Can Autoimmunity Against Calsequestrin Explain the Eye and Eyelid Muscle Inflammation of Thyroid Eye Disease?

Abstract

Extra-ocular and upper eyelid (levator) muscle damage in thyroid orbitopathy may be due to autoimmunity against eye muscle auto antigens. The main antigen appears to be the calcium binding protein calsequestrin. In this study we have tested for T lymphocyte sensitization to calsequestrin in patients with Graves' disease, with and without orbitopathy, in standard proliferation assay. We have also tested total RNA prepared from thyroid tissue of patients with Graves' disease with and without orbitopathy for expression across 20,589 genes using micro array analysis technology. We were looking for differences in gene expression between the two groups which might provide information about the early thyroid events that lead to the development of eye muscle autoimmunity. Positive lymphocyte reactivity to calsequestrin was demonstrated in 59% of Graves' patients with orbitopathy, 33% without evident ophthalmopathy and in 43% of patients with Hashimoto's thyroiditis and upper eyelid retraction (UER). Two hundred and ninety six genes were identified to be differentially expressed between in patients with Graves' disease with and without orbitopathy. Of these, the cardiac calsequestrin gene CASQ2 was the most highly up regulated, 2.2-fold. The closely related skeletal muscle calsequestrin gene CASQ1 was also up-regulated, 4.1 fold, but this was not significant, while genes encoding the thyroid antigens thyroglobulin, thyroid peroxidase and the TSH-receptor were not differentially expressed. These findings provide further evidence for a prominent role of autoimmunity against calsequestrin in the pathogenesis of the eye muscle components of thyroid orbitopathy.

The Evaluation of Neutrophil to Lymphocyte ratio and mean platelet volume in patients with active and inactive thyroid orbitopathy

“…[1] Bu antijenlerden TSH reseptör antijenleri en iyi bilinen antijen olmakla birlikte başka antijenler de son zamanlarda tanımlanmıştır. [4,15,16] Tiroid ve orbitadaki antijenleri tanıyan reaktif T lenfositler orbita ve ekstraoküler kasları invaze etmekte ve CD4+ T lenfositler üzerindeki T hücre reseptörleri aracılığıyla antijeni bulup, çeşitli sitokinlerin salgılanmasına yol aç-maktadır. Bu sitokinler daha sonra CD8+T lenfositleri ve B hücrelerini uyararak immün reaksiyonu kuvvetlendirir.…”

Calsequestrin: a well-known but curious protein in skeletal muscle

“…CASQ1 is also related to an abnormal thyroid status. Patients with Graves' disease (a thyroid disease) show increased mRNA levels of both the CASQ1 and CASQ2 genes in thyroid tissue 197 . Unlike normal subjects, patients with Graves' hyperthyroidism without ophthalmopathy and Hashimoto's thyroiditis with or without ophthalmopathy show significant levels of autoantibodies against CASQ1 in the serum 198,199 .…”

Ocular treatment of thyroid eye disease

“…Disease is associated with antibodies to the TSH receptor [17]. Other postulated autoantigens include the IGF receptor [18], extraocular muscle proteins [19] and thyroglobulin [15]. Although TSH receptor antibodies, especially the stimulating TSH receptor antibodies that activate the receptor on the follicular cells in the thyroid gland, conceptually explain the hyperthyroidism in systemic Graves' disease, other factors appear to be involved in the pathogenesis of TED.…”

“…These studies, while not replicating TED, can help to give us insight into the effects of the elevated thyroid hormone levels on orbital tissues. It may be that with an accelerated turnover of extraocular muscle fibers, cellular antigens such as calsequestrin may have an increased opportunity to be exposed to T and B lymphocytes [19]. Future studies are needed to examine this hypothesis.…”