Virologic and Immunologic Evidence Supporting an Association between HHV-6 and Hashimoto's Thyroiditis

Elisabetta Caselli,Ettore C Degli Uberti,Dario Di Luca,Enzo Cassai,Riccardo Dolcetti,Roberta Rizzo,Giorgio Trasforini,Maria Chiara Zatelli,Debora Martorelli,Sabrina Benedetti,Patrick S Moore

doi:10.1371/journal.ppat.1002951

Abstract

Hashimoto's thyroiditis (HT) is the most common of all thyroid diseases and is characterized by abundant lymphocyte infiltrate and thyroid impairment, caused by various cell- and antibody-mediated immune processes. Viral infections have been suggested as possible environmental triggers, but conclusive data are not available. We analyzed the presence and transcriptional state of human herpesvirus 6 (HHV-6) in thyroid fine needle aspirates (FNA) and peripheral blood mononuclear cells (PBMCs) from 34 HT patients and 28 controls, showing that HHV-6 DNA prevalence (82% vs. 10%, p≤0.001) and viral load were significantly increased in FNA from HT patients, and thyrocytes from HT FNA displayed a 100-fold higher HHV-6 DNA load compared to infiltrating lymphocytes. In addition, while HHV-6 was strictly latent in positive samples from controls, a low grade acute infection was detected in HT samples. HHV-6 variant characterization was carried out in 10 HT FNA samples, determining that all specimens harbored HHV-6 Variant A.The tropism of HHV-6 for thyroid cells was verified by infection of Nthy-ori3-1, a thyroid follicular epithelial cell line, showing that thyrocytes are permissive to HHV-6 replication, which induces de novo expression of HLA class II antigens. Furthermore, HHV-6-infected Nthy-ori3-1 cells become targets for NK-mediated killing, NK cells from HT patients show a significantly more efficient killing of HHV-6 infected thyroid cells than healthy controls, and HT patients have increased T-cell responses to HHV-6 U94 protein, associated to viral latency. These observations suggest a potential role for HHV-6 (possibly variant A) in the development or triggering of HT.

Highlights

Hashimoto’s thyroiditis (HT), or chronic lymphocytic thyroiditis, is a common autoimmune disease with unknown etiology and its prevalence has been increasing over the past 50 years [1,2,3]
Environmental factors are thought to be important in triggering autoimmune thyroid diseases (AITD), and viral infections have been suggested as possible environmental triggers [4], yet no conclusive evidence is available
We show that human herpesvirus 6 (HHV-6) establishes a productive in vivo infection of thyroid cells from HT patients, that infected thyrocytes become a target for innate NK killing, and that HT patients have

Summary

Introduction

Hashimoto’s thyroiditis (HT), or chronic lymphocytic thyroiditis, is a common autoimmune disease with unknown etiology and its prevalence has been increasing over the past 50 years [1,2,3]. Environmental factors are thought to be important in triggering autoimmune thyroid diseases (AITD), and viral infections have been suggested as possible environmental triggers [4], yet no conclusive evidence is available. Thyroid cells infected with human cytomegalovirus were shown to act as antigen presenting cells and might be involved in autoimmunity [7], patients with Graves’ disease display a higher frequency of EBV-infected B cells secreting antibody to TSH-R [8], and AITD patients have elevated antibody titers against EBV antigens [9]. Human herpesvirus 6 (HHV-6) DNA has been detected in HT tissue specimens, but not in tissues from Graves’ disease or multi nodular goiter [6]. Viral strains cluster in two variants: HHV-6A, with still unknown disease association, and HHV-6B, the etiologic agent of roseola (exanthem subitum), a childhood benign febrile disease

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