Antibodies targeting the calcium binding skeletal muscle protein calsequestrin are specific markers of ophthalmopathy and sensitive indicators of ocular myopathy in patients with Graves’ disease

Abstract

SummaryWe have identified several eye muscle antigens and studied the significance of the corresponding serum autoantibodies in patients with Graves' disease. Of these antigens, only calsequestrin is expressed more in eye muscle than other skeletal muscles, which could explain at least partly the specific involvement of eye muscle in patients with Graves' disease. Earlier, we found a modest relationship between anti-calsequestrin antibodies and ophthalmopathy, but in that study we used calsequestrin prepared from rabbit heart muscle and measured antibodies by immunoblotting. We have reinvestigated the prevalences of anti-calsequestrin antibodies in larger groups of well-characterized patients with thyroid autoimmunity with and without ophthalmopathy and control patients and healthy subjects, using standard enzyme-linked immunosorbent assay incorporating highly purified rabbit skeletal muscle calsequestrin, which has a 97% homology with human calsequestrin, as antigen. Anticalsequestrin antibodies were detected in 78% of patients with active congestive ophthalmopathy, in 92% of those with active inflammation and eye muscle involvement, but in only 22% of patients with chronic, 'burnt out' disease. Tests were also positive in 5% of patients with Graves' hyperthyroidism without evident ophthalmopathy (two patients) and one patient with 'watery eyes' but no other clear signs of congestive ophthalmopathy and IgA nephropathy and no known thyroid disease, but in no patient with Hashimoto's thyroiditis, toxic nodular goitre, non-toxic multi-nodular goitre or diabetes, or age-and sex-matched healthy subjects. In serial studies of all 11 patients with Graves' hyperthyroidism who had active ophthalmopathy at the time of the first clinic visit, or developed eye signs during the first 6 months, and positive anti-calsequestrin antibodies in at least one sample, anti-calsequestrin antibodies correlated with the onset of ocular myopathy in six patients. Antibodies targeting calsequestrin appear to be specific markers for ophthalmopathy and sensitive indicators of the ocular myopathy subtype of ophthalmopathy in patients with thyroid autoimmunity. However, these results must be considered preliminary until a large prospective study of patients with newly diagnosed Graves' hyperthyroidism, in which serum levels of calsequestrin antibodies are correlated with clinical changes and orbital eye muscle and connective tissue/fat volumes, has been carried out.

99Tcm-octreotide scintigraphy and serum eye muscle antibodies in evaluation of active thyroid-associated ophthalmopathy

“…In this study, we observed a close relationship between positive reactivity of serum calsequestrin antibodies (87.9%) and active TAO, which corroborates previous report. 30 Moreover, the level of calsequestrin antibody was strongly correlated with CAS in active TAO (r = 0.738, Po0.05) and also could be used to assess the efficacy of corticosteroids therapy (Po0.05), however, calsequestrin antibody levels were not as efficient as 99 Tc m -octreotide scintigraphy in evaluation of therapy response. Since calsequestrin was expressed 4.8 times higher in eye muscles compared to Figure 5 The level of serum extraocular muscle antibodies and efficacy in evaluation of the treatment of active TAO.…”

“…Eye other skeletal muscle, 17 calsequestrin antibodies may be correlated with the onset of ocular myopathy 30 rather than congestive ophthalmopathy. More interestingly, six GD patients (4.96% of GD patients) without ophthalmopathy, but with elevated levels of calsequestrin antibodies, developed signs of active TAO after 12 weeks.…”

Strabismus Surgery in Thyroid-Related Eye Disease: Strategic Decision Making

“…Therefore, it is felt that other antigenic stimuli may exist, including specific extraocular muscle antigens, namely, calsequestrin, that may be released secondary to tissue damage following the initial cell-mediated inflammation [21,22].…”

Antibodies against Calsequestrin and Type XIII Collagen are Good Markers for Chronic Upper Eyelid Retraction

“…7 Recently, we have shown that antibodies against calsequestrin are closely associated with eye muscle damage in patients with TAO and appear to be markers for Nunery type 2 ophthalmopathy 8 with eye muscle involvement. [9][10][11] Another protein that appears to be specifically targeted in TAO is type XIII collagen, 11,12 one of only two members of the collagen family that is expressed in the orbital fibroblast cell wall.…”