Dr. Ron’s Research Review – April 13, 2016

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This week’s research review focuses on Epstein-Barr virus and autoimmune thyroid disease (Grave’s and Hashimoto's disease).

Viral infection, including Epstein-Barr virus (EBV), is one of the most frequently considered environmental factors involved in autoimmunity. In 34.5% of Hashimoto's thyroiditis cases the cytoplasmic expression of EBV latent membrane protein 1 (LMP1) was detected in follicular epithelial cells and in infiltrating lymphocytes. Virus-encoded small nuclear non-polyadenylated RNAs (EBER) nuclear expression was detected in 80.7% of Hashimoto's thyroiditis cases and 62.5% of Graves' disease cases, with positive correlation between LMP1 and EBER positivity in all Hashimoto's thyroiditis LMP1-positive cases. (Janegova et al., 2015)
An earlier study using PCR did not detect herpes simplex viruses types 1 and 2 (HSV-1, HSV-2), Varicella Zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV) and human herpes virus type 6 (HHV-6). (AL-Zarzour and Monem, 2011)
A study found that in Graves' disease patients with thyrotropin receptor (TRAb) levels ≥ 10%, EA antibody levels, which indicate EBV reactivation, were moderately but significantly correlated with the levels of TRAb, and weakly but significantly correlated with IgE. EBV-encoded small RNA (EBER)- in-situ hybridization revealed that one of our patients had EBV-infected lymphocytes infiltrating the thyroid gland. EBV reactivation may stimulate antibody-producing B lymphocytes predisposed to make TRAb, and this may contribute to or exacerbate the disease. (Nagata et al., 2011)

Dr. Ron


 

Articles

Are human herpes viruses associated with autoimmune thyroid disease?
            (AL-Zarzour and Monem, 2011) Download
INTRODUCTION: Autoimmune diseases are complex diseases with genetic, endogenous and environmental etiologies. Viral infections have been postulated as one of the factors that may be the trigger of autoimmune diseases. METHODOLOGY: Thyroid peroxidase (TPO) and thyroglobulin (TG) antibodies were measured before thyroidectomy in 100 subjects by chemiluminescence method, 50 of whom were autoimmune thyroid diseases (AITD) patients and 50 of whom were multinodular goiter (MNG) patients used as a control group. Fresh thyroid samples were collected from all 100 subjects after thyroidectomy to investigate the DNAs of herpes simplex viruses types 1 and 2 (HSV-1, HSV-2), Varicella Zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV) and human herpes virus type 6 (HHV-6) by PCR. RESULTS: The DNA of HSV-1, HSV-2, VZV, EBV, CMV and HHV-6 were detected in neither the patient group nor in the control group. The mean values of anti-TPO and anti-TG antibodies ranged within 9.5-2000 units/ml (527.8 +/- 617.4) and 108-5000 units/ml (1458.2 +/- 1774.1) in the AITD patients group, respectively. A statistically significant difference of the mean level of anti-TPO and anti-TG antibodies among the two groups was found (p value < 0.05). CONCLUSIONS: The possible role of human herpes viruses in the pathogenesis of AITD is not supported by our study; hence our raised question stays open for more investigation on more patients and in different parts of the country using different sizes and sites of biopsies.

The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases.
            (Janegova et al., 2015) Download
INTRODUCTION:  Autoimmune thyroid diseases, including Graves' and Hashimoto's thyroiditis, are the most frequent autoimmune disorders. Viral infection, including Epstein-Barr virus (EBV), is one of the most frequently considered environmental factors involved in autoimmunity. Its role in the development of AITD has not been confirmed so far. MATERIAL AND METHODS:  Surgical specimens of Graves' and Hashimoto's diseases and nodular goitres were included in the study. The expression of EBV latent membrane protein 1 (LMP1) was analysed by immunohistochemistry, with the parallel detection of virus-encoded small nuclear non-polyadenylated RNAs (EBER) by in situ hybridisation. RESULTS:  In none of the Graves' disease specimens but in 34.5% of Hashimoto's thyroiditis cases the cytoplasmic expression of LMP1 was detected in follicular epithelial cells and in infiltrating lymphocytes. EBER nuclear expression was detected in 80.7% of Hashimoto's thyroiditis cases and 62.5% of Graves' disease cases, with positive correlation between LMP1 and EBER positivity in all Hashimoto's thyroiditis LMP1-positive cases. CONCLUSIONS:  We assume that high prevalence of EBV infection in cases of Hashimoto's and Graves' diseases imply a potential aetiological role of EBV in autoimmune thyroiditis. The initiation of autoimmune thyroiditis could start with EBV latency type III infection of follicular epithelium characterised by LMP1 expression involving the production of inflammatory mediators leading to recruitment of lymphocytes. The EBV positivity of the infiltrating lymphocytes could be only the presentation of a carrier state, but in cases with EBER+/ LMP1+ lymphocytes (transforming latent infection) it could represent a negative prognostic marker pointing to a higher risk of primary thyroid lymphoma development.

The influence of Epstein-Barr virus reactivation in patients with Graves' disease.
            (Nagata et al., 2011) Download
In Graves' disease, the IgG class autoantibody against thyrotropin receptor (TRAb) is produced excessively and induces hyperthyroidism. Epstein-Barr virus (EBV) is one of the human herpesviruses that persists for life, mainly in B lymphocytes, and is occasionally reactivated. Therefore, EBV may affect the antibody production of B lymphocytes that would normally produce TRAb. The purpose of the present study was to evaluate the association of EBV reactivation with the etiology of Graves' disease. Serum levels of EBV antibodies and IgE were determined by ELISA. TRAb levels were determined by radioreceptor assay. We performed in-situ hybridization (ISH) of EBV-encoded small RNA (EBER)1 on the thyroid tissue of one of our patients. In Graves' disease patients with TRAb levels ≥ 10%, EA antibody levels, which indicate EBV reactivation, were moderately but significantly correlated with the levels of TRAb, and weakly but significantly correlated with IgE. EBER1-ISH revealed that one of our patients had EBV-infected lymphocytes infiltrating the thyroid gland. EBV reactivation may stimulate antibody-producing B lymphocytes predisposed to make TRAb, and this may contribute to or exacerbate the disease.

References

Nagata, K, et al. (2011), ‘The influence of Epstein-Barr virus reactivation in patients with Graves’ disease.’, Viral Immunol, 24 (2), 143-49. PubMed: 21449724
AL-Zarzour, N and F. Monem (2011), ‘Are human herpes viruses associated with autoimmune thyroid disease?’, J Infect Dev Ctries, 5 (12), 890-92. PubMed: 22169789
Janegova, A, et al. (2015), ‘The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases.’, Endokrynol Pol, 66 (2), 132-36. PubMed: 25931043