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

Ana P Lopes; Maarten R Hillen; Anneline C Hinrichs; Sofie Lm Blokland; Cornelis Pj Bekker; Aridaman Pandit; Aike A Kruize; Timothy Rdj Radstake; Joel A van Roon

doi:10.1136/ard-2022-222728

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

Ann Rheum Dis. 2023 Mar;82(3):374-383. doi: 10.1136/ard-2022-222728. Epub 2022 Sep 28.

Authors

Ana P Lopes^{1

2}, Maarten R Hillen^{1

2}, Anneline C Hinrichs^{1

2}, Sofie Lm Blokland^{1

2}, Cornelis Pj Bekker^{1

2}, Aridaman Pandit^{1

2}, Aike A Kruize¹, Timothy Rdj Radstake^{1

2}, Joel A van Roon^{3

2}

Affiliations

¹ Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
² Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
³ Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands j.vanroon@umcutrecht.nl.

Abstract

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.

Keywords: Autoantibodies; Autoimmunity; Inflammation; Sjogren's Syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoimmunity
Epithelial Cells / metabolism
Humans
Interferon Type I* / genetics
Interferon-alpha
Sjogren's Syndrome*
Transcriptome

Substances

Interferon-alpha
Interferon Type I