Introduction
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the
neuromuscular junction. Its main clinical manifestations are fluctuating
weakness and fatigue of the involved skeletal muscles[1]. At
present, the predominant therapeutic strategies for MG include
cholinesterase inhibitors, immunosuppressive agents, thymectomy, and
short-term immunomodulation via intravenous immunoglobulin or plasma
exchange, which are selected according to the clinical characteristics
and the types of pathogenic antibodies [2]. Based on in-depth
studies of the pathogenesis of MG, the use of targeted biological agents
such as rituximab[3] improves the prognosis of patients with MG.
Nevertheless, some patients with refractory MG still have a poor
prognosis after humoral immune intervention[4], suggesting that both
humoral and cellular immunity may play a key role in the pathological
process of MG.
T cell activation requires the major histocompatibility complex
(MHC)-peptide complex to provide a first signal and a second signal
delivered by costimulatory molecules. A lack of costimulatory signals
can lead to T cells that are unable to respond and even programmed cell
death[5]. OX40 (also named CD134, TNFRSF4 or ACT35) and its cognate
ligand, OX40L (also called CD252, TNFSF4, gp34 or CD134L), which are
members of the tumor necrosis factor receptor (TNFR) and the tumor
necrosis factor (TNF) superfamily, respectively, play an important role
in regulating the immune response. OX40 is a type I transmembrane
glycoprotein that is mainly expressed on activated
CD4+ T cells. OX40L is a type II transmembrane
glycoprotein that is predominantly expressed on antigen-presenting cells
(ADCs), such as B cells, dendritic cells (DCs) and macrophages[6,
7]. OX40-OX40L interactions promote T cell proliferation,
differentiation, memory, and survival, increase effector cytokine
secretion, and suppress regulatory T cell function[8]. The
OX40/OX40L pathway plays a significant role in the pathogenesis of human
autoimmune diseases, including multiple sclerosis (MS)[9],
systemic lupus
erythematosus (SLE)[10],
rheumatoid arthritis
(RA)[11], and type 1 diabetes[12], and the expression of OX40 on
CD4+ T cells correlates with disease severity in
patients with SLE[13, 14]. Blockade of OX40-OX40L interactions
ameliorates disease in many animal models of autoimmunity[15].
In addition to membrane-bound OX40 (mOX40) and membrane-bound OX40L
(mOX40L) expression on peripheral
circulating lymphocytes, soluble
forms of OX40 (sOX40) and OX40L (sOX40L) have been detected in
plasma[8]. Soluble molecules regulate the OX40/OX40L axis by binding
to corresponding membrane-bound molecules and increase the diversity and
complexity of the OX40/OX40L pathways. However, the specific functions
and pathogenesis of the OX40/OX40L pathways in MG remain unclear, and
little research has been conducted on soluble molecules. Investigations
of whether OX40/OX40L (including membrane-bound and/or soluble forms)
are abnormally expressed in the peripheral blood of patients with MG and
whether the abnormal changes are relevant to the onset, recurrence,
remission, and activity and severity of MG are worthwhile. This study
detected the expression of mOX40 and mOX40L on the surface of peripheral
lymphocytes from patients with MG and healthy controls (HCs) and the
plasma levels of sOX40 and sOX40L to explore the functions, potential
mechanisms, and clinical implications of OX40/OX40L signaling in the
occurrence and development of MG.