Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

Abstract

STAT1 gain-of-function (GOF) mutations cause an inborn error of immunity with diverse phenotype ranging from chronic mucocutaneous candidiasis (CMC) to various non-infectious manifestations, the most precarious of which are autoimmunity and vascular complications. The pathogenesis centers around Th17 failure but is far from being understood. We hypothesized that neutrophils, whose functions have not been explored in the context of STAT1 GOF CMC yet, might be involved in the associated immunodysregulatory and vascular pathology. In a cohort of ten patients, we demonstrate that STAT1 GOF human ex-vivo peripheral blood neutrophils are immature and highly activated; have strong propensity for degranulation, NETosis, and platelet-neutrophil aggregation; and display marked inflammatory bias. STAT1 GOF neutrophils exhibit increased basal STAT1 phosphorylation and expression of IFN stimulated genes, but contrary to other immune cells, STAT1 GOF neutrophils do not display hyperphosphorylation of STAT1 molecule upon stimulation with IFNs. The patient treatment with JAKinib ruxolitinib does not ameliorate the observed neutrophil aberrations. To our knowledge, this is the first work describing features of peripheral neutrophils in STAT1 GOF CMC. The presented data suggest that neutrophils may contribute to the immune pathophysiology of the STAT1 GOF CMC.

Signal Transducer and Activator of Transcription Proteins at the Nexus of Immunodeficiency, Autoimmunity and Cancer

“…This leads to patients presenting with disturbed IL-17 immunity, with significant Th17 cytopenia [36,48,50] with an associated impairment in IL-17A and IL-22 production [52], but also defects in B cell differentiation [53]. There is proinflammatory skewing, with reduced tolerogenic function of dendritic cells (DCs) [54], monocytes polarized toward a proinflammatory state with enhanced responsiveness to Tolllike receptor (TLR) 7/8 stimulation [55] and neutrophils with inflammatory markers [56]. Patients with these mutations represent around 50% of all cases of chronic mucocutaneous candidiasis (CMC), which is characterized by recurrent/persistent mucocutaneous infection by Candida fungi [36,57], but also exhibit increased susceptibility to bacterial, viral and other fungal infections of the lower respiratory tract, autoimmune manifestations, such as enterocolitis, systemic lupus erythematosus and relevant thyroid diseases [46].…”