Abstract
The essential trace element selenium (Se) is needed for the biosynthesis of selenocysteine-containing selenoproteins, including the secreted enzyme glutathione peroxidase 3 (GPX3) and the Se-transporter selenoprotein P (SELENOP). Both are found in blood and thyroid colloid, where they serve protective functions. Serum SELENOP derives mainly from hepatocytes, whereas the kidney contributes most serum GPX3. Studies using transgenic mice indicated that renal GPX3 biosynthesis depends on Se supply by hepatic SELENOP, which is produced in protein variants with varying Se contents. Low Se status is an established risk factor for autoimmune thyroid disease, and thyroid autoimmunity generates novel autoantigens. We hypothesized that natural autoantibodies to SELENOP are prevalent in thyroid patients, impair Se transport, and negatively affect GPX3 biosynthesis. Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto’s thyroiditis as compared with healthy control subjects (6.6% versus 0.3%). Serum samples rich in SELENOP autoantibodies displayed relatively high total Se and SELENOP concentrations in comparison with autoantibody-negative samples ([Se]; 85.3 vs. 77.1 µg/L, p = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, p = 0.001), while GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.
Highlights
An immunoluminometric assay for the detection and quantification of selenoprotein P (SELENOP)-aAb was established by generating a fusion protein encoding-secreted alkaline phosphatase (SEAP) in frame with full length human SELENOP, where UGA codons had been replaced by cysteine codons
This result was replicated in dilution experiments with serum samples from patients identified as positive (P01–P05), whereas samples categorized as negative for SELENOP-aAb (N01–N03) showed background signals only (Figure 1B)
The results showed a skewed distribution of signals (Figure 1D), and relative binding indices (BI) were calculated by dividing the individual SELENOP-aAb
Summary
Autoimmune thyroid disease (AITD) is characterized by an inappropriate interaction of immune cells with thyroid proteins. Inflammation, and lymphocytic infiltration into the thyroid gland, accompanied with autoantibodies (aAb) to thyroid antigens, are hallmarks of AITD [1]. In Graves’ disease, natural aAb to the TSH-receptor (TSHR-aAb) are causative for the clinical phenotype, as they bind as endocrine active agonists to the TSH-receptor and stimulate hyperthyroidism and thyroid eye disease [2]. Natural aAb to another thyroid autoantigen, namely the thyroperoxidase (TPO-aAb), are detectable in both Graves’ disease and Hashimoto’s thyroiditis, where they are associated with cell-mediated cytotoxicity [3]. The TPO-aAb are not directly causing the disease but rather reflect disease activity and disease risk in asymptomatic healthy subjects [4]. TPO-aAb-positive healthy women who become pregnant are, for example, at relatively high risk for the development of postpartum thyroiditis, potentially due to the declining selenium (Se) status during pregnancy [5,6]
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