Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10.

Theresa Porst,Waldemar B Minich,Jörg Johannes,Sebastian Mehl,Susanna Wiegand,Peter Kühnen,Kostja Renko,Richard Köhler,Lutz Schomburg,Hans Gluschke

doi:10.3390/biomedicines9050496

Abstract

The monocarboxylate transporters 8 (MCT8) and 10 (MCT10) are important for thyroid hormone (TH) uptake and signaling. Reduced TH activity is associated with impaired development, weight gain and discomfort. We hypothesized that autoantibodies (aAb) to MCT8 or MCT10 are prevalent in thyroid disease and obesity. Analytical tests for MCT8-aAb and MCT10-aAb were developed and characterized with commercial antiserum. Serum samples from healthy controls, thyroid patients and young overweight subjects were analyzed, and prevalence of the aAb was compared. MCT8-aAb were additionally tested for biological effects on thyroid hormone uptake in cell culture. Positive MCT8-aAb and MCT10-aAb were detected in all three clinical cohorts analyzed. MCT8-aAb were most prevalent in thyroid patients (11.9%) as compared to healthy controls (3.8%) and overweight adolescents (4.2%). MCT8-aAb positive serum reduced T4 uptake in cell culture in comparison to MCT8-aAb negative control serum. Prevalence of MCT10-aAb was highest in the group of thyroid patients as compared to healthy subjects or overweight adolescents (9.0% versus 4.5% and 6.3%, respectively). We conclude that MCT8 and MCT10 represent autoantigens in humans, and that MCT8-aAb may interfere with regular TH uptake and signaling. The increased prevalence of MCT8-aAb and MCT10-aAb in thyroid disease suggests that their presence may be of pathophysiological relevance. This hypothesis deserves an analysis in large prospective studies.

Highlights

The majority of thyroid hormones (TH) circulating in blood are not free, but bound to TH binding proteins due to their hydrophobic nature, namely to albumin, thyroxine binding globulin, and transthyretin, respectively
The signals obtained from the commercial antiserum samples in dilution experiments with human serum as matrix were correlating positively to the antibodies in the novel autoantibody tests with the monocarboxylate transporters 8 (MCT8)-luciferase gene (Luc)-fusion protein (Figure 1A) and MCT10-Luc-fusion protein (Figure 1B), respectively
Few slightly positive serum samples were identified by the MCT8-aAb assay (Figure 2A), and several strongly positive samples were found by the MCT10-aAb assay (Figure 2B)

Summary

Introduction

The majority of thyroid hormones (TH) circulating in blood are not free, but bound to TH binding proteins due to their hydrophobic nature, namely to albumin, thyroxine binding globulin, and transthyretin, respectively. In order to exert TH signaling via the nuclear TH receptors, TH need to pass the plasma membrane of target cells [1]. TH are charged amino acid derivatives and unable to diffuse across the hydrophobic membrane segments. Transmembrane proteins enabling passive TH passage or capable of actively transporting TH are essentially needed [2]. There is a large number of potential TH transporters differing in structure, expression pattern, transport preferences and regulation of biosynthesis, activity and trafficking [3]. The gene encoding MCT8 (SLC16A2) is located on the X-chromosome, and transport-impeding mutations in SLC16A2 are interfering with regular TH signaling, thereby disturbing muscular, neuronal and intellectual development.

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Discussion

Conclusion