Plasmacytoid DCs From Patients With Sjögren's Syndrome Are Transcriptionally Primed for Enhanced Pro-inflammatory Cytokine Production

Frontiers in Immunology. 2019;10 DOI 10.3389/fimmu.2019.02096

 

Journal Homepage

Journal Title: Frontiers in Immunology

ISSN: 1664-3224 (Online)

Publisher: Frontiers Media S.A.

LCC Subject Category: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML, ePUB, XML

 

AUTHORS

Maarten R. Hillen (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Maarten R. Hillen (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Aridaman Pandit (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Aridaman Pandit (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Sofie L. M. Blokland (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Sofie L. M. Blokland (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Sarita A. Y. Hartgring (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Sarita A. Y. Hartgring (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Cornelis P. J. Bekker (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Cornelis P. J. Bekker (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Eefje H. M. van der Heijden (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Eefje H. M. van der Heijden (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Nila H. Servaas (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Nila H. Servaas (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Marzia Rossato (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Marzia Rossato (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Marzia Rossato (Department of Biotechnology, University of Verona, Verona, Italy)
Aike A. Kruize (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Joel A. G. van Roon (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Joel A. G. van Roon (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Timothy R. D. J. Radstake (Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)
Timothy R. D. J. Radstake (Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 14 weeks

 

Abstract | Full Text

Primary Sjögren's syndrome (pSS) is a systemic auto-immune disease typified by dryness of the mouth and eyes. A majority of patients with pSS have a type-I interferon (IFN)-signature, which is defined as the increased expression of IFN-induced genes in circulating immune cells and is associated with increased disease activity. As plasmacytoid dendritic cells (pDC) are the premier type-I IFN-producing cells and are present at the site of inflammation, they are thought to play a significant role in pSS pathogenesis. Considering the lack of data on pDC regulation and function in pSS patients, we here provided the first in-depth molecular characterization of pSS pDCs. In addition, a group of patients with non-Sjögren's sicca (nSS) was included; these poorly studied patients suffer from complaints similar to pSS patients, but are not diagnosed with Sjögren's syndrome. We isolated circulating pDCs from two independent cohorts of patients and controls (each n = 31) and performed RNA-sequencing, after which data-driven networks and modular analysis were used to identify robustly reproducible transcriptional “signatures” of differential and co-expressed genes. Four signatures were identified, including an IFN-induced gene signature and a ribosomal protein gene-signature, that indicated pDC activation. Comparison with a dataset of in vitro activated pDCs showed that pSS pDCs have higher expression of many genes also upregulated upon pDC activation. Corroborating this transcriptional profile, pSS pDCs produced higher levels of pro-inflammatory cytokines, including type-I IFN, upon in vitro stimulation with endosomal Toll-like receptor ligands. In this setting, cytokine production was associated with expression of hub-genes from the IFN-induced and ribosomal protein gene-signatures, indicating that the transcriptional profile of pSS pDCs underlies their enhanced cytokine production. In all transcriptional analyses, nSS patients formed an intermediate group in which some patients were molecularly similar to pSS patients. Furthermore, we used the identified transcriptional signatures to develop a discriminative classifier for molecular stratification of patients with sicca. Altogether, our data provide in-depth characterization of the aberrant regulation of pDCs from patients with nSS and pSS and substantiate their perceived role in the immunopathology of pSS, supporting studies that target pDCs, type-I IFNs, or IFN-signaling in pSS.