AI Article Synopsis

  • Heterozygous STAT1 Gain-of-Function mutations are linked to chronic mucocutaneous candidiasis (CMC) and can lead to various immune disorders like autoimmune diseases and malignancies, with JAK inhibitors showing promise in treatment.
  • In a study of five Taiwanese patients, two new STAT1 GOF mutations were discovered, revealing clinical symptoms like CMC and autoimmunity, along with notable changes in immune cell types.
  • This research provides key insights into the immune dysregulation seen in STAT1 GOF patients and suggests that baricitinib is safe and effective for treatment, although further studies are needed to understand the underlying mechanisms driving these immune changes.

Article Abstract

Purpose: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients.

Methods: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF.

Results: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38HLADR CD8 T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects.

Conclusion: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.

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Source
http://dx.doi.org/10.1007/s10875-024-01776-9DOI Listing

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