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.