HHV6 INFECTION OF THYROID CELLS MAY PROMOTE AUTOIMMUNE RESPONSES LEADING TO HASHIMOTO'S THYROIDITIS

Chronic lymphocytic thyroiditis, also known as Hashimoto's thyroiditis (HT) is the most common cause of hypothyroidism in the Western world. It is an autoimmune disease, where thyroid follicles are gradually destroyed by a variety of cell and antibody mediated immune processes. The involvement of viral infections has been frequently suggested as a major environmental factor, but no conclusive data are available. We analyzed fine needle biopsies from 34 HT patients for the presence and the transcriptional state of human herpesvirus 6 (HHV6). Controls, represented by 28 patients with benign follicular epithelial lesions, showed a low prevalence of HHV6 (10%, 3/28), with low viral load, and the transcriptional pattern showed a latent infection. Instead, samples from HT had a high prevalence of infection (82% vs 10%, p= 0.001), significantly higher viral load, and low-grade acute infection in 71% of HHV6 positive HT biopsies. HHV6 was latent in the blood of the same HT patients with acute thyroid infection. Purification of epithelial cells show that HHV6 is 100-fold more abundant in thyroid cells than in lymphocytes infiltrating the lesion. The tropism of HHV6 for thyroid cells was verified by infection of Nthy-ori3-l, a thyroid follicular epithelial cell line. The results showed that Nthy-ori3-l cells are permissive to HHV6 replication. Both HHV6 variants support productive infection for the first 7 days p.i., and subsequently persist establishing latency. HHV6 infection induce the expression of HLA class 11 antigens on thyroid infected cells, whereas HLA class 1 antigen expression is not affected. Furthermore, Nthy-ori3-l cells infected with HHV6 become target for innate NK cell killing and NK cells from HT patients show a significantly more efficient killing of HHV6 infected thyroid cells than healthy controls. These observations suggest a potential role for HHV6 in the development or triggering of HT.