Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role?

Abstract

Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease, is a complex inflammatory disorder of the eye that, as its name implies, is associated with thyroid disease. TAO can be divided into three subtypes: ocular myopathy, congestive myopathy and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TAO remains unclear it is likely to reflect an autoimmune reaction involving sensitized T-cells and autoantibodies directed against a thyroid and orbital tissue shared antigen. One well studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSH-r), expressed in the orbital fibroblast and pre adipocyte. In our studies of TAO, we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens. Our findings suggest that autoimmunity against the eye muscle antigen calsequestrin and the OCT antigen collagen XIII plays a role in the pathogenesis of TAO. We propose that ocular myopathy and chronic eyelid retraction are due to autoimmunity against skeletal muscle calsequestrin in the extraocular and eyelid muscles, respectively. This may be initiated in the thyroid where calsequestrin expression is upregulated, possibly due to a stimulatory effect of TSH-r antibodies. We also propose that congestive ophthalmopathy results from a reaction against the TSH-r or collagen XIII in orbital fibroblast cell membranes. Further insight into the role of eye muscle and OCT antigens in the pathogenesis of TAO may allow for the development of new therapies to treat the eye disorder and reduce patient morbidity.

Keywords: autoimmunity; collagen XIII; t calsequestrin; thyroid-associated ophthalmopathy.

Figure 1

Eye muscle and orbital fibroblast autoantigens recognized by T lymphocytes or antibodies in thyroid-associated ophthalmopathy (TAO). Our working hypothesis is that the ocular myopathy subtype of TAO is initiated by T lymphocyte-mediated targeting of calsequestrin or a yet unidentified eye muscle cell membrane antigen. Serum antibodies against flavoprotein, G2s and sarcalumenin are likely to be secondary to release of the proteins following muscle fiber necrosis. Chronic eyelid disease, which is a feature of TAO or a dominant sign in patients with Hashimoto’s thyroiditis, may be the result of T lymphocyte-mediated targeting of calsequestrin in the upper eyelid levator palpebrae superioris muscle. The congestive ophthalmopathy subtype of TAO is likely to result from a reaction against the TSH-r or collagen XIII in the fibroblast cell membranes, which leads to fibroblast stimulation and excess production of collagen and glycosaminoglycans. The different reactions shown in the figure may occur alone or in combination. Reproduced with the permission from Tani J, Wall JR. Autoimmunity against eye-muscle antigens may explain thyroid-associated ophthalmopathy. CMAJ. 2006;175(3):239. Copyright © 2006 Canadian Medical Association Abbreviations: MHC, major histocompatibility complex; TSH-r, thyroid-stimulating hormone receptor.

Figure 2

Orbital fibroblast activation in thyroid-associated ophthalmopathy. The main features of Graves’ ophthalmopathy include the enlargement of eye muscles and the expansion of the orbital fatty connective tissues. These changes result from accumulation of glycosaminoglycans (GAGs) and edema within these tissues and de novo adipogenesis. The orbital fibroblast (OF) appears to be the major effector cell in GO influencing both processes. In the active stage of disease, OF are capable of producing large amounts of GAGs following (i) stimulation by cytokines (especially Th-1 cytokines), (ii) activation of CD40 by CD40 ligand and (iii) activation of insulin growth factor receptor (IGF-1R) by autoantibodies. A subset of OF, the preadipocytes, are capable of differentiating into mature adipocytes following appropriate stimulation by cytokines (IL-6) and activation of thyroid-stimulating hormone receptor (TSH-r). In addition, OF have been shown to display the immunoregulatory molecules major histocompatibility complex MHC class II (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1), and also are capable of secreting chemokines and cytokines which stimulate the infiltration of activated T cells into areas of inflammation. In the ‘burn-out’ stage of ophthalmopathy, OF participate in tissue fibrosis. Reproduced with permission from Bednarczuk T, Gopinath B, Ploski R, Wall JR. Susceptibility genes in Graves’ ophthalmopathy: searching for a needle in a haystack? Clin Endocrinol (Oxf). 2007; 67(1):3–19. Copyright © 2007 Wiley Blackwell. Abbreviations: LFA, lymphocyte function-associated antigen; MHC, major histocompatibility complex.