Precision Medicine in Graves’ Disease and Ophthalmopathy

Abstract

Graves’ disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves’ ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

Serum Levels of CXCL-13, RBP-4, and IL-6, and Correlation Analysis of Patients with Graves’ Disease

“…Determination of their content can e ectively identify whether the thyroid function is abnormal, and it is an important index for the diagnosis of hyperthyroidism [6]. Similar to other autoimmune diseases, the pathogenesis of GD is related to the imbalance of related cytokines in the body [7]. e CXC chemokine 13 (CXCL-13) is a proin ammatory chemokine derived from stromal cells, which has a strong proinammatory capacity and can bind to its receptor CXCR-5, playing an important role in the regulation, aggregation, and migration of B lymphocytes proliferation and di erentiation [8,9].…”

Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy

“…Recently, cell metabolism has become highly involved in the mechanisms of autoimmune diseases pathogenesis. In TAO, TSAb induced the process of autoimmune stimulating the increased production of thyroid hormones (33). Thyroid hormones play an important role in regulating cholesterol metabolism, glucose metabolism, and lipid metabolism (34,35).…”

Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells

“…Second, in the current study, we used 3T3-L1 cells, a mouse embryonic fibroblast cell line, to study the drug-induced effects toward orbital fatty tissues. However, these adipocytes may have different characteristics, since it is known that obesity is associated with an increase in general adipocytes but not orbital adipocytes [ 50 ], but in turn, orbital adipocytes but not general adipocytes are increased in patients with Graves’ disease [ 51 ]. Third, the drug-induced effects of the mRNA expressions of ECMs molecules were quite different between 2D and 3D cell cultures, despite the lipid staining and mRNA expression of DIF+-related genes being similar.…”