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