Background/Purpose: SLE is characterized by persistently high type I IFN activity. Plasmacytoid dendritic cells (pDCs) produce large amounts of IFNs in viral infections in response to nucleic acids and they have therefore been postulated to be the main source of type I IFNs in SLE. However, the precise role of pDCs in autoimmunity still remains unclear. The aim of this study was to investigate the source of type I IFN in patients with established SLE and preclinical autoimmunity.

Methods: Patients with SLE meeting 2012 ACR/SLICC criteria and healthy donors were recruited alongside therapy-naïve individuals presenting with ANA and 1 clinical symptom (At-Risk). IFN activity was evaluated by a score of IFN-responsive genes in the peripheral blood using TaqMan. pDCs were immunophenotyped and studied in vitro for production of cytokines and induction of T cell responses using flow cytometry. pDCs were sorted and sequenced using high-sensitive RNA sequencing. IFN expression was visualised in skin biopsies using in situ hybridisation. Keratinocytes were isolated from fresh skin biopsies and cultured in vitro; IFN production was measured by qPCR and ELISA.

Results: Most of SLE and At-Risk patients had increased IFN activity, which correlated with disease activity. In contrast, circulating pDCs were decreased in both SLE and At-Risk patients and their numbers did not correlate with any clinical features or IFN status. In vitro stimulation with TLR9 or TLR7 agonists revealed that pDCs from SLE and At-Risk patients could not produce IFN-α and TNF-α. In addition, they induced significantly less T cell activation and proliferation compared to pDCs from healthy donors. RNA-seq data analysis showed an upregulation of IFN-responsive genes in most of the SLE and At-Risk pDCs as well as pathways related to immune regulation and senescence but not transcripts of any IFN subtypes. Phenotypically, SLE pDCs were characterised by increased telomeric erosion. In situ hybridization revealed high IFN expression in the epidermis but not in lymphocyte-infiltrating areas of lesional biopsies from SLE patients. High expression of IFN was also observed in epidermis of At-Risk individuals without any signs of cutaneous inflammation. In vitro stimulation of freshly isolated keratinocytes from these also showed a notable increase in IFN production.

Conclusion: In SLE, non-haematopoietic tissue resident cells are a dominant source of IFN and this is present prior to clinically overt disease. Meanwhile, the professional IFN-producing pDCs have lost their immunogenic properties. These findings suggest an important role for tissue resident cells in autoimmunity and may facilitate novel therapeutic interventions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-ifn-production-is-induced-by-non-haematopoietic-tissue-cells-but-not-plasmacytoid-dendritic-cells-in-preclinical-autoimmunity-and-sle/