Atypical B cell expansion and immune dysregulation are promoted by an inflammatory milieu in STAT1GOF and STAT3DN patients

Authors

• Z An
• M Bosticardo
• J Mackie
• G Magro
• HA Kenney
• SG Tanye
• DB Kuhns
• L Pettiford
• MD Keller
• JR Bergerson
• SM Holland
• AF Freeman
• LD Notarangelo
• OM Delmonte

Abstract

Background
Studies in autoimmune diseases have shown an expansion of CD21low T-bet+ atypical B cells (ABC) responding to an IFN-γ-driven inflammatory milieu, accompanied by higher 9G4 antibody levels recognizing the autoreactive VH4-34 immunoglobulin. In the JAK/STAT pathway, unbalanced STAT1/STAT3 signaling may contribute to dysreactivity. We examined immunological correlates of STAT1 gain-of-function (GOF) and STAT3 dominant-negative (DN) diseases, with similar infection rates, but different autoimmunity susceptibility, to better define the immune dysregulation of these conditions and envision new therapeutic targets.

Methods
Immunophenotype of T and B cells was studied by flow cytometry.
Soluble biomarker levels were assessed by MesoScale.

Results
We detected an expansion of CD21low and 9G4+ B cells in our entire cohort of 18 STAT1GOF patients, but only in 8/40 STAT3DN patients. A positive correlation was observed between CD21low and 9G4high B cell frequencies (r=0.46, p=0.003) in the STAT3DN patients. Furthermore, 5 out of the 6 STAT3DN patients with autoimmunity displayed high frequency of CD21low and 9G4high cells. We also analyzed subsets of T helper (Th) and T follicular helper (Tfh) cells and of ABCs. All STAT1GOF and the subset of STAT3DN patients with autoimmunity showed low proportions of Th17 and increased frequencies of CD19+CD21lowCD11c+IgD-CD27- activated naïve B cells and Th1/Tfh1 cells. High plasma levels of IFN-γ and CXCL10 were detected in both diseases.

Conclusions
Our data suggest immune tolerance disruption in STAT1 GOF and in a sub-cohort of STAT3DN with autoimmunity, accompanied by a chronic inflammatory milieu that may promote survival and differentiation of ABCs and/or antibody production.

Scientific Focus Area: Immunology

This page was last updated on Tuesday, August 6, 2024