4.Discussion
In this study, we have shown that serum CXCL13 levels were significantly higher in SLE patients, especially in the SLE anti-dsDNA-positive group. Moreover, we found the same tendency towards a significant decrease in the serum levels of CXCL13 after treatment between the SLE anti-dsDNA-positive group and the SLE anti-dsDNA-negative group. Furthermore, the SLE patients with severe disease activity had median levels of CXCL13 that were more than three times as high as those with no/mild disease activity or moderate disease activity. In addition, the levels of CXCL13 were significantly elevated in the renal involvement group and active LN group. CXCL13 levels were positively correlated with SLEDAI, the levels of anti-dsDNA, and ESR. However, CXCL13 levels were negatively correlated with complement levels of C3 and C4. This is consistent with previous research [7,9,17]. We first introduced the concept of an “HA IgG ANA” in our previous report [16]. Of interest, we demonstrated that CXCL13 levels were significantly higher in the high-avidity IgG ANA group than in the low-avidity IgG ANA group. Furthermore, the concentration of CXCL13 was positively correlated and significantly correlated with the RAI of HA IgG ANAs.
In our study, we enrolled the SLE group, RA group, other autoimmune diseases group and healthy control group as our research subjects at the same time. We subdivided the patients in the SLE group into two groups based on the presence and absence of anti-dsDNA (anti-dsDNA-positive and anti-dsDNA-nagative groups). The results presented here demonstrated that the levels of CXCL13 were significantly increased in the SLE anti-dsDNA-positive group compared with those in the other four groups. However, there were no differences in serum CXCL13 levels among the SLE anti-dsDNA-negative group, RA group and other autoimmune diseases group. Difference research has identified that SLE, RA, and Sjögren's syndrome are associated with the levels of CXCL13, as in previous studies [18]. Through cross-examination, we found more clearly that when CXCL13 coexisted with high levels of anti-dsDNA, the concentration of CXCL13 reached its peak value. These results indicate that CXCL13 may contribute somewhat to the production of anti-dsDNA antibodies. It is speculated that the production of CXCL13 by immune-activated cells may lead to the aggregation of antibody-producing B cells into the target organ, where destructive autoantibodies such as anti-dsDNA are released in large quantities, leading to significant tissue damage. This is in line with the results of a previous study[19]. It is well known that SLE, RA and other autoimmune diseases are characterized by increased production of autoantibodies that are produced long before the onset of clinical symptoms, leading to more chronic and severe consequences. Our results showed that there was a correlation between CXCL13 levels and SLE as well as RA and other autoimmune diseases. It was recommended that anti-dsDNA-negative SLE, RA and other autoimmune disease patients have significantly increased serum CXCL13 levels compared with healthy controls, although previous studies have never discussed this topic before[9]. It was suggested that CXCL13 plays a key role in the differentiation of B lymphocytes into plasma cells to generate antibodies [6]. However, the disease activity and correlation factors between CXCL13 and RA and other autoimmune diseases should be further studied.
Moreover, we first evaluated the regulatory response of serum concentrations of CXCL13 and anti-dsDNA IgG levels before and after treatment between the SLE anti-dsDNA-positive group and the SLE anti-dsDNA-negative group. Although Lee and co-workers divided SLE patients into anti-dsDNA-positive and anti-dsDNA- negative groups, they observed significantly different levels of CXCL13 between these groups before treatment[8]. Of note, CXCL13 serum levels remained significantly elevated in anti-dsDNA-negative SLE patients, probably demonstating aberrant B cell trafficking, even in remission. We further found the same tendency towards a significant decrease in the serum levels of CXCL13 after treatment, which was the same as the tendency of the anti-dsDNA levels. The present results indicate that CXCL13 is of great value for the prognosis of SLE, especially in the absence of anti-dsDNA antibodies.
As previous studies report, serum CXCL13 levels were associated with disease activity by the SLE Disease Activity Index (SLEDAI) and active lupus nephritis[20]. Consistent with the results of previous research, our study also showed that serum CXCL13 levels wererelated to SLEDAI in different disease activities of SLE, and the concentration of CXCL13 was higher in patients with renal involvement and active LN disease. Additionally, high baseline serum CXCL13 levels identify recent onset of inflammation with better response to early aggressive treatment in SLE patients. The mechanism of CXCL13 and SLE or CXCL13 and LN has attracted more attention from many scholars. It is well known that different chemokines are involved in the pathogenesis of LN by coordinating the pro-inflammatory microenvironments, recruiting immune cell subsets into the kidney, and inducing local activation of immune effector cells[21]. Different studies have consistently demonstrated that CXCL13 induces B cell infiltration into the kidneys via its receptor CXCR5 and enhances albuminuria and organ damage[22]. However, its exact place within the mechanisms that lead to SLE remains to be defined.
As previously reported, serum circulation of CXCL13 is positively related to disease activity (SLEDAI) and the concentrations of anti-dsDNA in SLE patients, but CXCL13 is negatively related to the complement factor C3. Likewise, the serum concentration of CXCL13 positively correlated with the SLEDAI, anti-dsDNA levels and ESR but negatively correlated with the complement factors of C3 and C4 in SLE patients in the present study. Circulating CXCL13 is a suitable supplementary biomarker of SLE activity. Furthermore, we found that the serum CXCL13 levels were robust in discriminating patients with active and inactive SLE, with an AUC of 0.832 (95% CI 0.741–0.922, P < 0.0001), and the sensitivity and specificity were 89 and 90%, respectively, according to the ROC curve analysis, which is consistent with results from a previous study[9].
In our previous reports, the concept of an “HA IgG ANA” that could distinguish between early-stage SLE and SLE that had been active for some time was firstly introduced . Our results indicated that the prevalence of HA IgG ANAs was significantly higher in the SLE groups. Notably, the serum concentration of CXCL13 in the HA group was similar to that of the active SLE group and LN group. In addition, we found that the level of serum CXCL13 was positively correlated with the RAI of HA IgG ANAs. Taken together, our results indicated that the high baseline plasma CXCL13 levels reflected the recent onset of inflammation with a better response to early aggressive treatment, which is consistent with a previous study[23]. This could also serve as a “window of opportunity” to treat SLE patients with very high CXCL13 levels accordingly.
Our study had several limitations. The experiment contained an insufficient number of people, and we should require a larger sample size to certify our conclusion. Moreover, we did not observe whether different treatments influenced the CXCL13 concentration. Therefore, we intend to study the correlation between treatment with complements C3 and C4 and CXCL13 levels, which requires further study.
In conclusion, our study demonstrated a clinical evaluation of circulation CXCL13 in SLE patients. The concentrations of CXCL13 could be used to identify the disease and the activity of SLE and LN. In addition, CXCL13 might promote the inflammatory process in SLE. Moreover, HA IgG ANAs might affect the concentration of CXCL13. Therefore, the chemokine CXCL13 might be a risk factor influencing the inflammatory process in SLE.