Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE.

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8

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Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests F.A. has received consulting fees and/or royalties from Celgene, Inova, Advise Connect Inspire, and Hillstar Bio, Inc. E.D. is currently a full-time employee at AztraZeneca and has received grants, consulting fees, royalties, and/or stocks from Pfizer, Celgene, Bristol Myers Squibb, Inova, and Ravel Therapeutics. E.D. is an inventor on a licensed patent (US patent #10,874,726) and licensed provisional patents (048317-642P01US and US 63/515,854) and a co-founder of Simmbion LLC. F.A. and E.D. are inventors on a licensed patent (US patent no. 14/617,412) and a licensed provisional patent (US patent no. 62/481,158).