Thyrotropin Receptor Antibody (TRAb)-IgM Levels Are Markedly Higher Than TRAb-IgG Levels in Graves' Disease Patients and Controls, and TRAb-IgM Production Is Related to Epstein–Barr Virus Reactivation

Kumata, Keisuke; Nagata, Kazuhiro; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Fukata, Shuji; Hayashi, Kazuhiko

doi:10.1089/vim.2016.0043

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…In this study, we measured plasma TRAbs with RRA and TRAb-isotype ELISA, which we used in previous studies (6). However, the results obtained did not necessarily correlate, which may be attributed to differences in the detection system between RRA and ELISA.…”

Section: Discussionmentioning

confidence: 99%

“…RRA assesses the inhibition of TSH binding to TSHR by serum TRAbs (3), whereas ELISA evaluates the binding of serum TRAb to recombinant human TSHR (6). The binding of TRAb-IgM to TSHR may be structurally varied (4), and neutral antibody, which is a type of TRAb, may only be measured by ELISA because they do not occupy TSHR (10).…”

Section: Discussionmentioning

confidence: 99%

“…We examined TRAb-IgG and TRAb-IgM according to a previously described method (6). In brief, all plate wells were coated by 0.1 mg/L anti-TSHR IgG, incubated at 4°C overnight, and then washed.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

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“…Kumata et al recently showed that serum levels of TRAb-IgM were higher than those of TRAb-IgG in patients with Graves' disease and healthy controls, in contrast to serum levels of total-IgG being higher than those of total-IgM (9). Both of these findings support the rescue of autoreactive B cells by polyclonal B cell activation due to EBV reactivation.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease

et al. 2017

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Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein–Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.

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“…Аутоантитела стимулируют фолликулярные клетки щитовидной железы к выработке избытка гормонов, которые приводят к тиреотоксикозу. Данное положение лежит в основе патогенеза болезни Грейвса и болезни Хашимото [11,36]. Клинические проявления тиреоидита Хашимото обусловлены избытком функционального Toll-подобного рецептора 3, который из-за мутаций в ДНК экспрессирует тиреоциты у пациентов с латентной формой ЭБВИ [31,36].…”

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Autoimmune and lymphoproliferative malignant diseases associated with Epstein-Barr viral infection

et al. 2019

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Currently, in medical practice, there is a high interest in diseases caused by herpes viruses, among them the Epstein-Barr virus (EBV) occupies the leading place. Almost 90% of the worlds population over the age of 40 are infected with VEB. In patients of the first two years, the proportion of asymptomatic carriage reaches 90%, and at the age of 2-10 30-50%. The article considers current data on the impact of EBV on cellular and humoral immunity, its connection with autoimmune and lymphoproliferative diseases. EBV has been shown to play a significant role in the onset of oncological diseases such as Hodgkins lymphoma, Burkitts lymphoma, nasopharyngeal carcinomas, as well as autoimmune diseases systemic lupus erythematosus, rheumatoid arthritis, Sjogrenʼs syndrome, autoimmune hepatitis, lymphoid interstitial hepatitis, lymphoid interstitial syndrome. The results of studies over the past 5 years of cases of activation of autoimmune processes associated with EBV infection, as well as predisposing factors underlying these manifestations, are presented. Due to the fact that the autoimmune effect of EBV infection is manifested in various organs and tissues, this problem is multidisciplinary, affecting such fields of medicine as pediatrics, infectious diseases, endocrinology, oncology, gynecology, ophthalmology, gastroenterology, etc.

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Thyrotropin Receptor Antibody (TRAb)-IgM Levels Are Markedly Higher Than TRAb-IgG Levels in Graves' Disease Patients and Controls, and TRAb-IgM Production Is Related to Epstein–Barr Virus Reactivation

Cited by 12 publications

References 22 publications

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

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

Epstein–Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease

Autoimmune and lymphoproliferative malignant diseases associated with Epstein-Barr viral infection

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