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Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors

Emilie W Borgström1,2, Marie Edvinsson3, Lucía P Pérez4

  • 1Department of Laboratory Medicine, Clinical Microbiology, Stockholm, Sweden. emilie.wahren-borgstrom@regionstockholm.se.

Journal of Clinical Immunology
|September 1, 2022
PubMed
Abstract

Insights

Janus kinase (JAK) inhibitors show promise for treating chronic mucocutaneous candidiasis (CMC) by improving symptoms and enhancing immune response against Candida albicans. Treatment affected various immune cells and altered plasma biomarkers.

Area of Science:

  • Immunology
  • Genetics
  • Pharmacology

Background:

  • Chronic mucocutaneous candidiasis (CMC) is an immune disorder often caused by genetic mutations.
  • Gain-of-function (GOF) mutations in the STAT1 gene impair immune responses, leading to recurrent Candida infections.
  • Janus kinase (JAK) inhibitors represent a potential therapeutic strategy for CMC.

Purpose of the Study:

  • To investigate the clinical effects of JAK inhibitors in patients with STAT1-GOF-related CMC.
  • To identify and characterize changes in biomarkers and immune cell populations during JAK inhibitor treatment.
  • To assess the impact of JAK inhibitors on immune reactivity against Candida albicans.

Main Methods:

  • Utilized mass cytometry (CyTOF) for detailed characterization of mononuclear leukocyte populations.
  • Employed Olink assay to quantify a panel of 265 plasma proteins.
  • Assessed Candida albicans-specific immune cell reactivity using the Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA).

Main Results:

  • JAK inhibitors improved CMC clinical symptoms, though two patients experienced side effects.
  • Treatment sustained absolute counts of neutrophils, T cells, B cells, and NK cells.
  • CyTOF revealed enhanced NK cell function (increased CD45, CD52, CD99) and reduced monocyte/eosinophil inflammation (downregulated CD16).
  • T and B cells showed increased activation markers; one patient exhibited enhanced C. albicans immune response.
  • Plasma biomarkers like CXCL10, granzyme B/H, and oncostatin M were downregulated, while FGF21 was upregulated; IFN-ɣ and CXCL10 decreased after 3 months.

Conclusions:

  • JAK inhibitor therapy demonstrates promising clinical efficacy for CMC.
  • Baricitinib treatment alters immune cell phenotypes and function, including lymphocytes, NK cells, monocytes, and eosinophils.
  • JAK inhibition enhances cellular immune reactivity against C. albicans, suggesting a restored immune response.
Keywords:
JAK inhibitorOlinkSTAT1chronic mucocutaneous candidiasismass cytometry

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