Although some biomarkers have been used as indicators of inflammatory activity in the lungs of DM, the pathogenesis of DM-ILD is unknown and still needs to be explored. Our study is of great significance. We demonstrated for the first time that serum LGALS3BP levels are elevated in DM patients and that serum LGALS3BP levels are associated with disease activity and may be involved in the pathogenesis of DM-ILD, which provides new insights into the pathogenesis of DM-ILD.
Type I interferon (IFN-Ⅰ) is involved in the pathogenesis of several autoimmune diseases. According to one report, the two autoimmune disorders with the highest levels of IFN score upregulation are SLE and IIM [25]. Additionally, type I interferon-induced stimulated genes (ISGs) accounted for up to 21 of the 25 highly expressed genes in the skin of DM patients [26]. In addition, LGALS3BP is highly connected in ISGs and is the center of IFN-Ⅰ connected immunity [27]. The association between LGALS3BP and IFN-Ⅰ in autoimmune diseases has been validated, e.g., in SLE patients, LGALS3BP levels were significantly correlated with IFN-Ⅰ scores; the expression of LGALS3BP was significantly increased after stimulation of PBMCs with IFN-α inducer, and was significantly decreased after addition of IFN-α inhibitor [28–30]. Together, these mechanisms may provide evidence for elevated serum LGALS3BP levels in IIM patients.
In our study, LGALS3BP may be involved in the pathogenesis of DM-ILD patients. Here we present this conclusion based on two points. First, from the macrophage side, different phenotypic characteristics and activation imbalance of macrophages are crucial in DM-ILD. On the one hand, a study analyzing serum cytokines in patients with PM/DM-ILD found that cytokines produced by M1 macrophages and M2 macrophages were closely associated with the pathogenesis and poor prognosis of PM/DM-ILD [31]. On the other hand, the number of macrophages infiltrating the lungs of patients with RP-ILD was significantly increased compared to those with C-ILD and without ILD [32]. In addition, macrophages play a key role in the production of LGALS3BP. Studies have demonstrated that LGALS3BP is a marker of macrophage inflammation, and it has been shown that LGALS3BP is mainly produced by M1 macrophages [33]. We propose the hypothesis that increased macrophages infiltrating the lungs of DM-ILD patients promote the secretion of LGALS3BP, which further stimulates cytokine production thereby participating in the pathogenesis of DM-ILD. In our study, serum LGALS3BP levels were higher in patients with RP-ILD than in patients with C-ILD and without ILD preliminarily validating our hypothesis. However, no concrete evidence supports the theory that macrophages cause elevated serum LGALS3BP levels in DM-ILD patients. Furthermore, Xiaohu Zhao et al. [34] showed increased infiltration of activated NK cells, M1, and M2 macrophages in DM muscle by immune cell infiltration analysis. In our findings, Serum LGALS3BP levels were higher in DM patients with muscle involvement than in those without, which further validated our hypothesis. Second, from the galectin-3 side, several studies have reported that galectin-3 is highly expressed in various fibrotic tissues and is a marker of fibrosis. Galectin-3 induces pulmonary fibrosis by promoting the activity of TGF-β, which is a crucial mediator of fibrosis [35]. TD139, an inhibitor that targets galectin-3, has entered clinical trials. The antifibrotic potential of TD139 lies mainly in inhibiting the growth of galectin-3-secreting macrophages and the blockade of TGF-β function, which has been shown to slow the progression of fibrosis [35, 36]. Interestingly, galectin-3 is the most studied interaction partner of LGALS3BP and a possible candidate biomarker of fibrosis.
There have been reports that patients with inflammatory bowel disease have higher serum levels of LGALS3BP, a novel predictive biomarker of responsiveness to infliximab treatment in IBD patients, which correlates positively with inflammatory markers like CRP [37]. This is similar to our findings. First, our study found that serum LGALS3BP levels in DM patients were correlated with disease activity and inflammatory markers, including CRP. This finding was significant for DM patients, suggesting that LGALS3BP may be a marker of DM disease activity. Second, we found that serum LGALS3BP levels in DM patients changed in response to treatment. However, due to the small sample size, changes in serum LGALS3BP levels before and after treatment were not sufficient to reach statistically significant levels. Interestingly, there was one patient whose LGALS3BP level increased instead after treatment, and a review of this patient's medical record revealed that this patient was repeatedly hospitalized and responded poorly to treatment. This suggests that serum LGALS3BP can be a valuable parameter for monitoring the response to therapy in patients with DM.
In our study, there was a strong correlation between LGALS3BP and IL-6. IL-6 is a significant contributor to ILD in DM, correlates with MDA5 antibody titers, and can indicate response to therapy in DM patients [38]. Growing evidence that IL-6 is produced by LGALS3BP stimulation. D2, a recombinant fragment of the LGALS3BP-binding region, stimulates IL-6 expression in colon and lung epithelial cell lines, and treatment with anti-LGALS3BP monoclonal antibody significantly reduced the increase in IL-6 secretion following D2 stimulation [39]. Furthermore, LGALS3BP stimulation of macrophages leads to a significant increase in IL-6 expression, especially in the presence of IFN-Ⅰ [15, 40].In conclusion, these data support the role of LGALS3BP's ability to stimulate an increase in IL-6 secretion in the inflammatory process of the disease. This inflammatory factor has been implicated in the inflammatory process of DM.
There were some limitations to this study. Firstly, this study was retrospective, which may have led to some bias. Secondly, the sample size in the IMNM group was small because fewer patients were diagnosed with IMNM at our institution when the patients' sera were collected. Thirdly, we excluded patients with concomitant tumors because LGALS3BP expression was elevated in most patients with tumors, so some antibodies were underrepresented, such as TIF1γ, and the probability of synchronous tumors was significantly higher in TIF1γ-positive patients [41, 42]. Finally, most of the data came from a cross-section of DM patients. Future studies need to focus on larger longitudinal cohorts of DM to assess the value of LGALS3BP as a predictive biomarker.