Thyroid autoimmunity

TOPIC: Use of Pendrin antibody measurement in AITD

Title: Pendrin is a novel autoantigen recognized by patients with autoimmune thyroid diseases.

Authors: Yoshida A, Hisatome I, Taniguchi S, Shirayoshi Y, et al.

Reference: Journal of Clinical Endocrinology & Metabolism94: 442-448, 2009

Context

Pendrin is an apical protein of thyroid follicular cells, responsible for the efflux of iodide into the follicular lumen via an iodide-chloride transport mechanism. Whether pendrin is recognized by autoantibodies is presently unknown.

Objective

The objective was to examine the prevalence of autoantibodies against pendrin in autoimmune thyroid diseases (AITD) and compare the prevalence with that of thyroglobulin, thyroperoxidase, TSH receptor, and sodium iodide symporter autoantibodies.

Design

In a prevalent case-control study, the authors analyzed the sera of 140 patients with AITD (100 cases with Graves’ disease and 40 with Hashimoto’s thyroiditis) and 80 controls (50 healthy subjects, 10 patients with papillary thyroid cancer, 10 with systemic lupus erythematosus, and 10 with rheumatoid arthritis). Pendrin antibodies were measured by immunoblotting using extract of COS-7 cells transfected with pendrin and a rabbit polyclonal pendrin antibody.

Results

Pendrin antibodies were found in 81% of the cases and 9% of controls (O.R.: 44;P< 0.0001). Among the patients, pendrin antibodies were more frequent and with higher titers in Hashimoto’s thyroiditis than in Graves’ disease. Pendrin antibodies correlated significantly with thyroglobulin, thyroperoxidase, and sodium iodide symporter antibodies but not with TSH receptor antibodies. Pendrin antibodies were equally effective as thyroglobulin and thyroperoxidase antibodies in the diagnosis of AITD, especially in Hashimoto’s thyroiditis.

Conclusions

The study identifies pendrin as a novel autoantigen recognized by patients with autoimmune thyroid diseases and proposes the use of pendrin antibodies as an accurate diagnostic tool.

Commentary

More than 50 years ago the detection of thyroglobulin autoantibodies in sera form patients with Hashimoto’s thyroiditis provided the basis for the discovery of thyroid autoimmunity. Since then several thyroid autoantigens have been identified at the molecular level including thyroglobulin (Tg), thyroid peroxidase (TPO), TSH-receptor (TSHR) and, more recently, the sodium/iodide symporter (NIS), megalin, and a protein named uveal autoantigen with colloid domains and ankyrin repeats (UACA). While Tg, TPO and TSHR may be considered almost completely thyroid-specific (at least as expression of mature protein), NIS, megalin and UACA are expressed not only in the thyroid, but also in a limited number of other organs. In this article, Yoshida et al. provide compelling evidence that auto-antibodies reacting with pendrin are frequently present in the sera of patients with autoimmune thyroid diseases (AITD) (Hashimoto’s thyroiditis & Graves’ disease). These auto-antibodies recognize denatured and native pendrin protein as assessed, respectively, by western blot (showing both monomeric 90 Ka & dimeric 180 KDa bands) and by pokie games online immunofluorescence and flow cytometry on pendrin-trasfected COS-7 cells. Anti-pendrin amtobodies were detected more frequenly (97% versus 74%) and also at higher titers (median titer 150 U versus 50 U) in Hashimoto’s thyroiditis, compared to Graves’ disease. Anti-pendrin antibodies were absent in 50 healthy controls and in 10 patients with thyroid carcinoma. Presence of anti-pendrin antibodies were correlated to anti-Tg, anti-TPO, and (to a lesser degree) to anti-NIS antibodies, while they were not correlated with TSHR-Abs. In keeping with this finding, anti-pendrin antibodies preformed equally well compared to anti-Tg and Anti-TPO as diagnostic markers of AITD. Anti-pendrin antibodies were detected in a substantial minority of patients with other autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. However, these patients were all positive for anti-TPO and/or anti-Tg antibodies, strongly suggesting that the presence of pendrin antibodies may actually reflect the presence of an underlying coexisting autoimmune thyroid disease. Taken together, the present results strongly support the authors’ conclusion that pendrin is indeed an important novel thyroid autoantigen which may be proposed as a new diagnostic tool for AITD. The titer and frequency of anti-pendrin autoantibodies are much higher, compared to those reported so far for NIS, megalin and UACA antibodies. The importance of this study is far beyond the simple discovery of a new sensitive and specific serological marker of thyroid autoimmunity, since the recognition of pendrin autoimmunity could be the clue to understanding better some elusive features associated with AITD. Pendrin (first identified in 1997) belongs to a superfamily of anion transporters localized in the thyroid gland, inner ear and kidney. In the thyroid, pendrin is expressed at the apical surface of follicular cells, where it acts as a Cl-/I- exchanger regulating chloride transport from the cytoplasm to the colloid space. Pendrin acts also as a Cl-/HCO3- exchanger in the inner ear (stria vascularis of cochlea and endolymphatic duct and sac). Discovery of pendrin led to our understanding of the main clinical features of the “Pendred syndrome”, a genetic disorder transmitted as an autosomal recessive trait and characterized by sensorineural deafness and goiter, caused by mutations of the PDS gene coding for pendrin. It is therefore reasonable to hypothesize that anti-pendrin antibodies (or underlying anti-pendrin autoimmunity) might be responsible for some recently reported associations beween AITD and inner ear diseases, such sensorineural hearing loss in children born to mothers with positive circulating anti-TPO and increased prevalence of Hashimoto’s disease in patients with Menière syndrome. It can be anticipated that additional studies will soon be perfomed in order to assess the relevance of pendrin autoimmunity in the above conditions. Summary and Commentary prepared by Stefano Mariotti (Related to Chapters 6 (E) & 7 of TDM)