Summary
Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated autoimmune disease. The OX40/OX40L pathways play a crucial role in the pathogenesis or development of human autoimmune diseases. This study aimed to investigate the functions, potential mechanisms, and clinical significance of the OX40/OX40L pathways in the pathological process of MG. Ninety patients diagnosed with MG, as well as 39 patients with untreated stage MG (USMG), 22 patients with recurrence stage MG (RSMG), 42 patients with paracmasis stage MG (PSMG), and 36 healthy controls (HC), were enrolled in this study. Peripheral blood (PB) was collected from patients with MG and HCs. The expression of membrane-bound OX40 (mOX40) and OX40L (mOX40L) on immune cells was detected using flow cytometry. The levels of soluble OX40 (sOX40) and OX40L (sOX40L) in plasma were analyzed using ELISA. The expression levels of OX40 on T cells in peripheral blood from the MG group and OX40L on B cells and mononuclear cells were significantly increased compared to those in the HC group. The levels of sOX40 were significantly decreased in patients with MG compared to those in HCs, while the levels of sOX40L were not different. A subgroup analysis revealed that the expression of OX40 on CD4+ T cells, OX40L on CD14+ mononuclear cells and sOX40 in the generalized MG (GMG) group was significantly higher than that in the ocular MG (OMG) group. The expression of OX40 on CD4+T cells in patients with thymoma or thymic hyperplasia was significantly upregulated compared with participants without thymoma or thymic hyperplasia. Correlation analyses with clinical data showed that OX40 expression on CD4+ T cells was positively correlated with the quantitative myasthenia gravis scores (QMGs) and the concentrations of acetylcholine receptor antibodies (AchR-Ab) in the MG group. sOX40 levels were positively correlated with QMGs and disease duration, while sOX40L levels were negatively correlated with the disease duration. Dynamic observations of the expression of these molecules showed significantly increased expression of OX40 on CD4+ T cells in the peripheral blood from the USMG, RSMG and PSMG groups compared to that in the HC group. Compared with the USMG and PSMG groups, OX40 expression was significantly increased on CD4+ T cells from the RSMG group. OX40L expression on CD19+ B cells was significantly increased in the PSMG group compared with the HC group. OX40L was expressed at significantly higher levels on CD14+ mononuclear cells from the RSMG group than on cells from the HC group. However, no significant difference in OX40L expression on CD19+ B cells and CD14+ mononuclear cells was observed among the USMG, RSMG and PSMG groups. The plasma sOX40 levels in the USMG group were significantly lower than those in the HC group. Compared with the USMG and PSMG groups, the levels of sOX40 in the RSMG group were significantly increased. sOX40L levels in the PSMG group were significantly lower than those in the USMG, RSMG and HC groups. The expression of OX40 on CD4+ T cells was positively correlated with the concentration of AchR-Ab in the RSMG group, while the expression of OX40L on CD19+ B cells and CD14+ mononuclear cells was negatively correlated with the disease duration. ROC curves showed that the expression levels of CD4+ OX40 and sOX40L had moderate predictive value for monitoring MG recurrence. Based on these results, the OX40/OX40L pathways are involved in the immunopathological process of MG and might be valuable therapeutic targets for MG. Abnormal sOX40L levels might promote the positive signal transduction of OX40 on T cells in the later stages of MG, causing excessive activation of T cells and disease progression. CD4+ OX40 and sOX40 may be associated with MG disease activity and severity, and CD4+ OX40 may be related to the recurrence of MG.
Keywords : myasthenia gravis; peripheral blood; mOX40; mOX40L; sOX40; sOX40L