ABSTRACT
BACKGROUND: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. OBJECTIVE: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. METHODS: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. RESULTS: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. CONCLUSION: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.
Subject(s)
Coccidioidomycosis/genetics , Histoplasmosis/genetics , Mutation , STAT1 Transcription Factor/genetics , Adolescent , Adult , Cell Line, Transformed , Child , Coccidioidomycosis/diagnosis , Coccidioidomycosis/immunology , Cytokines/biosynthesis , Female , Gene Expression Regulation , Histoplasmosis/diagnosis , Histoplasmosis/immunology , Humans , Male , Phosphorylation , Protein Inhibitors of Activated STAT/metabolism , STAT1 Transcription Factor/metabolism , Th17 Cells/immunology , Transcriptional Activation , Young AdultABSTRACT
Recently, several studies have revealed a subset of patients who have positive nasal provocation to allergens despite having a negative skin prick test. It has been hypothesized that these patients have localized allergic rhinitis. However, the prevalence varies greatly, ranging from 0% to 100% of skin test-negative individuals. This wide range in prevalence is likely related to differences in methodology, including differences in allergen manufacturers, concentrations, and numbers of allergens tested and, perhaps most importantly, criteria for a positive nasal challenge. Despite the evidence to date, many challenges exist with regard to the concept of localized nasal allergy. Further studies will be required to further define the immunopathology, prevalence, practical diagnostic tests, and management.
Subject(s)
Rhinitis, Allergic, Perennial/diagnosis , Allergens , Diagnosis, Differential , Humans , Prevalence , Rhinitis, Allergic, Perennial/epidemiology , Rhinitis, Allergic, Perennial/pathology , Rhinitis, Allergic, Perennial/physiopathology , Skin Tests/methods , Skin Tests/standardsABSTRACT
As food allergies become increasingly prevalent and testing methods to identify "food allergy" increase in number, the importance of careful diagnosis has become even more critical. Misdiagnosis of food allergy and inappropriate use of unproven testing modalities may lead to a harmful food-elimination diet. This case is an example of an infant who was placed on an overly restrictive elimination diet at the recommendation of her health care providers, resulting in kwashiorkor and acquired acrodermatitis enteropathica.