40 research outputs found
Composition and Diversity of Lawn Flora in Differently Managed Village Yards – A Case Study from Southwestern Hungary
BIMBY’s first steps: a pilot study on the contribution of residential front-yards in Phoenix and Maastricht to biodiversity, ecosystem services and urban sustainability
The role of private sector for reducing disaster risk in large scale infrastructure and real estate development: Case of Delhi
Hypothalamic-Pituitary-Adrenal Axis and Interleukin-6 Activity in Children with Head Trauma and Syndrome of Inappropriate Secretion of Antidiuretic Hormone
Interferon Alpha Treatment of Patients with Impaired Interferon Gamma Signaling
Patients with deficiency in the interferon gamma receptor (IFN-gamma R) are unable to respond properly to IFN-gamma and develop severe infections with nontuberculous mycobacteria (NTM). IFN-gamma and IFN-alpha are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-alpha for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-gamma signaling defect. We treated four patients with IFN-gamma R deficiency with adjunctive IFN-alpha therapy in addition to best available antimicrobial therapy, with or without IFN-gamma, depending on the defect. During IFN-alpha treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-alpha driven gene expression in patients' cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-alpha therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-gamma signaling who have refractory infections, IFN-alpha may have adjunctive anti-mycobacterial effects
A 38-year-old woman with necrotising cervical lymphadenitis due to Histoplasma capsulatum
Immunogenetics and cellular immunology of bacterial infectious disease
Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis
Background: Impaired signaling in the IFN-gamma/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-gamma/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-gamma-induced gene expression, but we found impaired respo Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-gamma-mediated inflammation