Deciphering the role of cDC2s in Sjögren's syndrome: transcriptomic profile links altered antigen processes with IFN signature and autoimmunity.

Autor:	Lopes AP; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Hillen MR; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Hinrichs AC; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Blokland SL; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Bekker CP; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Pandit A; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Kruize AA; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Radstake TR; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van Roon JA; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands j.vanroon@umcutrecht.nl.; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2023 Mar; Vol. 82 (3), pp. 374-383. Date of Electronic Publication: 2022 Sep 28.
DOI:	10.1136/ard-2022-222728
Abstrakt:	Objective: Type 2 conventional dendritic cells (cDC2s) are key orchestrators of inflammatory responses, linking innate and adaptative immunity. Here we explored the regulation of immunological pathways in cDC2s from patients with primary Sjögren's syndrome (pSS). Methods: RNA sequencing of circulating cDC2s from patients with pSS, patients with non-Sjögren's sicca and healthy controls (HCs) was exploited to establish transcriptional signatures. Phenotypical and functional validation was performed in independent cohorts. Results: Transcriptome of cDC2s from patients with pSS revealed alterations in type I interferon (IFN), toll-like receptor (TLR), antigen processing and presentation pathways. Phenotypical validation showed increased CX3CR1 expression and decreased integrin beta-2 and plexin-B2 on pSS cDC2s. Functional validation confirmed impaired capacity of pSS cDC2s to degrade antigens and increased antigen uptake, including self-antigens derived from salivary gland epithelial cells. These changes in antigen uptake and degradation were linked to anti-SSA/Ro (SSA) autoantibodies and the presence of type I IFNs. In line with this, in vitro IFN-α priming enhanced the uptake of antigens by HC cDC2s, reflecting the pSS cDC2 profile. Finally, pSS cDC2s compared with HC cDC2s increased the proliferation and the expression of CXCR3 and CXCR5 on proliferating CD4 + T cells. Conclusions: pSS cDC2s are transcriptionally altered, and the aberrant antigen uptake and processing, including (auto-)antigens, together with increased proliferation of tissue-homing CD4 + T cells, suggest altered antigen presentation by pSS cDC2s. These functional alterations were strongly linked to anti-SSA positivity and the presence of type I IFNs. Thus, we demonstrate novel molecular and functional pieces of evidence for the role of cDC2s in orchestrating immune response in pSS, which may yield novel avenues for treatment. Competing Interests: Competing interests: TRDJR was the principal investigator in the immune catalyst programme of GlaxoSmithKline, which was an independent research programme. He did not receive any financial support other than the research funding for the current project. Currently, He is an employee of Abbvie, where he holds stock. He had no part in the design and interpretation of the study results after he started at Abbvie.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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