Introduction
In the thymus, T-cell precursors differentiate to T regulatory cells (Tregs) and naïve T cells. Naive CD4+T cells differentiate into one of several CD4+T cell subpopulations including Th1, Th2, Th17, and T regulatory cells (iTregs). Over the past decade, T helper type 17 (Th17) cells producing interleukin-17 (IL-17) have emerged as the major pathogenic T cell subset in many pathological conditions[1,2]. In addition, the role of CD4+CD25+ Tregs in controlling the activity of Th17 and other T cell subsets has increasingly been realized [3]. Th17 and Treg development is governed by lineage-specific transcription factors. Retinoid-related orphan receptors gamma t (RORγt) is the master transcription factor of Th17 cell differentiation from naïve T cells and can induce the expression of IL-17A and IL-17F [4]. Forkhead transcription factor 3 (FOXP3) is a core subset-specific transcription factor expressed by Tregs, and its sustained expression is critical for the development and suppressive function of Tregs [5]. The reciprocal inhibition of RORγt and FOXP3 maintains the balance of differentiation to Th17 and Treg [6,7]. This balance plays a crucial role in the maintenance of immune homeostasis.
Th17/Treg imbalance has an important function in the pathogenesis of many autoimmune and inflammatory diseases, such as autoimmune arthritis, multiple sclerosis, intestinal inflammation, and sarcoidosis [8-11]. Similarly, myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by muscle weakness, which is caused by autoantibodies directed against neuromuscular junctions. Th17/Treg imbalance is also an important factor in the pathogenesis of MG [12]. Higher levels of IL-17 were found in the serum of generalized AChR-MG patients than in control serum [13], and Treg functional defects associated with reduced expression of FOXP3 appeared to be more pronounced in MG patients [14].
Thymoma, which is a neoplasm of thymic epithelial cells, can cause defects in immune regulation and immune tolerance, resulting in autoimmune disease. The most common autoimmune disease associated with thymoma is MG. Wang et al. reported that an increase in Th17 cells and Th17-associated cytokines was observed in peripheral blood mononuclear cells (PBMCs) from MG patients with thymoma [15]. In our previous research, lower levels of FOXP3 mRNA and protein in thymoma tissue and CD4+CD25+FOXP3+ Tregs in PBMCs were associated with thymoma-related MG [16]. However, direct proof that thymoma induces a Th17/Treg imbalance is lacking. In this study, the imbalance of Th17/Treg was studied through an analysis of the relationship between Th17/Treg and transcription factors and cytokines in thymoma and peripheral blood. This study indicates the potential pathogenesis of thymoma-associated MG.