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Systems biology demonstrates the predominant role of circulating interferon-alpha in primary Sjögren's syndrome and a genetic association with the class II HLA DQ locus

ABSTRACT: Primary Sjögren’s syndrome (pSS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. No specific immunomodulatory drug has demonstrated efficacy for this disease, and no biomarker is available to identify patients at risk of developing systemic complications. To characterize the molecular and clinical variability across pSS patients, we integrated transcriptomic, proteomic, cellular and genetic data with clinical phenotypes in a cohort of 351 pSS patients. Unbiased global transcriptomic analysis revealed an IFN gene signature as the strongest driver of transcriptomic variability. The resulting stratification was replicated in three independent cohorts. As transcriptomic analysis did not discriminate between type I and II interferons, we applied digital ELISA to find that the IFN transcriptomic signature was driven by circulating IFNɑ protein levels. This cytokine, detectable in 75% of patients, was significantly associated with clinical and immunological features of disease activity at enrollment, and with increased frequency of systemic complications during the 5-year follow-up. Genetic analysis revealed a significant association between IFNɑ protein levels and an MHC-II HLA-DQ locus and anti-SSA antibody. Additional cellular analysis revealed that the polymorphism acts through upregulation of HLA II molecules on conventional DCs. Our unbiased analysis thus identified the predominance of IFNα as driver of pSS variability, and revealed an association with HLA gene polymorphisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140161 | GEO | 2020/11/04

REPOSITORIES: GEO

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Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by infiltration of the exocrine glands and prominent B cell hyperactivity. Considering the key role of monocytes in promoting B cell hyperactivity, we performed RNA-sequencing analysis of CD14+ monocytes from patients with pSS, non-Sjögren’s sicca (nSS), and healthy controls (HC). We demonstrated that the transcriptomic profile of pSS patients is enriched in intermediate and non-classical monocyte profiles, and confirmed the increased frequency of non-classical monocytes in pSS patients by flow-cytometry analysis. Weighted gene co-expression network analysis identified four molecular signatures in monocytes from pSS patients, functionally annotated for processes related with translation, IFN-signaling, and toll like receptor signaling. Systemic and local inflammatory features significantly correlated with the expression of these signatures. Furthermore, genes highly associated with clinical features in pSS were identified as hub-genes for each signature. Unsupervised hierarchical cluster analysis of the hub-genes identified four clusters of nSS and pSS patients, each with distinct inflammatory and transcriptomic profiles. One cluster showed a significantly higher percentage of pSS patients with higher prevalence of anti-SSA autoantibodies, interferon score, and erythrocyte sedimentation rate compared to the other clusters. Finally, we showed that the identified transcriptomic differences in pSS monocytes were induced in monocytes of healthy controls by exposure to serum of pSS patients. Representative hub-genes of all four signatures were partially inhibited by interferon-a/b receptor blockade, indicating that the circulating inflammatory mediators, including type I interferons have a significant contribution to the altered transcriptional profile of pSS-monocytes. Our study suggests that targeting key circulating inflammatory mediators, such as type I interferons, could offer new insights into the important pathways and mechanisms driving pSS, and holds promise for halting immunopathology in Sjögren’s Syndrome.

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Systems biology demonstrates the predominant role of circulating interferon-alpha in primary Sjögren's syndrome and a genetic association with the class II HLA DQ locus

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