Comparative studies connecting IFN dysregulation with pathway dysregulation in 2 autoinflammatory diseases, SAVI and CANDLE (HUM1P.274)

Abstract

Abstract Type I interferon dysregulation is associated with some autoinflammatory diseases. Gain-of-function mutations in TMEM173 encoding Stimulator of Interferon Genes (STING) lead to constitutive production of Type I IFN and the clinical syndrome, STING associated vasculopathy with onset in infancy (SAVI). In another IFN mediated disease, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE), disease causing mutations cause global proteasome dysfunction and increase in IFN message. The cellular source of the IFNs in blood and the dominant isoforms remain unclear. We examined the expression of 5 type I IFN genes among FACS sorted PBMCs: T-, B-, NK cells and monocytes in SAVI (n=2) and total PBMCs from CANDLE patients (n=2) by qRTPCR. We found in SAVI that monocytes expressed the highest level of type I IFN message. Among the IFN genes tested and normalized to healthy monocytes, patients’ IFNβ is over 250-fold higher than IFNα; following the notion that STING pathway activation leads to IFNβ transcription. Depleting monocytes from SAVI PBMCs reduced 90% of the IFN message, confirming that monocytes not dendritic cells are the main source of IFNs. In contrast, CANDLE patients’ IFN alpha and beta genes are comparably upregulated. Although IFN dysregulation is identified in blood, determining the cellular origin of the IFN production and the pathways that drive IFN dysregulation will allow us to develop better targets for therapy.