Abstract
Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future.
Highlights
Graves’ disease (GD) is an organ-specific autoimmune disease that arises due to the breakthrough of tolerance to thyroid stimulating hormone receptor (TSHR)
In the present study we investigated the underlying perpetuating factors that maintain the autoimmune response in GD through flow cytometric, T cell receptor sequencing (TCR-seq), and RNA sequencing (RNA-seq) analyses, and our findings emphasized the essential role of T cells
This is the first research that exploring the mechanism of persistent GD (pGD) by T cell receptor (TCR)-seq and RNA-seq
Summary
Graves’ disease (GD) is an organ-specific autoimmune disease that arises due to the breakthrough of tolerance to thyroid stimulating hormone receptor (TSHR). GD has an annual incidence of 20 to 50 cases per 100,000 persons, and females are more susceptible than males [1] This disease is manifested as weight loss, fatigue, heat intolerance, tremor, and palpitations [1]. After anti-thyroid drugs (ATDs) withdrawal (12–18 months), 40–50% of GD patients achieve durable remission with euthyroidism, while others will be trapped in long-lasting disease phase [1, 2]. Those patients who have been taking ATDs treatment for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies (TRAb) value are classified as persistent GD (pGD) cases, namely refractory GD (rGD) patients in previous studies [3]. Considering the unsatisfactory treatment effects of current pGD patients, there is an urgent need to develop novel therapies targeting the underlying accumulated immune factors
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