JAK/STAT signaling in rheumatoid arthritis leukocytes is uncoupled from serum cytokines in a subset of patients.

Autor: Dreo B; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Muralikrishnan AS; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Husic R; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Lackner A; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Brügmann T; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Haudum P; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Bosch P; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Thiel J; Division of Rheumatology and Immunology, Medical University of Graz, Austria., Fessler J; Division of Immunology, Otto Loewi Research Center, Medical University of Graz, Austria. Electronic address: johannes.fessler@medunigraz.at., Stradner M; Division of Rheumatology and Immunology, Medical University of Graz, Austria.
Jazyk: angličtina
Zdroj: Clinical immunology (Orlando, Fla.) [Clin Immunol] 2024 Jul; Vol. 264, pp. 110238. Date of Electronic Publication: 2024 May 08.
DOI: 10.1016/j.clim.2024.110238
Abstrakt: Objective: Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA.
Methods: The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA).
Results: We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations.
Conclusion: Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.
Competing Interests: Declaration of competing interest The authors have no conflicting interests concerning this work.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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