The pathogenesis of SLE is complex and heterogeneous, rendering diagnosis and treatment of the disease very difficult. SLE also has characteristics of female dominance, immune dysregulation, multisystem involvement, and organ damage . Therefore, understanding the mechanisms of the immune dysregulation and tissue damage in female SLE patients is of particular importance. LncRNAs have many functions, including involvement in the progression of various diseases such as SLE [4, 19, 20]. Previous studies demonstrated that changes in expression of the lncRNA XIST can silence linked genes on the X chromosome that may be related to the pathogenesis of SLE in female patients [8, 9]. However, the relationships between XIST expression and SLE clinical features and the contribution of XIST to the pathogenesis of SLE at other levels remain unclear.
In the present study, we found the lncRNA XIST was significantly upregulated in SLE patients and had a good diagnostic value for SLE. Furthermore, XIST expression was elevated in young or female patients and patients with arthralgia or anti-Ro-52 antibody positivity. It was reported that SLE mainly affects young women of reproductive age, with initial signs of physical symptoms, rash, and arthritis . This suggests that XIST may be a potential biomarker for the diagnosis of early SLE. However, the sample size in the present study was not sufficiently large, and the results require verification in a large prospective cohort. Nevertheless, the present study lays a partial foundation for future cohort research.
To explore the effects of XIST on SLE at different levels, we analyzed the correlations between XIST expression and clinical features. Interestingly, we found that patients with elevated XIST expression tended to have high levels of total T cells and CD8 + T cells, but reduced levels of Treg cells, activated CD25 + lymphocytes, and NK cells. T cells contribute to the initiation and persistence of immunity in SLE and are involved in organ damage in the disease . Blanco et al.  found that activated CD8 + T cells were significantly increased, had a cytotoxic effector T cell phenotype, and generated high levels of soluble nucleosomes and granzyme B in patients with active SLE. Furthermore, CD8 + T cells not only had a role in the blood, but also accumulated and infiltrated in the glomerular guard region of the kidney, leading to tissue injury and organ pathology . On the contrary, in patients with active SLE, the number of CD4 + CD25 + Treg cells was reduced, and their inhibitory function was insufficient, allowing overactivation of other T cells to cause tissue inflammation and damage [24, 25]. Like Treg cells, the number of NK cells was significantly decreased in patients with active SLE . However, Suárez-Fueyo et al.  reported that NK cells in SLE patients exhibited increased cytotoxicity and pro-inflammatory phenotypes that were associated with down-regulation of CD3ζ. These observations are consistent with the present findings. On the one hand, XIST may promote the increase and overactivation of total T cells and CD8 + T cells by affecting the number and function of Treg cells, leading to immune dysregulation and tissue damage in SLE. On the other hand, XIST may lead to stronger cytotoxicity and inflammatory phenotypes of NK cells by reducing the number of NK cells, and ultimately reducing their protective function. Therefore, we believe that XIST has multiple regulatory effects on the immune system in SLE patients, regulating not only adaptive immunity, but also innate immunity. This is achieved by altering the balance of immune cells in the peripheral blood of SLE patients.
To explore the molecular mechanism of lncRNA XIST involvement in the pathogenesis of SLE, we constructed a ceRNA network that can reflect the regulatory mechanism of an lncRNA at the transcriptome level . A lncRNA can act as a sponge body for miRNAs to regulate gene expression . Here, we found that XIST may affect the expression of 115 genes by regulating 8 miRNAs. Enrichment analyses for these 115 genes indicated that XIST may be involved in leukocyte-mediated immunity and immune response through MAP2K and MAPK activation, C-type lectin receptor signalling pathway, or HIF-1 signalling pathway. These findings are consistent with our conclusion that XIST can change the balance of peripheral blood immune cells in SLE. Moreover, we selected two hub genes, OLFM4 and CEACAM8, to verify the accuracy and reliability of the predicted results. We found that both of these genes were significantly upregulated in SLE patients and had significant positive correlations with expression of XIST. These findings not only indicate that our prediction results are relatively reliable, but also suggest that XIST may regulate the expression of OLFM4 and CEACAM8 by acting as a spongy body for miR-20a, miR-92a, miR-106a, and miR-449a, thereby exerting its functions. Interestingly, miR-20a, miR-92a, miR-106a, and two other miRNAs, miR-17 and miR-19b, belong to the miR-17-92 cluster or its paralog . This family has been shown to play important roles in the immune system, cardiovascular system, and tumours, among others. In the adaptive immune system, miR-17-92 has a key role in the antigen response of T lymphocytes . In Treg cells, miR-17-92 is critical for the function and accumulation of Treg cells during the autoimmune-mediated stress response. Once miR-17-92 is lost, Treg cells lose their regulatory function . Similarly, both the number and function of Treg cells were partially deficient in SLE, which may be related to the low expression of miR-17-92. In CD8 + T cells, miR-17-92 decreased gradually during the differentiation of CD8 + T cells, which was associated with increased proliferation potential [31, 32]. These lines of evidence also support our conclusion. However, the association between miR-17-92 and NK cells remains unclear. Further research is needed to explore this issue in the future. It will be an interesting and meaningful topic to pursue.