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.

Comparison of orbital fibroblasts from Graves’ ophthalmopathy and healthy control

“…The activation of TSHR and IGF-1R by their respective autoantibodies (TSH and IGF-1) in OFs of GO initiates a cascade of events, including OF proliferation, inflammatory cytokine production, and HA secretion. These processes contribute significantly to the development of orbital tissue edema and inflammation [ 24 , 25 ]. Our identification of elevated TSHR and IGF-1R expression in GO-OFs aligns with prior research, emphasizing the central roles of these receptors in the pathogenesis of GO [ 24 , 26 ].…”

“…These processes contribute significantly to the development of orbital tissue edema and inflammation [ 24 , 25 ]. Our identification of elevated TSHR and IGF-1R expression in GO-OFs aligns with prior research, emphasizing the central roles of these receptors in the pathogenesis of GO [ 24 , 26 ]. Notably, a study [ 27 ] reported a subpopulation of cells exhibiting the CD34+Col1+ phenotype within the orbit of GO during flow cytometric analysis, which suggests that the TSHR + subpopulation of GO-OFs might represent CD34 + fibrocytes originating from peripheral blood mononuclear cells (PBMCs).…”

Role of Inositol-Requiring Enzyme 1 and Autophagy in the Pro-Fibrotic Mechanism Underlying Graves’ Orbitopathy

“…These proteins were previously shown to contribute to GO pathogenesis. 36 Therefore, IRE1 and autophagy can play essential roles in both SMAD-dependent and SMAD-independent signaling pathways in GO orbital fibroblasts. Unlike SMAD2, SMAD3 and SMAD4 did not show significant expression differences.…”

Immunological Processes in the Orbit and Indications for Current and Potential Drug Targets

“…Thyroid eye disease (TED) is an extrathyroidal manifestation of GD [ 5 , 6 , 7 , 8 ]. Studies show that TED occurs in 13–69% of GD cases [ 9 , 10 ]. Similar to GD, TED is caused by an autoimmune response.…”

“…Similar to GD, TED is caused by an autoimmune response. The pathophysiology underlying TED is complex, with key factors being the infiltration of activated T and B lymphocytes, activation of orbital fibroblasts (OFs), and the presence of autoantibodies targeting a common autoantigen (i.e., TSHR) expressed in thyroid and orbital tissues [ 6 , 7 , 9 , 10 , 11 , 12 , 13 , 14 ]. In TED, TSHR receptor antibodies (TRABs) and antibodies to insulin-like growth factor 1 receptor (anti-IGF-1R) interact with OFs.…”