Patients with STAT1 gain-of-function mutations display increased IFNα-induced T cell apoptosis and upregulation of interferon signature that are responsive to ruxolitinib treatment.

Abstract

Introduction. The signal transducer and activator of transcription (STAT1) gain of function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The spectrum of immunological abnormalities may vary and influence the infectious morbidity. Methods. We investigated the mechanisms that may determine T lymphopenia in STAT1-GOF patients and evaluate the interferon signature in patients exhibiting autoimmunity. Results. STAT1-GOF patients may manifest T lymphopenia particularly by adult age. We observed how the hyperactivation of STAT1 associated with a disrupted pattern of apoptosis as the stimulation with IFNα increased the expression of markers of apoptosis via caspase activation and significantly increased the apoptosis of T cells in STAT1-GOF patients. The use of a JAK inhibitor, ruxolitinib, was effective in controlling the hyperphosphorylation of STAT1 and reducing T cells apoptosis. This effect was translated in vivo to the increase of lymphocyte count in two treated adult patients. Similarly, ruxolitinib modulated the activation of interferon signature following IFNα stimulation, that may correlate with autoimmune complications. Conclusion. In STAT1-GOF patients, the hyperactivation of IFNα-mediated response may contribute to T lymphopenia throughout increased cellular apoptosis and determine immunedysregulation manifestations. Our results support the use of JAK inhibitor to revert the pathogenesis of T lymphopenia thus reducing the risk of life-threatening infections and suggest the evaluation of interferon score in STAT1-GOF patients as a marker to monitor the risk of autoimmune manifestations.