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Background: Systemic autoimmune diseases such as Mixed Connective Tissue Disease (MCTD), Sjögren's disease (SjD) and systemic lupus erythematosus (SLE) are clinically heterogeneous. At the molecular level, they share some common features such as expression of autoantibodies. The presence of an IFN stimulated gene (ISG) signature in many patients suggests that pathways that drive ISG induction, such as Toll-like receptor (TLR) 7, may be activated across systemic autoimmune diseases, and that targeting these pathways may lead to clinical benefit 1. Objectives: To identify a novel functional TLR-driven endotype across systemic autoimmune diseases. Methods: Common serum auto-antibodies (anti-dsDNA and Extractable Nuclear Antigen (ENA) antibody panel) were measured in >300 patients diagnosed with MCTD, SjD or SLE. PBMCs from healthy donors were stimulated with immune complexes (ICs) of patient sera and necrotic cells or purified recombinant antigens, and cytokine release measured. The impact of standard of care, and novel compounds on cytokine responses was compared. Patient blood transcriptomic profiles were probed with a TLR7/8 gene signature from ex vivo stimulated PBMCs. Results: ICs formed from MCTD, SjD, and SLE patient sera and necrotic cells triggered cytokine release. Using specific autoantigens and compounds, we found a correlation of specific patient autoantibody profiles and distinct molecular pathways of inflammation. Of particular interest were autoantibodies against ribonucleoproteins (RNPs), i.e. SS-A and RNP/Sm, as they are observed across disease entities (76% in SjS, 52% in SLE and 86% in MCTD). In line with previous studies, we found that the active moiety of RNPs is ssRNA, which is protected from RNAse degradation by formation of ICs, and that ICs are internalized via FcγR. Using the specific TLR7/8 antagonist MHV370 (1), we demonstrated that anti-SSA and anti-RNP/Sm drive activation of endosomal TLR7/8, while not affecting cytokine release by dsDNA ICs from SLE sera. Of note, only the Ro60 subunit of SS-A activated a functional response (not Ro52 or La). MHV370 differentiated from other compounds used for SLE therapy, e.g. hydroxychloroquine or inhibitors of IFN signaling, suggesting that TLR7/8 responses are a likely contributor to pathology. We also detected a TLR7/8 transcriptomic signature in patient blood. Conclusion: Functional characterization of patient sera uncovered a TLR7/8 driven endotype across certain systemic autoimmune diseases. These translational studies highlight the potential of targeting TLR7/8 and support clinical basket trials. REFERENCES: 1 Hawtin S, André C, Collignon-Zipfel G, Appenzeller S, Bannert B, Baumgartner L, et al. Preclinical characterization of the Toll-like receptor 7/8 antagonist MHV370 for lupus therapy. Cell Reports Medicine. 2023 May 16;4(5):101036. Acknowledgements: NIL. Disclosure of Interests: Stuart Hawtin shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Sarah Dyball: None declared, Cédric André shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Simone Appenzeller investigator sponsored studies with GSK, speaker fees from GSK and Astra Zeneca, Bettina Bannert: None declared, Hermine Brunner contributions from AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, UCB, Janssen, Eli Lilly, Idorsia, Cerocor, F. Hoffmann-La Roche, Merck, Novartis and Sanofi, grants from Pfizer and support by the NIH Center of Excellence in Clinical Research PORTICO, Ian N. Bruce speaker fees from UCB, Astra Zeneca, Janssen and GSK, consultancy fees from Astra Zeneca, UCB, Aurinia, Takeda, GSK, Lilly, Horizon Therapeutics and Dragonfly Therapeutics, grants from Astra Zeneca, GSK, Janssen and Novartis, Enrico Ferrero shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Anne Gernand shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Diego Kyburz honoraria from AbbVie, BMS, Janssen, Novartis, Pfizer, Roche and Eli Lilly, Britta Maurer Speaker fees from Boehringer-Ingelheim, GSK, Novartis, Otsuka and MSD, consultancy fees from Novartis, Boehringer Ingelheim, Jannsen-Cilag and GSK, grants from Novartis and congress support from Medtalk, Pfizer, Roche, Actelion, Mepha and MSD, Richard Siegel shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Tamas Shisha shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Jonas Zierer shareholder of Novartis Pharma AG, employee of Novartis Pharma AG, Tobias Junt shareholder of Novartis Pharma AG, employee of Novartis Pharma AG.
Hawtin et al. (Sat,) studied this question.