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Wasserer, S.* ; Seiringer, P.* ; Kurzen, N.* ; Jargosch, M. ; Eigemann, J. ; Aydin, G.* ; Raunegger, T.* ; Schmidt-Weber, C.B. ; Eyerich, S. ; Biedermann, T.* ; Eyerich, K.* ; Lauffer, F.*

TYK2 inhibition improves clinical and molecular hallmarks in various subtypes of cutaneous lupus.

Br. J. Dermatol., DOI: 10.1093/bjd/ljaf293 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
BACKGROUND: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease (ISD) with various clinical subtypes. Though the pathogenesis is not yet fully understood T cell mediated autoimmunity and elevated levels of type 1 interferons are two major factors contributing to the development of cutaneous lesions. Type 1 interferons transduce their signal via TYK2. OBJECTIVE: To investigate the impact of TYK2 signaling in pre-clinical models of CLE. METHODS: CLE skin biopsies were investigated by RNA-seq and immunohistochemistry. T cells isolated from CLE skin biopsies (lesional T cells) were re-stimulated with anti-CD2/anti-CD28 and cytokine release was quantified by ELISA and Luminex. Primary human keratinocytes and three-dimensional skin models were stimulated with IFN-α or lesional T-cell supernatant in presence or absence of the TYK2 inhibitor deucravacitinib followed by RNA-seq. Skin biopsies from different CLE subtypes were treated ex vivo with deucravacitinib followed by qRT-PCR. RESULTS: Bulk RNA sequencing revealed a strong correlation between TYK2 and interface dermatitis (ID), a histological hallmark of CLE. Immunohistochemistry confirmed a high abundance of TYK2 amongst different CLE subtypes. Inhibiting TYK2 reduced inflammation and normalized epidermal impairments in primary human keratinocytes, reconstructed human epidermis and CLE T cells. Ex vivo TYK2 inhibition in CLE skin biopsies reduced IFN-response- and necroptosis-related gene expression. Finally, four patients with different therapy-refractory CLE (acute, subacute, chronic discoid, chilblain CLE) were successfully treated with deucravacitinib. CONCLUSION: IFN-α and T cell derived cytokines both contribute to skin inflammation in CLE. TYK2 inhibition is a promising approach for different subtypes of CLE as it controls inflammation in various pre-clinical models and therapy refractory CLE patients.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Interferon-alpha; Immune-response; Erythematosus; Expression; Anifrolumab; Il-22
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0007-0963
e-ISSN 1365-2133
Zeitschrift British Journal of Dermatology - BJD
Verlag Wiley
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Allergy Research (IAF)
POF Topic(s) 30202 - Environmental Health
Forschungsfeld(er) Allergy
PSP-Element(e) G-505490-001
G-505400-001
Förderungen German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
Bristol Myers Squibb
DOI 10.1093/bjd/ljaf293
WOS ID 001575494200001
PubMed ID 40795287
Erfassungsdatum 2025-11-05
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