cSLE, a common chronic systemic autoimmune disease in children, involves multiple systems and organs throughout the body; its clinical manifestations are complex, the course of the disease is protracted, and the disease can recur[14]. The pathogenesis of cSLE is not fully clear, but this disease mainly involves dysregulation of the immune system, including excessive T and B cell activation, providing large amounts of a variety of autoantibodies, and immune complex deposition, which causes multiple organ damage[4, 15]. Disruption of the immune state may be the key mechanism in a range of autoimmune diseases, including SLE. T cell-mediated immunoreaction plays an important role in specific immunity in the human body. One of the characteristics of SLE is abnormality in the differentiation and regulation of T cells. Previous studies found that the pathogenesis of SLE is related to an imbalance in the proportion of regulatory T (Tregs) cells and helper T (Th) cells and an increase in the proportion of Th cells[16]. The Th subgroup itself is also altered during the development of SLE. In recent years, Th cells have been found to play an important role in autoimmune diseases by secreting a variety of cytokines and mediating interactions between cells. Overexpression of IL-6, IL-10, IL-17, and TNF-α, etc., plays an important role in the pathogenesis of SLE, polymyositis (PM), dermatomyositis (DM) and rheumatoid arthritis (RA) and is significantly related to disease activity[17–19]. SLE is a prototypical autoimmune disease. Cytokines play an important role in the pathogenesis of SLE and determine the degree of disease activity.
In this study, serum IL-2 levels were increased in children with cSLE and positively correlated with disease activity. The level of IL-2 in active cSLE was significantly higher than that in inactive cSLE. IL-2 is a soluble molecule that promotes the clonal proliferation of T cells. Mice and people deficient in IL-2 were shown to develop severe autoimmune diseases, possibly due to the uncontrolled proliferation of autoreactive T cells and B cells and the proliferation of immature, non-functional Tregs caused by their defects. Recent studies have shown that small doses of IL-2 can selectively promote the growth of Treg cells[20]. In addition, low-dose IL-2 treatment in adult SLE patients increased Tregs in the blood and reduced the number of Th17 cells, thus exerting an immunosuppressive effect. At the same time, the SLEDAI-2K score after 12 weeks of treatment was found to be significantly reduced compared with that before treatment, and hormone levels were reduced, significantly alleviating disease[21]. It was also found in mouse studies that IL-2 can regulate the Th17 cell/Treg balance, enhance the function of Tregs, and inhibit Th17 cell differentiation[22]. Interestingly, based on laboratory test results in the literature and in our study, serum IL-2 deficiency was not observed in either adults with SLE or children with cSLE, especially active SLE. The role of IL-2 in the pathogenesis of SLE and whether low-dose treatment with IL-2 is as equally effective in children with cSLE compared with adults with SLE remain to be clarified in further studies.
IL-6, which can be secreted by a variety of immune cells, mainly functions to stimulate the proliferation and differentiation of B cells and their development into mature B cells capable of secreting antibodies. IL-6 also stimulates the IL-2 receptor, which, as it induces the growth of T cells and differentiation of cytotoxic T cells, plays an important role in immune activation. The expression of IL-6 and IL-6r in various lupus mouse models was upregulated. However, the rates of IgG and complement C3 deposition and the permeability of macrophages in IL-6-deficient mice were decreased compared with those in normal mice. Increased expression of IL-6 in SLE patients is associated with anti-dsDNA, an indicator of SLE. Our study also shows that the expression level of serum IL-6 in children with cSLE was positively correlated with the degree of disease activity, indicating a potential certain correlation between IL-6 and the pathogenesis of SLE. In studies of adults with SLE, IL-6 was found to be associated with anaemia in patients with lupus nephritis. Furthermore, the higher the IL-6 concentration is, the more severe the anaemia is[23]. Additionally, IL-6 can stimulate activation of the STAT3 signalling pathway, reduce the cell circulation speed in the blood and prevent the apoptosis of immune cells[24]. In addition, IL-6 can inhibit the proliferation of Tregs and promote the development of autoimmunity[25]. All these results suggest the possibility of IL-6 as a predictor of SLE.
In this study, the serum IL-10 level in children with cSLE was significantly higher than that in the normal group, and the IL-10 level in the active stage was significantly higher than that in the inactive stage. IL-10 is an anti-inflammatory cytokine, and Th2 cells and various types of regulatory T cells are generally thought to be the source of its production in T cells. IL-10 stimulates B cell proliferation and IgG synthesis. Previous studies have confirmed that the IL-10 gene is a susceptibility gene for SLE. In adult patients with SLE, serum levels of IL-10 were positively correlated with the SLEDAI-2K score and anti-dsDNA antibody levels, consistent with the results of this study. IL-10 can inhibit cytokine production, downregulate monocyte antigen presentation and co-stimulation, and inhibit T cell proliferation, thereby increasing immunosuppression and achieving anti-inflammatory effects[26]. Although IL-10 plays a typical role in the immune process, recent studies have shown that IL-10 also plays a role in cytokine activation and induction. In the investigation of SLE patients, IL-10 was found to be associated with the pathogenesis of SLE, and when IL-10 mRNA levels in peripheral blood mononuclear cells from the patients and healthy controls were detected by competitive primer PCR, a difference was found between the two. In a study by Liu et al., the serum IL-10 level was significantly higher in patients than in the healthy control group, and IL-10 was positively correlated with the SLEDAI-2K score[27], consistent with the conclusions of our study.
The authors found that serum IL-21 levels in children with cSLE were significantly higher than those in the normal group, and IL-21 levels in the children with inactive cSLE were remarkably higher than those in the healthy control group. IL-21 can activate B cells to secrete IgG1 and IgG3 and induce all B cell subsets to differentiate into Ig-secreting cells, thus producing large amounts of IgM, IgG and IgA[28]. IL-21 produced by Tfh cells plays a major role in the initial immune response, secondary immune response, and long-term maintenance of humoural immunity of B cells to T cell-dependent antigens. Terrier et al found that serum IL-21 levels in SLE patients were significantly increased compared with those in a healthy control group, which is consistent with the results of this study. The study also indicated that IL-21 is closely related to changes in peripheral blood T cells and B cell subtypes, and IL-21 has certain therapeutic prospects as a target in SLE patients[29]. Thus, the significant increase in Tfh cell-related cytokine IL-21 levels in the serum of children with cSLE suggests that Tfh cells also play a crucial role in the pathogenesis of cSLE in children. The immune system stimulates B cells by producing cytokines such as IL-21, causing abnormal humoural immune responses and participating in the pathogenesis of cSLE. In view of this, IL-21 may become a target molecule for the treatment of SLE in children, and the study of Tfh cell-related cytokines will also open up new approaches for the treatment of SLE in children.
IL-22 is produced by a variety of cell types, including Th17 cells, natural killer (NK) cells, and Th22 cells. Th22 cells are the main cell type that secretes IL-22. Research by Lin et al. showed that in patients with newly diagnosed SLE, the concentration of IL-22 was reduced compared with that of patients with relapsed SLE and healthy controls[30]. In our study, the serum IL-22 concentration in cSLE was lower than that of the normal group, and the IL-22 level in children with active disease was significantly different from that of children in the normal group, consistent with the results of a previous study on SLE in adults. This finding suggests that IL-22 plays an opposite role in the pathogenesis of this disease. However, in a study by Zhao et al., the serum IL-22 concentration in SLE patients was significantly higher than that in the normal group. After glucocorticoids were administered to the patients, the number of cells associated with IL-22 secretion was reduced. IL-22 is believed to play a role in the development of this disease. Under normal circumstances, Th22 cells, Th17 cells, Treg cells and other cell subsets interact and regulate each other to maintain the body in a state of immune equilibrium. In chronic inflammatory diseases, loss of the functions of key transcription factors that regulate Th22 cell differentiation exacerbates the occurrence of chronic inflammatory diseases[31]. The decreased number of Th22 cells in SLE patients may be because AhR, a key transcription factor that regulates Th22 cell differentiation, directly or indirectly regulates the production and secretion of inflammatory cytokines such as IL-22, leading to immune imbalance in different immune cell subsets[32, 33]. This also suggests that changing or promoting the pathways upstream or downstream of Th22 cell differentiation may reduce the immune inflammatory response in SLE, and cytokine levels in Th22 cells may be used as a potential target and auxiliary marker for the diagnosis and treatment of SLE.
Our study has several limitations. First, there was a minimum detection concentration in our detection kit, so we have to eliminate the data below the detection lower limit, which may bring some interference to the research results. Second, patients were treated with drugs before the test, although no correlation between different drugs and cytokine levels were found in our study, it may still influence the results to some extent. Third, it is a small sample study, further randomized and controlled clinical trials are needed to determine the efficacy of this cytokines in predicting activity in cSLE. However, the strength of the study was that for the first time, we comprehensively analyzed the level of serum Th cytokines in cSLE and its correlation with disease activity.