Implications of FoxP3-positive and -negative CD4⁺ CD25⁺ T cells in Graves’ ophthalmopathy

Abstract

Graves' ophthalmopathy (GO) is a common manifestation of Graves' disease (GD); however, its pathogenesis is not well understood. Recently, the dysregulation of regulatory T cells (Tregs) has been thought to be closely associated with the pathogenesis and clinical symptoms of autoimmune disease. We therefore evaluated whether T cell subsets, including Tregs, are associated with GO pathogenesis and clinical symptoms. In this observational study we evaluated 35 GD patients with overt ophthalmopathy (GOs) and 28 patients without ophthalmopathy (non-GOs). Fifteen healthy euthyroid patients served as healthy controls (HCs). Peripheral blood mononuclear cells from GOs, non-GOs and HCs were analyzed for CD4, CD25, and FoxP3 expression using flow cytometry. We also evaluated their correlation with disease activity according to the clinical activity score (CAS) and magnetic resonance imaging (MRI) findings. Disease severity was evaluated using the NOSPECS score, and clinical progression of GO was followed for 24 weeks. The main outcome measures were the frequencies of FoxP3-positive and -negative CD4(+) CD25(+) T cells at study outset, namely Tregs and effector T cells (Teffs), respectively. GOs had higher frequencies of Teffs (30.8±8.4%) than non-GOs (19.4±7.1%) and HCs (22.7±7.9%). Notably, patients with improved GOs had lower frequencies of Tregs (5.8±1.1%) than patients with stable or deteriorated GOs (7.3±1.2%), although ophthalmic and radiological parameters were not significantly different at the start of the study. In conclusion, an expanded Teff population may be associated with GO pathogenesis. Additionally, decreased Tregs in peripheral blood may predict a good clinical outcome.

Pathophysiology of Graves’ Ophthalmopathy: A Literature Review

“…As well as in other studies, it was also found that fibrocytes derived from cultures of peripheral blood mononuclear cells are rare in patients with any chronic disease known [11]. On the other hand, patients with GD, regardless of duration, thyroid hormone levels, or pathology treatment time, have numerous fibrocytes originated by peripheral blood mononuclear cells that exhibit the phenotype CXCL-12/CXCR4 [9] [12]. In contrast to the previous statement, not all individuals with GD have an increased level of circulating fibrocytes and fibroblasts compared to the controls, as well as the levels of IGF-1R those affected by GO and are absent in controls.…”

“…Th17 lymphocytes will also stimulate B lymphocytes in the orbit to produce autoantibodies against autoantigens such as TSH-R and IGF-1R, which originated, in turn, from the orbital fibroblasts [8]. A larger population of FoxP3-positive and -negative CD4(+) CD25(+) T cells was also observed in patients with the development of GO [9].…”

“…These levels were similar to those found in the epithelial cells of the thyroid, where hormone production is mediated. More importantly, they were also functional [9]. When related to a bovine thyroid stimulating hormone (bTSH) or M22, which constitutes a monoclonal antibody against TSHR, the production of inflammatory cytokines such as TNF-α and IL-6 is significantly upregulated [13].…”

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis

“…1. There were fourteen studies [11][12][13][14][15][16][17][18][19][20][21][22][23][24] included in the meta-analysis after screening 905, 516 and 1,997 potential articles obtained from PubMed, Embase and ISI Web of Knowledge, respectively. The characteristics of the fourteen studies as well as their NOS scores are summarized in Table 1.…”

“…Some studies have compared differences between the proportions of circulating Tregs among CD4+ T cells of AITDs in different treatment statuses and the proportions in HCs in recent years, but the results were variable. Some studies have reported that the proportions of circulating Tregs in AITDs tended to be lower than those in HCs [11][12][13][14][15][16][17][18][19][20][21][22], while others reported the opposite result [23,24]. Considering that drugs including methimazole [25] might affect the differentiation and proliferation of Tregs through regulation of AMP-activated protein kinase (AMPK) [26] and signal transducer and activator of transcription 3 (STAT3) [27], we speculated that the origins of these differences between results lie in differences in the treatment statuses of the AITDs involved in the studies.…”