CXCL9 may serve as a potential biomarker for primary Sjögren’s syndrome with extra-glandular manifestations

Abstract

Background Primary Sjögren's syndrome (pSS) is an autoimmune condition that causes harm to exocrine glands and also has extra-glandular manifestations (EGM). pSS patients with EGM have a worse prognosis than those with only sicca symptoms. Previous studies have shown that the minor salivary glands (MSG) of pSS patients exhibit a unique profile of cytokines and chemokines compared to healthy controls. However, there is a lack of research comparing pSS with EGM (pSS-EGM) and pSS without EGM (pSS-non-EGM). This study aims to explore potential biomarkers associated with pSS, particularly pSS with EGM. Methods By utilizing RNA sequencing, we conducted an analysis on the gene expression profiles of MSG in 63 patients diagnosed with pSS, as well as 12 non-pSS individuals. Furthermore, we also investigated the MSG of pSS patients, both with and without EGM. Through bioinformatics analysis, we identified genes with differential expression (DEGs) and determined the core hub genes using PPI network. We then analyzed the top 20 DEGs and their correlation with the patients' clinical characteristics, and validated our findings using peripheral blood plasma. Results A total of 725 differentially expressed genes (DEGs) were identified in the comparison between pSS and non-pSS groups, and 727 DEGs were observed between pSS-EGM and pSS-non-EGM. It is noteworthy that the expression levels of CXCL9 were higher in both pSS patients and pSS-EGM when compared to the control group. Taking into consideration the significance of the top 20 DEGs in relation to clinical parameters and the central hub genes, we ultimately chose CXCL9. In comparison to the non-pSS group, pSS patients exhibited notably greater expression of the CXCL9 gene in the MSG, as well as higher levels of CXCL9 protein in their plasma (p < 0.001). Furthermore, the expression of the CXCL9 gene and levels of CXCL9 protein were notably higher in pSS patients accompanied by EGM and those with SSA antibodies. Additionally, a correlation was found between the expression of the CXCL9 gene and the EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI), as well as with immunoglobulin G (IgG) levels and erythrocyte sedimentation rate (ESR). Meanwhile, the protein levels of CXCL9 were found to be correlated with IgG levels and ESSDAI. Conclusion CXCL9 proves to be a valuable biomarker in pSS, specifically due to its strong ability to differentiate between pSS patients with EGM and those without EGM. There is a significant correlation between CXCL9 and various clinical parameters both at the gene and protein level. Therefore, CXCL9 could be a potential target for future treatment of pSS.

Role of chemokines CXCL9, CXCL10, CXCL11, and CXCR3 in the serum and minor salivary gland tissues of patients with Sjögren’s syndrome

“…Contrary to other studies, serum CXCL9 levels in pSS did not show significant differences compared with RA and HC in this study [ 27 ]. In previous studies using patients with pSS or SS-like mouse models, CXCL9 expression increased significantly in most cases [ 27 , 28 ].…”

“…Contrary to other studies, serum CXCL9 levels in pSS did not show significant differences compared with RA and HC in this study [ 27 ]. In previous studies using patients with pSS or SS-like mouse models, CXCL9 expression increased significantly in most cases [ 27 , 28 ]. In studies similar to ours, insignificant results were obtained, possibly because of accompanying clinical features or serological characteristics [ 29 ].…”

“…The higher the expression levels of each chemokine in the tissue, the better they reflected the clinical symptoms. In this study, the tissue expression level of CXCL9 was found to correlate with the inflammation and hematologic abnormalities observed in pSS, which is consistent with previous reports, indicating that CXCL9 is more significantly expressed in pSS patients with extraglandular manifestations [ 27 ]. Although CXCL10 and CXCL11 showed a relatively lower capability to reflect clinical symptoms than CXCL9 in minor salivary gland tissue, significant findings emerged, indicating that CXCL11 expression increases notably with severe salivary gland dysfunction, as confirmed by salivary gland scintigraphy.…”