Background/Purpose: Heterozygous gain-of-function mutations in STAT1 promote a complex disorder of immune dysregulation including chronic mucocutaneous candidiasis (CMC) and systemic autoimmunity. However, given widespread expression of STAT1 in immune and non-immune lineages and engagement by multiple cytokine receptors, the immune mechanisms driving breaks in immune tolerance in STAT1 GOF syndrome remain poorly understood.

Methods: We performed multiparameter immunophenotyping of peripheral blood mononuclear cells (PBMCs) from 8 pediatric STAT1 GOF patients and 9 age-matched controls. Affected subjects were studied prior to treatment with JAK inhibitors, allowing unique insight into the immune landscape of STAT1-driven immune dysregulation. In parallel, we generated a novel murine knock-in strain allowing cell-intrinsic expression of a pathogenic human STAT1 GOF mutation.

Results: We performed deep immunophenotyping of pediatric STAT1 GOF patients and age-matched controls to identify immune characteristics of STAT1-driven inflammation. Affected patients exhibited dysregulated CD4+ T cell and B cell activation which correlated with serum autoantibody titers. In the parallel murine model, Stat1 GOF transgenic mice, which developed spontaneous humoral autoimmunity recapitulating the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency (IPEX syndrome), Stat1^GOF mice and humans exhibited normal Treg development and function. Rather, STAT1 GOF autoimmunity was driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. Surprisingly, autoimmunity in Stat1^GOF mice lacking the type 1 IFN receptor (IFNAR) was only partially ameliorated, whereas loss of type 2 IFN (IFN-γ) signals prevented disease. Strikingly, IFN-γR deletion abolished the known increase in total STAT1 expression in STAT1 GOF syndrome resulting in normalization of STAT1-dependent systemic inflammation. Since STAT1 regulates its own transcription, these findings highlight IFN-γ as the critical driver of a feedforward inflammatory cascade in STAT1 GOF syndrome.

Conclusion: Human genetic variations resulting in immunodeficiency and/or the propensity for autoimmunity represent “experiments of nature” that can advance our understanding of the human immune system and may inform the development of targeted therapies for inflammatory disease. Our data provide new insights into the STAT1-dependent cellular mechanisms underlying both rare monogenic and more common polygenic autoimmune diseases, such as systemic lupus erythematosus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dysregulated-interferon-gamma-signals-promote-systemic-autoimmunity-in-stat1-gain-of-function-syndrome/