Purposes: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
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Orv Hetil
December 2024
3 Semmelweis Egyetem, Általános Orvostudományi Kar, Belgyógyászati és Hematológiai Klinika, Infektológiai Tanszéki Csoport Budapest Magyarország.
Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is a chronic disease characterised by progressive inflammatory lung damage due to infection by non-tuberculous mycobacteria (NTM). Global prevalence of NTM-PD is generally low but is rising, likely due to a combination of increased surveillance, increasing multimorbidity and improved diagnostic techniques. Most disease is caused by Mycobacterium avium complex species.
View Article and Find Full Text PDFMicrobiome
December 2024
Department of Biochemistry, Western University, Middlesex Drive, London, N6G 2V4, Ontario, Canada.
Background: The application of '-omics' technologies to study bacterial vaginosis (BV) has uncovered vast differences in composition and scale between the vaginal microbiomes of healthy and BV patients. Compared to amplicon sequencing and shotgun metagenomic approaches focusing on a single or few species, investigating the transcriptome of the vaginal microbiome at a system-wide level can provide insight into the functions which are actively expressed and differential between states of health and disease.
Results: We conducted a meta-analysis of vaginal metatranscriptomes from three studies, split into exploratory (n = 42) and validation (n = 297) datasets, accounting for the compositional nature of sequencing data and differences in scale between healthy and BV microbiomes.
Lancet Digit Health
December 2024
Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address:
Microbiology reference laboratories perform a crucial role within public health systems. This role was especially evident during the COVID-19 pandemic. In this Viewpoint, we emphasise the importance of microbiology reference laboratories and highlight the types of digital data and expertise they provide, which benefit national and international public health.
View Article and Find Full Text PDFBest Pract Res Clin Gastroenterol
December 2024
Department of Gastrointestinal Surgery and Solid Organ Transplant, Amrita Institute of Medical Sciences and Research Centre, Amrita University, Kochi, Kerala, India. Electronic address:
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