Immunopathogenesis of Graves orbitopathy
Graves orbitopathy (GO) is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves hyperthyroidism and GO suggest that both conditions derive from a single systemic process and share the thyrotropin receptor (TSHR) as autoantigen. Autoimmunity directed against the TSHR on orbital fibroblasts sets in motion connective tissue remodeling within the orbit that leads to the various clinical expressions of the disease. Hyaluronic acid (HA) accumulation, expansion of orbital adipose tissues and the presence of inflammatory cells and pro-inflammatory cytokines appear to be the salient histologic features of the disease. Orbital fibroblasts express functional TSHR and are considered to be the target cells. Several laboratories have explored the impact of TSHR activation in these cells on signaling and cellular functions relevant to the orbital tissue changes. Both HA synthesis and new fat cell development are enhanced by activation of orbital fibroblast TSHR, whether effected through ligation of the receptor by TSH or monoclonal antibodies directed against the receptor (TRAb), or by the introduction of an activating mutant TSHR. The phosphoinositide 3-kinase/Akt signaling cascade appears to be an important effector pathway in this process, with input from adenylyl cyclase/cAMP and other signaling pathways. Circulating TRAb in patients with Graves hyperthyroidism are heterogeneous and have differing potency and affinities. Stimulatory TRAb activate various TSHR signaling cascades in thyrocytes, resulting in the over-production of thyroid hormones. It appears likely that they similarly activate orbital fibroblast TSHR to modulate HA synthesis and adipogenesis. While IGF1 and other growth factors may act in an autocrine or paracrine fashion to impact TSHR signaling, little evidence supports a role in GO for circulating autoantibodies directed against IGF1R. Future therapies may involve the inhibition of TSHR signaling in orbital fibroblasts, perhaps using small molecular ligands that antagonize TSHR effector pathways.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.