Affiliation:
1. Mayo Clinic College of Medicine, Rochester, MN, USA
Abstract
AbstractEnvironmental, genetic, and immune factors are at play in the development of the
variable clinical manifestations of Graves’ ophthalmopathy (GO). Among the
environmental contributions, smoking is the risk factor most consistently linked
to the development or worsening of the disease. The close temporal relationship
between the diagnoses of Graves’ hyperthyroidism and GO have long suggested that
these 2 autoimmune conditions may share pathophysiologic features. The finding
that the thyrotropin receptor (TSHR) is expressed in orbital fibroblasts, the
target cells in GO, supported the notion of a common autoantigen. Both cellular
and humeral immunity directed against TSHR expressed on orbital fibroblasts
likely initiate the disease process. Activation of helper T cells recognizing
TSHR peptides and ligation of TSHR by TRAb lead to the secretion of inflammatory
cytokines and chemokines, and enhanced hyaluronic acid (HA) production and
adipogenesis. The resulting connective tissue remodeling results in varying
degrees extraocular muscle enlargement and orbital fat expansion. A subset of
orbital fibroblasts express CD34, are bone-marrow derived, and circulate as
fibrocytes that infiltrate connective tissues at sites of injury or
inflammation. As these express high levels of TSHR and are capable of producing
copious cytokines and chemokines, they may represent an orbital fibroblast
population that plays a central role in GO development. In addition to TSHR,
orbital fibroblasts from patients with GO express high levels of IGF-1R. Recent
studies suggest that these receptors engage in cross-talk induced by TSHR
ligation to synergistically enhance TSHR signaling, HA production, and the
secretion of inflammatory mediators.
Subject
Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,General Medicine,Endocrinology, Diabetes and Metabolism
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