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

Autor:	Gómez-Bañuelos E; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224. Electronic address: jgomezb1@jhmi.edu., Goldman DW; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224., Andrade V; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224., Darrah E; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224., Petri M; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224., Andrade F; Division of Rheumatology, The Johns Hopkins School of Medicine, Baltimore, MD 21224. Electronic address: andrade@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 May 21; Vol. 5 (5), pp. 101569. Date of Electronic Publication: 2024 May 13.
DOI:	10.1016/j.xcrm.2024.101569
Abstrakt:	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 + GZMH + cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials. Competing Interests: 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). (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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