. Human immunodeficiency virus test results were negative. Therefore, we suspected chronic mucocutaneous candidiasis (CMC). The signal transducer and activator of transcription (STAT) mutation, the leading cause of CMC, was detected by exome sequencing. Most cases of STAT1 mutations are diagnosed in childhood, but a few are diagnosed in adulthood because Candida infections may not be severe.

Lessons from prospective longitudinal follow-up of a French APECED cohort.

APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.