Vol 62, Supp. I (2011)
Review paper
Published online: 2011-09-19
Pathogenesis of thyroid eye disease — does autoimmunity against the TSH receptor explain all cases?
DOI: 10.5603/ep.v62iI.25220
Abstract
Thyroid associated ophthalmopathy, or thyroid eye disease (TED), is a complex inflammatory disorder of the eye that, as its name implies,
is usually associated with thyroid disease. Clinical observation supports the existence of three main TED subtypes, namely ocular myopathy,
congestive myopathy, and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TED remains
unclear, it is likely to reflect an autoimmune reaction involving sensitised T lymphocytes and autoantibodies directed against a specific
orbital or thyroid-and-orbital shared antigen(s). One well-studied candidate in this immune reaction is the thyroid-stimulating hormone
receptor (TSHR), which is also expressed in the orbital fibroblast and preadipocyte. Most patients with ophthalmopathy have associated
Graves’ disease, 10% have Hashimoto’s thyroiditis in which the eye changes are often mild and expressed mainly as upper eyelid retraction
(UER), and 10% have no apparent associated thyroid disease — so-called “euthyroid Graves’ disease”. Ophthalmopathy can also
occur in some patients with transient thyroiditis, thyroid cancer, and Graves’ disease many years after treatment of the hyperthyroidism
— situations where TSHR antibodies are not expected to be present, suggesting that the relationship between TSHR antibodies and the
eye disorder has not been established for all cases. In our studies of TED we have investigated the nature and significance of antibodies
targeting other eye muscle and orbital connective tissue (OCT) antigens, in particular the calcium binding protein calsequestrin (CASQ1)
and the orbital fibroblast membrane antigen collagen XIII. Our working hypotheses for the pathogenesis of TED are: i) the initial reaction in the orbit is antibody and T lymphocyte targeting of the TSHR in the OCT compartment, and ii) the associated extra ocular and upper
eyelid muscle inflammation reflects either autoimmunity against primary skeletal muscle antigens such as CASQ1 or a secondary, non
specific effect of the OCT reactions as proposed by the main proponents of the “TSHR hypothesis”. Here, we review the evidence that
autoimmunity against the TSHR expressed in the orbit can be implicated in the development of all cases of TED. Although there is a close
general correlation between ophthalmopathy and TSHR antibodies there are many exceptions, suggesting that the continued study of the
possible role of autoimmunity against calsequestrin and collagen XIII is justified.
(Pol J Endocrinol 2011; 62 (education supplement I): 1–7)
(Pol J Endocrinol 2011; 62 (education supplement I): 1–7)
Keywords: ophthalmopathyTSH-receptorGraves’ diseaseextra ocular muscleHashimoto’s thyroiditiseuthyroid Graves’ diseaseautoimmunity