Mechanisms That Underly T Cell Immunity in Graves' Orbitopathy.

Sijie Fang,Xianqun Fan,Yazhuo Huang,Yi Lu,Huifang Zhou

doi:10.3389/fendo.2021.648732

Abstract

Graves’ orbitopathy (GO), also known as thyroid-associated ophthalmopathy, is the most common ocular abnormality of Graves’ disease. It is a disfiguring, invalidating, and potentially blinding orbital disease mediated by an interlocking and complicated immune network. Self-reactive T cells directly against thyroid-stimulating hormone receptor-bearing orbital fibroblasts contribute to autoimmune inflammation and tissue remodeling in GO orbital connective tissues. To date, T helper (Th) 1 (cytotoxic leaning) and Th2 (antibody leaning) cell subsets and an emerging role of Th17 (fibrotic leaning) cells have been implicated in GO pathogenesis. The potential feedback loops between orbital native residential CD34- fibroblasts, CD34+ infiltrating fibrocytes, and effector T cells may affect the T cell subset bias and the skewed pattern of cytokine production in the orbit, thereby determining the outcomes of GO autoimmune reactions. Characterization of the T cell subsets that drive GO and the cytokines they express may significantly advance our understanding of orbital autoimmunity and the development of promising therapeutic strategies against pathological T cells.

Highlights

Graves’ orbitopathy (GO), known as thyroid-associated ophthalmopathy, is the ocular abnormality of Graves’ disease (GD)
Loss of T cell receptor (TCR) gene restriction was observed in four late GO patients and no TCR gene restriction was found in samples from three non-GO control subjects [49, 50]. These findings suggest that oligoclonality of T cell immunity may be lost during GO, which indicates that antigen specificity of orbit-infiltrating T cells occurs in the early active phase of GO
Using single cell sequencing analysis, we showed that various genes are expressed in GO orbital connective tissues, which can be classified into six independent cell types: antigen-presenting cell (APC), lymphocytes including T and B cells, orbital fibroblasts (OFs), adipocytes, endothelial cells, and myocytes [31]

Summary

INTRODUCTION

Graves’ orbitopathy (GO), known as thyroid-associated ophthalmopathy, is the ocular abnormality of Graves’ disease (GD). In the late 1980s, the role of T cell immunity was investigated in the orbital connective tissues of GO patients [9]. The relatively low ratios of CD4/CD8 in orbital connective tissue-derived T cell lines and clones indicate that there is a disorder of cellular immune function in GO orbits. The same research group analyzed 10 of 17 T cell lines derived from orbital connective tissues of six severe GO patients and found mainly CD4+ T cells (six of 10 strains) with a similar CD4+/CD8+ T cell distribution [40]. Förster et al established 18 T cell lines from orbital connective tissues of six severe GO patients and reported that 10 were predominantly the CD4+ phenotype, whereas three were mostly CD8+ cells [42].

GO controls

PRIMARY IMMUNE REACTION IN THE ORBIT

Findings

FUTURE PERSPECTIVES