A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy

Abstract

Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. β-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.

Keywords: Graves’ orbitopathy; insulin-like growth factor-1 receptor; orbital adipocytes; orbital fibroblasts; thyrotropin receptor.

Figure 1

Schematic of the theoretical pathogenesis of GO Bone marrow mononuclear cell-derived CD34+ fibroblasts enter the orbit from the circulation and express low levels of TSHR, thyroglobulin and other thyroid antigens. APCs, such as B lymphocytes or macrophages, present antigens to antigen-specific T lymphocytes and activate them. Activated T lymphocytes release cytokines and chemokines, further causing B lymphocytes to produce antibodies. These processes form an inflammatory microenvironment in the orbit. OFs can also act as APCs. In the inflammatory microenvironment, activated T lymphocytes activate OFs. Activated OFs further secrete cytokines and chemokines and produce excessive levels of GAGs, leading to swelling of the orbital tissue. CD34+ fibroblasts are found in orbit with CD34− fibroblasts. CD34+ fibroblasts further differentiate into myofibroblasts or adipocytes, resulting in thickening of the extraocular muscles and exophthalmos. TSHR expression is increased during adipogenesis. IGF-1R, TSHR, IL-6R, CD20 and TNF-α are current therapeutic targets for GO. APC, antigen-presenting cell; GAG, glycosaminoglycan; GO, Graves’ orbitopathy; OFs, orbital fibroblasts; TSHR, thyrotropin receptor; IGF-1R, insulin-like growth factor-1 receptor.

Figure 2

Schematic of the TSHR and IGF-1R signalling pathways in the pathogenesis of GO In OFs and OAs of GO patients, TSH and TRAb bind to TSHR to induce activation of AC. This causes an increase in cAMP production and activates PKA. Activated PKA inhibits FOXOs and activates the transcription factor CREB. CREB further acts on the promoters of HASs to increase HA production. Binding of IGF-1 to IGF-1R activates PI3K, resulting in AKT activation. Activated AKT inhibits FOXOs and activates mTOR to promote adipogenesis via PPARγ. TSHR/IGF-1R crosstalk depends on β-arrestin 1 acting as a scaffold, leading to interaction of the two signalling pathways. This figure is adapted from Draman Mohd Shazli,Zhang Lei,Dayan Colin et al. Front Endocrinol (Lausanne), 2021, 12: 739994. AC, adenylate cyclase; AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; FOXOs, Forkhead box O; GO, Graves’ orbitopathy; HA, hyaluronan; HASs, hyaluronan synthases; mTOR, mammalian target of rapamycin; OAs, orbital adipocytes; OFs, orbital fibroblasts; PI3K, phosphatidylinositol-3-kinase; PKA, protein kinase A; PPARγ, peroxisome proliferator activator gamma; TRAb, thyrotropin receptor antibody; TSH, thyrotropin; TSHR, thyrotropin receptor.