Neutrophil transcriptomics in SLE reveals intrinsic disease signatures, shared ex vivo adaptation, and transcriptional reset after CAR T-cell therapy

Dehdashtian E, Hu G, Whiteman L, Islam MT, Gallucci S, Garber M, Borie D, Schett G, Caricchio R (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

DOI: 10.1016/j.ard.2026.02.013

Abstract

ObjectivesSystemic lupus erythematosus (SLE) is an autoimmune disease characterised by dysregulation of the adaptive and innate immunity. This study aimed to identify transcriptomic differences in neutrophils from patients with SLE and healthy individuals, analyse ex vivo adaptation dynamics, and evaluate the impact of chimeric antigen receptor (CAR) T-cell therapy on neutrophil transcriptomic profiles.MethodsNeutrophils were isolated via negative selection from 7 patients with SLE and 7 healthy individuals. RNA sequencing was performed to assess transcriptomic differences, ex vivo dynamics over 60 minutes, and responses to lipopolysaccharide (LPS) stimulation. In addition, longitudinal transcriptomic data from a patient with SLE undergoing KYV-101 anti-CD19 CAR T-cell therapy were evaluated.ResultsWe identified 258 differentially expressed genes consistently distinguishing SLE from healthy neutrophils; they spanned multiple clusters, enriched in interferon-related and DNA damage repair genes (upregulated), and ribosomal protein genes (downregulated). Ex vivo adaptation revealed shared activation pathways, such as NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) and apoptosis, in both groups. LPS stimulation highlighted overlapping inflammatory responses, demonstrating retained functional capacities in SLE neutrophils. Following CAR T-cell therapy of a patient with SLE, neutrophil transcriptomic profiles were realigned with healthy controls by 3 months posttreatment.ConclusionsNeutrophils in SLE exhibit intrinsic, disease-specific transcriptomic alterations while sharing ex vivo adaptation dynamics with healthy individuals. The disease-specific alterations appear to be modifiable through targeted therapeutic intervention, as anti-CD19 CAR T-cell therapy resets neutrophil gene expression towards healthy patterns despite targeting B cells rather than neutrophils directly. These findings provide insights into SLE pathogenesis and highlight potential therapeutic strategies targeting both adaptive and innate immunity.

Authors with CRIS profile

Georg Schett Lehrstuhl für Innere Medizin III

Involved external institutions

University of Massachusetts Medical School US United States (USA) (US) Kyverna Therapeutics, Inc. US United States (USA) (US)

How to cite

APA:

Dehdashtian, E., Hu, G., Whiteman, L., Islam, M.T., Gallucci, S., Garber, M.,... Caricchio, R. (2026). Neutrophil transcriptomics in SLE reveals intrinsic disease signatures, shared ex vivo adaptation, and transcriptional reset after CAR T-cell therapy. Annals of the Rheumatic Diseases. https://doi.org/10.1016/j.ard.2026.02.013

MLA:

Dehdashtian, Ehsan, et al. "Neutrophil transcriptomics in SLE reveals intrinsic disease signatures, shared ex vivo adaptation, and transcriptional reset after CAR T-cell therapy." Annals of the Rheumatic Diseases (2026).

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