Active TED is characterized by inflammation and infiltration of the thyroid and orbital tissues by immune cells. The loss of tolerance by T cells to the thyrotropin receptor (TSHR) allows for the development of autoimmunity directed against it. Subsequent activation and differentiation of B cells into plasma cells leads to the production of anti-TSHR antibodies. Another crucial autoantigen involved in TED pathogenesis is the insulin-like growth factor 1 receptor (IGF-1R). This is overexpressed in thyrocytes and fibroblasts in patients with GD and TED.[14,15] IGF-1R and TSHR colocalize to the perinuclear and cytoplasmic compartments in fibroblasts and thyrocytes. Cross-reactivity against this complex is thought to underlie the autoimmune ophthalmic response, leading to the TED cycle.
Immune recognition of the TSHR and IGF-1R complex on orbital fibroblasts leads to orbital tissue reactivity and remodeling via induction of cytokines and hyaluronan synthesis. Cytokines stimulate secretion of glycosaminoglycans, including hyaluronan, which increases intraorbital tissue volume via adipose and muscle expansion and tissue inflammation. Activated orbital fibroblasts proliferate and differentiate into adipocytes and myofibroblasts, also increasing orbital tissue volume. Consequently, the eyeball may protrude beyond the bony orbit, the extraocular muscles may enlarge restricting eye movement, the optic nerve can be compressed or stretched affecting vision, and the inflammatory cascade can result in eye pain, redness, and swelling.
J Endo Soc. 2021;5(5) © 2021 Endocrine Society