1. Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein–Barr virus infection
- Author
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Amelia Biasiucci, Carmelo Giardina, Carlo Antozzi, Claudia Barzago, Silvia Bonanno, Barbara Galbardi, Lorenzo Maggi, Francesca Andreetta, Teresio Motta, Giorgia Camera, Renato Mantegazza, Stefania Marcuzzo, Dimos Kapetis, Pia Bernasconi, Paola Cavalcante, Sara Franzi, Fulvio Baggi, Cavalcante, P, Galbardi, B, Franzi, S, Marcuzzo, S, Barzago, C, Bonanno, S, Camera, G, Maggi, L, Kapetis, D, Andreetta, F, Biasiucci, A, Motta, T, Giardina, C, Antozzi, C, Baggi, F, Mantegazza, R, and Bernasconi, P
- Subjects
Adult ,Male ,0301 basic medicine ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Myeloid ,Adolescent ,Immunology ,Myasthenia gravi ,Thymus Gland ,Biology ,Lymphocyte Activation ,03 medical and health sciences ,Antigen ,Interferon ,Myasthenia Gravis ,medicine ,Humans ,Immunology and Allergy ,RNA, Messenger ,Thymu ,Antigens, Viral ,Cell Proliferation ,Autoimmune disease ,B-Lymphocytes ,Innate immune system ,Macrophages ,virus diseases ,TLR9 ,Germinal center ,Toll-like receptor 9 ,Dendritic Cells ,Interferon-beta ,Epstein-Barr viru ,Hematology ,Germinal Center ,medicine.disease ,Myasthenia gravis ,Toll-like receptor 7 ,Ki-67 Antigen ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Female ,Signal Transduction ,medicine.drug - Abstract
Considerable data implicate the thymus as the main site of autosensitization to the acetylcholine receptor in myasthenia gravis (MG), a B-cell-mediated autoimmune disease affecting the neuromuscular junction. We recently demonstrated an active Epstein-Barr virus (EBV) infection in the thymus of MG patients, suggesting that EBV might contribute to the onset or maintenance of the autoimmune response within MG thymus, because of its ability to activate and immortalize autoreactive B cells. EBV has been reported to elicit and modulate Toll-like receptor (TLR) 7- and TLR9-mediated innate immune responses, which are known to favor B-cell dysfunction and autoimmunity. Aim of this study was to investigate whether EBV infection is associated with altered expression of TLR7 and TLR9 in MG thymus. By real-time PCR, we found that TLR7 and TLR9 mRNA levels were significantly higher in EBV-positive MG compared to EBV-negative normal thymuses. By confocal microscopy, high expression levels of TLR7 and TLR9 proteins were observed in B cells and plasma cells of MG thymic germinal centers (GCs) and lymphoid infiltrates, where the two receptors co-localized with EBV antigens. An increased frequency of Ki67-positive proliferating B cells was found in MG thymuses, where we also detected proliferating cells expressing TLR7, TLR9 and EBV antigens, thus supporting the idea that EBV-associated TLR7/9 signaling may promote abnormal B-cell activation and proliferation. Along with B cells and plasma cells, thymic epithelium, plasmacytoid dendritic cells and macrophages exhibited enhanced TLR7 and TLR9 expression in MG thymus; TLR7 was also increased in thymic myeloid dendritic cells and its transcriptional levels positively correlated with those of interferon (IFN)-β. We suggested that TLR7/9 signaling may be involved in antiviral type I IFN production and long-term inflammation in EBV-infected MG thymuses. Our overall findings indicate that EBV-driven TLR7- and TLR9-mediated innate immune responses may participate in the intra-thymic pathogenesis of MG.
- Published
- 2016