Hypothesis: bipolar disorder is an Epstein–Barr virus‐driven chronic autoimmune disease – implications for immunotherapy

Abstract

Bipolar disorder (BD) is a chronic disease characterised by episodes of major depression and episodes of mania or hypomania, with a worldwide prevalence of 2.4%. The cause of BD is unknown. Here, I propose the hypothesis that BD is a chronic autoimmune disease caused by Epstein-Barr virus (EBV) infection of autoreactive B cells. It is postulated that EBV-infected autoreactive B cells accumulate in the brain where they provide costimulatory survival signals to autoreactive T cells and differentiate into plasma cells producing pathogenic autoantibodies targeting brain components such as the N-methyl-D-aspartate receptor. It is also proposed that the accumulation of EBV-infected autoreactive B cells in the brain is a consequence of a genetically determined defect in the ability of CD8 + T cells to control EBV infection. The theory is supported by studies indicating that autoimmunity, EBV infection and CD8 + Tcell deficiency all have roles in the pathogenesis of BD. According to the hypothesis, BD should be able to be treated by EBV-specific T-cell therapy and to be prevented by vaccination against EBV in early childhood. Exposure to sunlight or appropriate artificial light should also be beneficial in BD by augmenting CD8 + T-cell control of EBV infection.

First-episode mania after COVID-19: A case series in Iran

“…Regarding potential neurotropic pathways for COVID-19 to trigger manic episodes, previous research has associated several viral infections with BD, including Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis B virus (HBV), and hepatitis C virus (HCV) ( 34 – 38 ). It has been hypothesized that an immune/inflammatory mechanism could induce changes in neurotransmitters at the limbic network ( 39 ), and several studies have found associations between BD and inflammation ( 34 , 35 , 40 , 41 ).…”

Circulating T‐cell subsets discrepancy between bipolar disorder and major depressive disorder during mood episodes: A naturalistic, retrospective study of 1015 cases

“…Though the results of different studies were conflicting, they all suggested that there were differences in T‐cell immune regulation between patients with BD and MDD. As potentially chronic and non‐infectious inflammatory diseases, BD and MDD were thought to be associated with abnormal levels of circulating immune cells and regulatory cytokines 12,22–24 . Several studies have shown that T cells were involved in the pathogenesis of mood disorders, and the interactions between mood, behavior, and the immune system were mediated by the endocrine and nervous systems 12,25–27 .…”

T cells: an emerging cast of roles in bipolar disorder

“…In addition, CD8 + T cells play a principal role in the regulation of Epstein-Barr virus (EBV) infection and psychological stress compromises the ability of CD8 + T cells to prevent the reactivation of latent EBV infection [ 106 , 107 ]. Stress may therefore increase the number of EBV-infected self-reactive B cells and plasma cells, thereby exacerbating BD, leading to increased stress and further affecting CD8 + T cell function in a vicious cycle [ 108 ]. At this stage, the pathways and potential mechanisms used by the microbiota to promote BD are only just emerging, all findings were associative, without establishing a causal relationship with BD pathogenesis, and their impact on T cell plasticity remains to be fully understood.…”

“…In addition, light therapy indirectly promotes cytokine production in Th1 cells and reduces the anti-inflammatory response of Th2 cells by enhancing melatonin on the one hand, and regulates lymphocyte function by directly restoring the balance between Th1 and Th2 functions and increasing the release of IL-2 and IL-10 [ 131 , 132 ]. The therapeutic role of EBV-specific T-cell therapy in BD has also been reported in the literature, considering the role of EBV infection in the pathogenesis of BD [ 108 ]. Many potential new strategies for normalizing neuroimmune pathways require further validation for their promise in BD treatment, and a better understanding of the role of the immune system, including T cells, in BD is a prerequisite for designing the most effective drugs.…”