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.