Reviews and feature articleMolecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species
Section snippets
STAT family members
Cytokine binding to hemopoietin receptors initiates signaling through Janus kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) and STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6).17, 36, 37 STAT-mediated signaling is the transmission of signals from various receptors of cytokines and growth factors after ligand binding. STAT proteins are present in the cytoplasm as inactive monomers and typically form homodimers or heterodimers after being phosphorylated by
Mutations in STAT3 cause autosomal dominant hyper-IgE syndrome
STAT3 has been implicated in host defenses against extracellular bacteria, including S aureus, and fungi, including C albicans, by recent investigations of patients with autosomal dominant hyper-IgE syndrome (AD-HIES).38, 39, 40, 41 It is now established that heterozygous dominant negative mutations in STAT3 cause autosomal dominant, familial, or sporadic form of the disease.42, 43, 44, 45 Patients with AD-HIES typically have skin and sinopulmonary infections with S aureus and skin and mucosal
Autoimmune polyendocrine syndrome 1
The involvement of IL-17 in host defense against Candida species on body surfaces precipitated mechanistic studies in patients with autoimmune polyendocrine syndrome (APS) 1; these patients have CMC, which is one of the 3 major criteria of the disease.49 Two groups independently discovered that patients with APS-1 have high circulating titers of neutralizing antibodies against the cytokines IL-17 (IL-17A and IL-17F) and IL-22.50, 51, 52 These patients also have increased titers of antibodies to
IL-12 receptor β1 and IL-12p40 deficiencies
CMC often affects patients with PIDs, such as IL-12 receptor β1 (IL-12Rβ1) deficiency, the most common form of Mendelian susceptibility to mycobacterial disease. IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis; recurrent thrush caused by Candida species has been found in 24% of 141 reported patients.56 CMC has also been observed in 7.5% of 44 patients with IL-12p40 deficiency.57 We recently reviewed the clinical course of 26 patients with IL-12Rβ1
TYK2 deficiency
Most cases of HIES are inherited as an autosomal dominant trait or are sporadic presentations. However, the autosomal recessive variant of the syndrome has also been described.59 A Japanese patient with autosomal recessive HIES has been reported and carries a homozygous nonsense mutation in TYK2, which encodes TYK2.59 The patient presented with atopic dermatitis, markedly increased serum IgE titers, and recurrent infections with Staphylococcus species, herpes simplex virus (HSV), BCG, and
IL-17 and IL-17 receptor deficiencies
Patients with chronic mucocutaneous candidiasis disease (CMCD) but without any other severe infection or severe noninfectious disease manifestation, such as autoimmunity, or known genetic defect have been described. Investigations in 2 families led to the discovery of new genetic defects of IL-17–mediated immunity.27 In a Moroccan patient born to consanguineous parents, an autosomal recessive premature stop codon mutation of the IL17RA gene, leading to complete loss of protein expression, was
Gain-of-function STAT1 mutations
Surprisingly, a STAT1 coiled-coil domain (CC-D) mutation was discovered in an index patient from Ukraine and in a large number of patients in other kindreds all over the world.61, 62, 63 JAK-STAT1–mediated molecular pathways have been extensively studied in recent years because of the importance of this pathway in IFN-γ–mediated host defense against intracellular pathogens.17 STAT1 mutations had long been known to underlie mycobacterial and viral diseases.14, 15, 64, 65 New genetic causes of
Caspase recruitment domain 9 deficiency
Caspase recruitment domain (CARD) 9 deficiency has been proposed to predispose 7 patients in a large consanguineous Iranian family to candidal disease. Only 4 of the 7 patients had CMC since early childhood, and 1 patient presented with invasive candidiasis without CMC.67 It appears that in patients with CARD9 deficiency, CMC is part of a phenotype more complex than that of patients with CMC disease (CMCD) caused by IL-17F or IL-17RA deficiency or gain-of-function mutations in STAT1. Recently,
Dectin-1 polymorphism
In their recent report about human Dectin-1 deficiency and mucocutaneous fungal infections, Ferwerda et al68 suggested that familial CMC can be caused by a homozygous or heterozygous Tyr238X defect of the β-glucan receptor Dectin-1. However, both homozygous and heterozygous early stop codon mutations in Dectin-1 have subsequently been found in healthy subjects (L. Maródi and J.-L. Casanova, unpublished observation). Moreover, 6% to 8% of Europeans might be heterozygous for the disabling variant
Conclusion
Recent research on mechanisms of candidiasis in patients with the mucocutaneous but not the invasive forms of the disease has consistently identified and firmly established the involvement of IL-17 in mucocutaneous host defense against Candida species. Cases with abnormal IL-17 immunity (through impaired IL-17 or IL-17 receptor function or STAT1 gain-of-function mutation) serve as naturally occurring experiments, the results of which support the hypothesis that CMC can be caused by deficiencies
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How to: Diagnose inborn errors of intrinsic and innate immunity to viral, bacterial, mycobacterial, and fungal infections
2022, Clinical Microbiology and InfectionCitation Excerpt :Table 2 reports the most appropriate testing for infectious phenotypes associated with non-conventional IEIs. The molecular and cellular mechanisms underlying these infectious phenotypes, which constitute the rationale for specific testing, are not covered by this review and have been reviewed elsewhere [9–12,29,30,32,34,35,71–73,77–82]. It is important to underscore that excluding a conventional IEI may not be a black or white process due to overlapping infectious phenotypes with nonconventional IEIs and variable expressivity, penetrance, and age at onset of immunological and extra-immunological signs.
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2017, Dental Clinics of North AmericaCitation Excerpt :When symptoms of esophageal candidiasis are present, the gold standard is for direct endoscopy, and if patches or lesion are observed, then direct brush or incisional biopsy is indicated. Radiographic evaluation of the esophagus will also aid in the diagnosis of obstruction, fistula, bleeding, perforation, or stricture, which may require endoscopic dilation.29 Medical management via antifungals, in conjunction with urgent referral to a gastrointestinal specialist, is indicated when suspicious of esophageal candidiasis.
Host Defense Mechanisms Against Fungi
2017, Fetal and Neonatal Physiology, 2-Volume Set
Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Supported by TÁMOP 4.2.1./B-09/1/KONV-2010-0007 to L.M. The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from the St Giles Foundation and Rockefeller University grant no. 8UL1TR000043 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health, and the ANR (grant no. GENCMCD 11-BSV3-005-01). S.C. is supported by the AXA Research Fund.