Background Heterozygous STAT1 gain-of-function (GOF) mutations result in a predisposition to early-onset humoral autoimmunity, including lupus-like disease. Since multiple STAT1-dependent cytokines are implicated in lupus pathogenesis, we hypothesized that insights into STAT1 GOF disease mechanisms might inform our understanding of polygenic SLE.
Methods We performed multiparameter CyTOF immunophenotyping of human STAT1 GOF syndrome (8 pediatric STAT1 GOF patients and 9 age-matched controls). In parallel, we generated an inducible knock-in mouse strain allowing lineage-specific expression of the pathogenic STAT1 R274Q human mutation.
Results STAT1 GOF subjects exhibited dysregulated CD4+ T cell and B cell activation, including expansion of Th1-skewed CXCR3+ circulating T follicular helper (cTFH) cells and CXCR3+ activated B cells. These expanded B and T cell populations correlated with autoantibody titers, suggesting a mechanistic link with breaks in tolerance. Notably, STAT1 GOF B cells downregulated CXCR5, reminiscent of extra-follicular B cell activation in SLE.
To gain mechanistic insights, we used our new murine model to study the cytokine signals driving STAT1 GOF autoimmunity, focusing on STAT1-dependent Type 1 and Type 2 interferon (IFN) receptors. As predicted, Stat1 GOF transgenic mice developed spontaneous lupus-like autoimmunity. However, in contrast to the prevailing Type 1 IFN-centric model for STAT1 GOF and lupus autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor (IFNAR) were only partially protected from STAT1-driven systemic inflammation, whereas loss of Type 2 IFN (IFN-γ) signals abrogated autoimmunity. Finally, we show that pathogenic mutations promote increased total STAT1 protein levels, while IFN-γ receptor deletion normalized total STAT1 expression across immune lineages.
Conclusions We identify IFN-γ as the critical driver of feedforward STAT1 elevation and humoral autoimmunity in STAT1 GOF syndrome. These data implicate a similar STAT1-dependent mechanism in lupus pathogenesis, by driving the extra-follicular activation of autoreactive B cells.
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