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

Abstract

ObjectiveType 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).MethodsRNA 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.ResultsTranscriptome 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.ConclusionspSS 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.

Clinical characteristics and risk factors of Helicobacter pylori infection‐associated Sjogren's syndrome

“…Notably, the exclusion criteria were set as follows: (a) The age of patients lesser than 20 years old; (b) patients with incomplete or missing data; (c) patients diagnosed with gastric cancer; (d) patients diagnosed with other infectious diseases (tuberculosis, Epstein‐Barr virus, EBV, cytomegalovirus, CMV, and human immunodeficiency virus, HIV); (e) patients with negative H. pylori infection result after systemic H. pylori treatment; and (f) Patients with a history of antibiotic usage within 4 weeks before gastroscopy. Considering these criteria, a total of 689 patients were first included in this study, along with the subjects who satisfied the 2002 classification criteria of the American‐European Consensus Group (AECG) for pSS 11 . Further, the final count of 224 cases was recruited, of which 94 cases were H. pylori ‐positive pSS and 130 cases were H. pylori ‐negative pSS patients (Figure 1).…”

“…Considering these criteria, a total of 689 patients were first included in this study, along with the subjects who satisfied the 2002 classification criteria of the American‐European Consensus Group (AECG) for pSS. 11 Further, the final count of 224 cases was recruited, of which 94 cases were H. pylori ‐positive pSS and 130 cases were H. pylori ‐negative pSS patients (Figure 1 ).…”

The Spectrum of Extraglandular Manifestations in Primary Sjögren’s Syndrome

“…Type 2 conventional dendritic cells (cDC2s) from patients with pSS are transcriptionally altered, inducing increased chemokine receptor CXCR5 expression and proliferation of tissue homing CD4+ T cells in pSS salivary glands [ 300 ]. Further investigation of cDC2s pathway in pSS may lead to future, more efficient therapies for patients [ 301 ].…”

Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response

“…Further, treatment of healthy controls' cDC2s with IFN-α in vitro leads to impairment of antigen processing and increased antigen uptake capacity in these cells, reaching levels similar to those seen in patients with pSS. 118 Additionally, it has been proposed that the aberrant release of NETs could be another mechanism associated with IFN-I dysregulation in pSS. In this sense, local IFN-I could lead to mitochondrial damage and increase reactive oxygen species production by neutrophils, with subsequent increased NETosis and eventual salivary gland damage.…”