Subclinical Epstein-Barr Virus Primary Infection and Lytic Reactivation Induce Thyrotropin Receptor Autoantibodies

Abstract

Epstein-Barr virus (EBV) is a herpes virus that mainly infects in B lymphocytes and occasionally reactivates lytically. Most individuals have been infected with EBV primarily in their childhood with no symptoms, and the virus persists latently for life. We have previously reported that EBV-infected B cells with thyrotropin receptor autoantibodies (TRAbs) on their surface [TRAb(+) EBV(+) cells] were present in the peripheral blood mononuclear cells (PBMCs) of healthy adult controls and patients with Graves' disease, and that TRAbs released in the culture medium of PBMCs containing TRAb(+) EBV(+) cells by EBV reactivation. EBV lytic reactivation induced the differentiation of host B cells into plasma cells and antibody production. Various autoantibodies have been detected during the acute phase of infectious mononucleosis (IM) that is the symptomatic primary infection of EBV. Therefore, the autoantibody production may be induced by the asymptomatic primary infection. In this study, we examined the presence of TRAb(+) cells, EBV(+) cells, and TRAb(+) EBV(+) cells in PBMCs from 29 healthy or subclinical children without Graves' disease and one cord blood that were divided into six age groups, and also measured plasma TRAb levels. The results obtained demonstrated that low levels of TRAb production occurred with EBV primary infection and lytic reactivation in children without symptoms of IM. Furthermore, the populations of TRAb(+) cells, EBV(+) cells, and TRAb(+) EBV(+) cells were small in the period of primary infection, but they potentially expand with repeated EBV lytic reactivation. This may partly explain why the onset of Graves' disease often occurs in young adults, but rarely in infancy.

Epstein–Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity

“…We also noted some reports that had detected autoantibodies released from lymphocytes infected with exogenously-added EBV [18][19][20][21]. Tamoto et al recently reported that serum thyrotropin receptor antibodies (TRAbs) may be present even in asymptomatic EBV primary infection [22]. These findings support a relationship between EBV infection and autoimmunity.…”

HLA‐DRA Gene Polymorphisms Are Associated with Graves’ Disease as an Autoimmune Thyroid Disease

“…More recently, rs7197 SNP has been found to be closely related to the antibody response to viral elements such as capsid antigen of Epstein-Barr virus, and it is speculated that rs7197 genetic variation may play a role in disease susceptibility through immune-mediated specific microbial genes [31]. Combining our study with previous in vitro and in vivo evidence that Epstein-Barr virus infection is associated with TRAb production and GD occurrence [38,39], it is reasonable to infer that there is a natural association between rs3177928, rs7197 polymorphisms, and AITD development.…”

Graves’ disease: Epidemiology, genetic and environmental risk factors and viruses

“…Moreover, during the primary infection, TRAb(+) cells, EBV(+) cells, and TRAb(+) EBV(+) cells were small, but they expanded during EBV lytic reactivation. EBV infection reactivation might be associated with B lymphocytes expansion, and GD recurrence in Japanese patients (64).…”

“…In primary EBV infection, some infected cells become lytic. During infectious mononucleosis (IM), in the acute phases, defined as the symptomatic EBV primary infection, different autoantibodies are present in the serum of patients (64). EBV primary infection and lytic infection induce the production of antibodies.…”