Epstein-Barr Virus Lytic Reactivation Induces IgG4 Production by Host B Lymphocytes in Graves' Disease Patients and Controls: A Subset of Graves' Disease Is an IgG4-Related Disease-Like Condition.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory disease with characteristic histological findings and high serum IgG4 levels. Epstein-Barr virus (EBV) is a persistent herpesvirus in B lymphocytes, and we previously reported EBV reactivation-induced Ig production. We showed that EBV reactivation induced the production of thyrotropin receptor antibodies, the causative antibodies of Graves' disease. In the present study, we investigated whether EBV reactivation induced IgG4 production and if EBV-positive B cells or IgG4-positive plasma cells are present in the thyroid tissues of Graves' disease patients with lymphoplasmacytic infiltration. EBV-encoded small RNA1 (EBER1) in situ hybridization and immunohistochemistry for IgG and IgG4 were performed on seven resected thyroid tissues with lymphoplasmacytic infiltration collected from the thyroids of 11 Graves' disease patients. We then cultured the lymphocytes of 13 Graves' disease patients and 14 controls and induced EBV reactivation to measure IgG4 levels in culture fluids. We detected EBER1-positive cells and IgG4-positive plasma cells in the same area of thyroid tissues. EBV-reactivated cells with IgG4 on their surface were observed in culture cells, and IgG4 production was detected in culture fluids. The IgG4/IgG percentage was higher than that in normal serum level. A subset of Graves' disease is an IgG4-RD-like condition, not an IgG4-RD. EBV reactivation stimulates IgG4 production, which may result in high serum IgG4 levels and promote IgG4-positive plasma cell infiltration. EBER1 needs to be examined when an increase in IgG4-positive plasma cell numbers is noted.

Low prevalence of Merkel cell polyomavirus with low viral loads in oral and maxillofacial tumours or tumour-like lesions from immunocompetent patients: Absence of Merkel cell polyomavirus-associated neoplasms.

It was recently demonstrated that ~80% of Merkel cell carcinomas (MCCs) harbour a novel polyomavirus, Merkel cell polyomavirus (MCPyV). MCPyV has been detected in various human tissue samples. However, previous studies on the prevalence of MCPyV in oral tumours or tumour-like lesions are incomplete. To address this issue, we measured MCPyV DNA quantity using quantitative polymerase chain reaction (qPCR) in 327 oral tumours or tumour-like lesions and 54 jaw tumours or cyst lesions from 381 immunocompetent patients, as well as in 4 oral lesions from 4 immunosuppressed patients. qPCR revealed a low MCPyV prevalence (25/381, 6.6%) with low viral loads (0.00024-0.026 copies/cell) in oral and maxillofacial tumours and tumour-like lesions from immunocompetent patients. The prevalence was 7/176 (4.0%) in invasive squamous cell carcinomas (SCCs) [2/60 (3.33%) SCCs of the tongue, 4/52 (7.7%) SCCs of the gingiva and 1/19 (5.3%) SCCs of the floor of the mouth], 1/10 (10%) in dysplasias, 1/5 (20%) in adenocarcinomas, 2/13 (15.4%) in adenoid cystic carcinomas, 1/10 (10%) in non-Hodgkin's lymphomas, 3/10 (30%) in lipomas, 3/5 (60%) in neurofibromas, 1/3 (33.3%) in Schwannomas, 2/12 (16.7%) in Warthin's tumours, 2/11 (18.2%) in pyogenic granulomas, 1/14 (7.1%) in radicular cysts and 1/12 (8.3%) in ameloblastomas. The prevalence in lesions from immunosuppressed patients (1/4, 25%) was higher compared with that in lesions from immunocompetent patients (25/381, 6.6%), but the difference was not statistically significant. To the best of our knowledge, this study was the first to report prevalence data of MCPyV in tumours and cysts of the jaws (2/54, 3.7%). These data indicated absence of MCPyV-related tumours or tumour-like lesions in the oral cavity and jaws and suggested that the detected MCPyV DNA was derived from non-neoplastic background tissues with widespread low-level MCPyV infection.