Background/Purpose: STING Associated Vasculopathy with onset in Infancy (SAVI)is caused by gain-of-function mutations in TMEM173/STING and Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) by loss-of-function mutations in proteasome subunits. Both are IFN-mediated disease but the origin of the IFN production has not been systematically evaluated in patients. The purpose of our study was to determine the cellular origin of IFNs, from SAVI and CANDLE patients (PTs) compared to healthy controls (HC).

Methods: We evaluated sorted PBMCs (n=5 HC, PTs) and lesional skin biopsies (n=2-3 HC, PTs) for detection of IFN production by qRT-PCR.

Results: In both diseases, pan-interferon (IFN)-α serum levels are 8 and 25-fold increased, respectively. PTs had a mean of 12-fold increase in IFN-response-gene (IRG) signatures compared to HC. SAVI pts. constitutively expressed elevated IFN-transcript levels and qPCR results showed a 450-fold and 280-fold increase in IFNB1 [IQR 0.5-61, 60.6], and 3.5-fold and 4.4-fold increase in IFNA7 [IQR 0-2.93, 2.93] transcription in monocytes (n=5) and dendritic cells (n=3) respectively, compared to CANDLE and HC. During disease flares but not at rest, CANDLE monocytes increased IFNB1 production 4.6 and 184-fold and IFNA72.5 to 110-fold (n=2). In contrast to CANDLE and HC monocytes, SAVI monocytes cannot be differentiated into macrophage and 82%±14 SD died in culture within 24-hours. SAVI monocytes expressed 24-fold increase of actively cleaved caspase-1 in the supernatant from the immunoblot analysis compared to HC and did not show active form of caspase-3. ELISA demonstrated low expression of IL-1b β the supernatant and immunofluorescence showed elevated intracellular staining of gasdermin-D and NLRP3, suggesting cell death occurs through pyroptosis.

Conclusion: The cellular sources of IFN production vary in CANDLE and SAVI; Type I IFN transcription in SAVI patients occurs mainly in monocytes and in dendritic cells, in contrast, in CANDLE patients, Type I IFNs are only expressed in monocytes prior to JAK inhibitor treatment during a disease flare (Tx). However interferon-response genes are expressed in all cell types. Constitutively active STING from SAVI monocytes undergo rapid cell death in culture,which may indicate rapid cell turnover in the blood. Studies evaluating the mechanism that leads to monocyte death is ongoing. Understanding the signaling pathways in autoinflammatory diseases assocaited with high IFN signatures is important in our ability to identify and interpret biomarkers that will aid in the diagnosis and the design of targeted treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoinflammatory-diseases-particularly-savi-and-candle-are-driven-by-chronically-active-type-i-interferons/