Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis.

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

Chronic mucocutaneous candidiasis, a case study and literature review.

Chronic mucocutaneous candidiasis (CMC) is a clinically heterogeneous disease. Some immunologic and hormonal abnormalities have been associated with CMC. The factors that predispose host to CMC infection could be autosomal or acquisitive. The disease usually occurs in childhood. Here, we reviewed the published literature on chronic mucocutaneous candidiasis and a four years old girl is presented with CMC. She had a history of recurrent thrush and otomycosis since the age of one. Candida albicans was detected in skin scraping and biopsy samples. Serum iron was low. TSH hormone level was high and T4 level was low. Giardia cysts were found in stool sample. Mucocutaneous and nail manifestations of the disease were disappeared after a period of Itraconazole therapy.

Defective trained immunity in patients with STAT-1-dependent chronic mucocutaneaous candidiasis.

Patients with signal transducer and activator of transcription-1 (STAT1)-dependent chronic mucocutaneous candidiasis (CMC) and patients with STAT3-dependent hyper-immunoglobulin (Ig)E syndrome (HIES) display defects in T helper type 17 (Th17) cytokine production capacity. Despite this similar immune defect in Th17 function, they show important differences in the type of infections to which they are susceptible. Recently, our group reported differential regulation of STAT-1 and STAT-3 transcription factors during epigenetic reprogramming of trained immunity, an important host defence mechanism based on innate immune memory. We therefore hypothesized that STAT1 and STAT3 defects have different effects on trained immunity, and this may partly explain the differences between CMC and HIES regarding the susceptibility to infections. Indeed, while trained immunity was normally induced in cells isolated from patients with HIES, the induction of innate training was defective in CMC patients. This defect was specific for training with Candida albicans, the main pathogen encountered in CMC, and it involved a type II interferon-dependent mechanism. These findings describe the role of STAT-1 for the induction of trained immunity, and may contribute to the understanding of the differences in susceptibility to infection between CMC and HIES patients. This study could also provide directions for personalized immunotherapy in patients suffering from these immunodeficiencies.

Altered immune responses in patients with chronic mucocutaneous candidiasis.

OBJECTIVE: The purpose of this study was to investigate the lymphocyte transformation responses and cytokine secretion of peripheral blood mononuclear cells (PBMC) from patients with chronic mucocutaneous candidiasis (CMC). METHODS: Phytohaemagglutinin (PHA) mitogen and Candida albicans (C. albicans) antigen proliferation assays were performed by culturing PBMCs in RPMI 1640. The levels of interleukin (IL)-2, IL-10, IL-17 and interferon (IFN)-γ present in the supernatant of cultures were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed that most patients (92.3%) had a low proliferative response to C. albicans antigens and PHA. PBMCs from CMC patients produced lower levels of T (h)-1 cytokines IL-2 (78.5±59.8 pg/mL) and IFN-γ (115.1±43.3 pg/mL) in response to Candida antigens when compared to controls (Il-2: 177±103.6 pg/mL; IFN-γ: 330.3±21.6 pg/mL) (P<0.05). Conversely, we observed a partial enhancement of IL-10 in the patients (213.7±86.1 pg/mL). Production of IL-17 indicated no significant differences between patients and controls when stimulated by Candida antigens (21.5±8.6 pg/mL versus 32.4±12.2 pg/mL) and PHA (27.7±11.5 pg/mL versus 36.2±9.1 pg/mL), respectively. CONCLUSION: These findings suggest that Candida antigens trigger a Th2 instead of Th1 cytokine response in patients with CMC. For better understanding, further studies require on a larger number of patients into the future.

Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I.

Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-gamma, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1beta, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-beta, tumor necrosis factor [alpha], or transforming growth factor beta). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.

Chronic mucocutaneous candidiasis and primary hypothyroidism in two families.

UNLABELLED: We describe the clinical and immunological features of two families with chronic mucocutaneous candidiasis (CMC) and primary hypothyroidism. Family A includes three siblings with both candidiasis and hypothyroidism and four individuals with hypothyroidism only. Family B includes four members with candidiasis, of whom one (a male child) also had hypothyroidism. All individuals affected with CMC had suffered from oral candidiasis and onychomycosis since infancy. Facial seborrhoic dermatitis, general folliculitis and scaling blepharitis were main manifestations. Hypothyroidism became evident during childhood. No thyroid antibodies were present in the affected siblings in family A, while the male in family B with hypothyroidism had antibodies against thyroid peroxidase at diagnosis. Immunological evaluation revealed intra-individual variations in serum immunoglobulin levels, lymphocyte subsets and proliferative responses, but there were no consistent abnormalities. Vaccine responses were normal. AIRE gene region microsatellite markers did not segregate with disease nor were autoantibodies typical for autoimmune polyendocrine syndrome type 1 detected in the families. CONCLUSION: The link between hypothyroidism and chronic mucocutaneous candidiasis remains to be identified.

Serum levels of malondialdehyde and 4-hydroxy-2,3-nonenal in patients affected by familial chronic nail candidiasis.

Familial chronic nail candidiasis (FCNC.MIM 607644) is a rare disorder characterized by early onset infections caused by different species of Candida and restricted to the nails; this disorder is genetically associated with low serum concentration of intercellular adhesion molecule 1 (ICAM-1). Herein we report the evidence of high circulating levels of malondialdehyde (MDA) and 4-hydroxy-2,3-nonenal (HNE) in seven patients of a five-generation Italian family affected by FCNC.MIM 607644. The present data evidence, in these patients, an increase in circulating MDA and HNE levels. Only some merely speculative hypotheses may be suggested to explain the mechanisms subserving the oxidative stress condition observed in these genetically ICAM-1 deficient patients; however, one has to point out that a chronic oxidative stress condition could contribute to the development of concurrent pathological alterations in which an overproduction of free radicals may play a central role.

Protein carbonyl group content in patients affected by familiar chronic nail candidiasis.

Familiar chronic nail candidiasis (FCNC) is a rare disorder characterized by early-onset infections caused by different species of Candida, restricted to the nail of the hands and feet, and associated with a low serum concentration of intercellular adhesion molecule 1. Host defense mechanisms against candidiasis require the cooperation of many immune cells through several candidacidal mechanisms, including oxygen-dependent killing mechanisms, mediated by a superoxide anion radical myeloperoxidase--H2O2--halide system, and reactive nitrogen intermediates. We analyzed protein carbonyl groups (considered a useful marker of oxidative stress) in the serum of patients belonging to a five-generation Italian family with an isolated form of FCNC. Serum protein carbonyl groups in FCNC patients were significantly lower than those measured in healthy donors. Also, if this hypothesis is merely speculative, we could suggest that the decreased circulating level of protein carbonyl groups in these patients is not a marker of a lower oxidative stress condition, but might be linked to a lower protease activity.

Chronic mucocutaneous candidosis associated with hypothyroidism: a distinct syndrome?

Chronic mucocutaneous candidosis (CMC) is a rare, complex disorder characterized by chronic and recurrent candida infections of the skin, nails and oropharynx. In over 50% of cases there is an associated endocrine disease, the complex being described as the candida endocrinopathy syndrome. Inheritance of familial endocrine associated cases has been thought to follow an autosomal recessive pattern. In addition, autosomal recessive and autosomal dominant forms of CMC not associated with endocrinopathy have been described. We report a new syndrome in which there is vertical transmission of CMC within families associated with primary hypothyroidism. This suggests that the candida endocrinopathy syndrome can be subdivided into at least two types, one associated with hypoparathyroidism and/or hypoadrenalism which is inherited as an autosomal recessive trait, the other associated with hypothyroidism which is an autosomal dominant disease. We emphasize the importance of early and regular monitoring thyroid function in individuals with CMC and a need to provide appropriate genetic counselling to affected members.

Case report: successful treatment with cimetidine and zinc sulphate in chronic mucocutaneous candidiasis.

The authors evaluated the clinical efficacy of a treatment with cimetidine and zinc sulphate in a patient with chronic mucocutaneous candidiasis. Cimetidine was given at a dose of 400 mg three times daily; zinc sulphate at a dose of 200 mg daily, then adjusted to maintain blood zinc levels at the upper normal range. This treatment lasted 16 months. An impressive and significant reduction of the infectious events and an increased CD4 (helper/inducer) cell counts were observed. The authors conclude that this combined immunopotentiating treatment is safe and inexpensive to treat immunodeficiency disorders.

Autoimmune hemolytic anemia in chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is an immunodeficiency disease characterized by T-cell dysregulation and chronic superficial candidal infections. We report on three patients with chronic mucocutaneous candidiasis who developed autoantibodies to erythrocytes. Our first patient, a 19-year-old female, developed autoimmune hemolytic anemia (AIHA) that required multiple courses of treatment, including corticosteroids, intravenous immunoglobulin, and danazol. During the last exacerbation of AIHA, intensive treatment with corticosteroids and intravenous immunoglobulin failed and yet the patient responded to plasmapheresis. Our second patient, a 21-year-old male, developed AIHA which responded to oral corticosteroid therapy. Our third patient, a 6-year-old female without evidence of hemolysis, was found to have erythrocyte autoantibodies on routine screening. These three patients had positive direct antiglobulin tests, and the first patient had both immunoglobulin G (IgG) and IgM erythrocyte autoantibodies, while the remaining two patients had only IgG autoantibody. This is the first report of the association of AIHA with chronic mucocutaneous candidiasis. We suggest that all patients with chronic mucocutaneous candidiasis be screened periodically for erythrocyte autoantibodies. Plasmapheresis, a safe ancillary procedure in the management of AIHA, may be life-saving in some cases. The occurrence of erythrocyte autoantibodies in mucocutaneous candidiasis may be related to immunoregulatory disorders in this disease.

Elevated phagocytosis, oxidative burst, and F-actin formation in PMNs from individuals with intraoral manifestations of HIV infection.

Alterations in polymorphonuclear leucocyte (PMN) function are frequently associated with intraoral disease. The purpose of this study was to evaluate if alterations exist in three early stimulatory events of PMN function in individuals with intraoral manifestations of human immunodeficiency virus (HIV) infection. Peripheral PMNs were isolated from nine HIV-seropositive male homosexuals with HIV-associated periodontitis and intraoral candidiasis and healthy HIV-seronegative age-matched heterosexuals (controls). Phagocytosis was assessed using fluorescent microspheres, oxidative burst was assessed via hydrolysis of 2',7'-dichlorofluorescein (FCDH) to 2',7'-dichlorofluorescein (FCDA) with PMA stimulation, and F-actin formation was assessed with NBD-phallacidin stain after stimulation with f-Met-Leu-Phe. Compared to controls, seven of nine HIV-seropositive patients demonstrated a significant increase in the percentage of phagocytic cells while seven of nine HIV-seropositive patients demonstrated a 5-59% increase in number of beads per cell. In the oxidative burst assay, seven of seven HIV-seropositive patients demonstrated a significant increase over controls in FCDA stain with PMA stimulation. In the F-actin assay, four of five HIV-seropositive patients demonstrated a significant increase over controls in NBD-phallacidin staining after f-Met-Leu-Phe stimulation.

Evaluation of auto-antibodies in chronic mucocutaneous candidiasis without endocrinopathy.

Six patients with chronic mucocutaneous candidiasis (CMCC) were investigated for the presence of auto-antibodies during the course of the infection. Sera were tested for antibodies to native DNA (dsDNA) and denatured DNA (ssDNA), mitochondrial and microsomal antigens, smooth muscle, gastric parietal cells, basal membrane and skin intercellular substance, parathyroid glands, thyroglobulin and microsomal antigen, immunoglobulins and for anti-nuclear antibodies. Auto-antibodies were detected by radioimmunoassay, immunofluorescence, hemagglutination and other routine methods. Tests were performed at the end of the observation period, with the same batches of antigens and at the same time for all patients. Organ-specific antibodies (gastric parietal cells and intercellular substance) were found at low titers in five patients. Anti-smooth muscle antibodies were increased in two patients. In four patients antibodies to ssDNA were elevated. Moreover high titers of anti-ssDNA antibodies correlated well with disease activity after treatment with Ketoconazole in four tested patients. The possibility that C. albicans infection may induce auto-antibodies should be considered in assessing their disease activity significance in other chronic infected patients. The mechanisms of appearance of auto-antibodies and their immunopathological significance in CMCC are discussed.