The cytokines might be involved in the development and progression of pSS-ILD. clinical symptoms and serological data including cyclic citrullinated peptide (CCP) antibody (anti-CCP), antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB, C-reactive protein, IgG, IgM, IgA, C3, C4, and 10 cytokines and chemokines were obtained. Wilcoxon test, chi-square test, Spearman correlation analysis, and logistics regression analysis were performed. Results Higher positive rates of anti-SSB and higher incidence of dry cough, dyspnea, and arthrosis symptoms were shown in pSS-ILD patients than in the pSS-N-ILD cases. Anti-CCP antibodies and cytokines (IL-1, TNF, IL-6, IL-5, IL-12p70, and IL-17) were higher, while C3 was lower in pSS-ILD patients than in pSS-N-ILD cases. Significant negative correlations of IgG with C3 and C4 and positive correlations of IL-12p70 and IL-17 with IL-6 were only shown in pSS-ILD patients. The anti-CCP antibody was positively correlated with IL-5 in pSS-ILD patients, but not in pSS-N-ILD cases. Multi-variable logistics regression analysis revealed the combination of anti-CCP, IL-17, IL-12p70, and IL-5 was effective in predicting the status of pSS-ILD in the pSS cases. Conclusion There were significant differences in serum marker levels between pSS-ILD and pSS-N-ILD cases. The combination of anti-CCP, IL-17, IL-12p70, and IL-5 might be a potential risk predictor for pSS-ILD occurrence. The cytokines might be involved in the development KDR antibody and progression of pSS-ILD. These results would provide new therapeutic targets for pSS-ILD treatment. Keywords: serum biomarkers, cytokines, primary Sj?grens syndrome, interstitial lung disease, immune response Background Primary Sj?grens syndrome (pSS) is a systemic autoimmune disease characterized by impaired functions of DNA31 exocrine glands and the involvement of multiple organs (Luppi et al., 2020a). It is typically associated with the presence of antinuclear antibodies, including anti-SSA, anti-Ro52, and anti-SSB. The extra-glandular involvement determines the prognosis of the patients. The lung is the most commonly involved extra-glandular organ and the source of DNA31 many symptoms (Mestre-Torres and Solans-Laque, 2022). Interstitial lung disease (ILD) is the main manifestation of lung dysfunctions in pSS patients. It is considered to be the most frequent and serious pulmonary complication in pSS, with a prevalence of approximately 20%, and results in significant morbidity and mortality (Luppi et al., 2020a; Gao et al., 2021; He et al., 2022; Kawada, 2022). Historically, ILD was described as a late manifestation of pSS. However, a high variability of the time of onset of pSS associated with ILD has been observed recently. In fact, from 10% to 51% of the patients can develop ILD years before the onset of pSS (Sambataro et al., 2020). While the underlying causes of pSS-ILD are not completely clear, it is believed that the cytokines from T and B cells are crucial in triggering and advancing the inflammatory processes (Zhao et al., 2013). pSS patients show an increase in Th17 cells and their characteristic cytokine IL-17, which triggers tissue injury and stimulates responses from autoreactive B cells (Pontarini et al., 2018; Verstappen et al., 2018). IL-12 can affect the production and secretion of IFN- (Fogel et al., 2018). IL-5 plays important roles in regulating the differentiation and activation of B cells (Ehrens et al., 2022). It has been noted that Th1 cells generate increased amounts of IFN- and TNF-, which not only lead to the impairment of epithelial cells and glandular function but also stimulate the activity DNA31 of other immune cells, with a particular impact on B cells (Ewert et al., 2010; Maehara et al., 2012; Ros-Ros et al., 2020). TNF- is a key pro-inflammatory cytokine with a complex involvement in the development of fibrosis (Ros-Ros et al., 2020). Sustained activation of TNF- can initiate pathological fibrosis, identified by DNA31 an excessive buildup of extracellular matrix (ECM) elements, such as collagen. This excessive accumulation of the ECM disrupts tissue integrity and diminishes organ performance, a defining attribute of fibrotic disorders (Wang et al., 2020). The crucial associations of TGF- with ILD have been reported in many studies (Godoy et al., 2024; Huang et al., 2024; Xiao et al., 2024). Noticeably, TNF- can also collaborate with TGF- to enhance the fibrotic process (Yuan, 2024). Although the disturbance of cytokine network and immune response have been reported in pSS (Rizzo et al., 2020), the pathogenesis of pSS-ILD is still poorly.
The cytokines might be involved in the development and progression of pSS-ILD
