Schizophrenia Is Associated With an Aberrant Immune Response to Epstein–Barr Virus

Faith Dickerson; Lorraine Jones-Brando; Glen Ford; Giulio Genovese; Cassie Stallings; Andrea Origoni; Colm O'Dushlaine; Emily Katsafanas; Kevin Sweeney; Sunil Khushalani; Robert Yolken


Schizophr Bull. 2019;45(5):1112-1119. 

In This Article

Abstract and Introduction


Background: Epstein–Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection.

Methods: We employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures.

Results: Individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis.

Conclusions: Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders.


Schizophrenia is a serious neuropsychiatric disorder of uncertain etiology with a lifetime prevalence of approximately 1% in the United States. While schizophrenia has clear genetic underpinnings, currently known genes explain only a portion of disease risk.[1,2] In addition to genetic factors, environmental exposures have been identified as increasing risk for the disease. Environmental factors associated with increased risk of schizophrenia include winter-spring birth, urban birth, maternal preeclampsia, and perinatal and postnatal infections.[3–6] The potential role of infections in the etiopathogenesis of schizophrenia is supported by the associations between schizophrenia risk and genes which encode HLA and other factors which control the immune response to infectious agents.[1,7]

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae family. EBV is a lymphotropic virus that produces latent infections with immunomodulatory effects.[8,9] Primary infection with EBV is often associated with self-limited fever and adenopathy. Following acute infection, the virus persists in host B and T lymphocytes, monocytes, and epithelial cells; asymptomatic salivary viral shedding leads to onward transmission.[10] EBV can establish latency in many body sites including the brain where reactivation can be associated with encephalitis[11] and brain-specific immune responses.[12] The immune response to EBV infection can be monitored by the measurement of levels of antibody directed at antigens derived from virions as well as specific EBV proteins. Commonly measured anti-EBV antibodies include: anti-early antigen (EA) that arises early in the course of infection and decreases after 3–6 months; viral capsid antibody (VCA) that also arises early in infection but persists for extended periods of time; anti-EB nuclear antigen (EBV NA or EBNA) that does not arise until late in infection but does persist for extended periods of time[13,14] (supplementary figure 4). The response to additional EBV proteins can be measured by western blotting techniques[15] to further define the immune response to infection.

Supplemental Figure 4.

Classic time course of anti-EBV antibodies. Following acute infection, IgG class anti-EBV antibodies arise first to early antigens (EA) followed closely by viral capsid antigens (VCA). Anti-EBV nuclear antigen (NA) arises slowly over a period of months until reaching a plateau in the chronic infection stage. Antibodies not measured in the current report are labeled in grey. Modified from Wong, G. 1999.

EBV infections have been associated with a number of autoimmune disorders including multiple sclerosis, systemic lupus, autoimmune encephalitis, and fibromyalgia.[16,17] In many cases the immune response to EBV in individuals with these disorders is aberrant and differs from the immune response noted in otherwise healthy individuals in terms of the response to EA, VCA, and EBNA antigens.[18,19]

Many individuals with EBV-associated disorders have psychiatric symptoms during the course of their illness. For example, in the disorder systemic lupus, cognitive dysfunction is reported to occur in more than 80% of patients and psychosis in more than 20%.[20] Individuals with multiple sclerosis also have relatively high rates of cognitive impairment[21] and psychiatric symptoms[22] including psychosis.[23] However, there have been few studies of EBV exposure in individuals with schizophrenia. We thus measured the levels of antibodies to EBV virions and defined EBV proteins in a cohort of individuals with schizophrenia and compared these to levels in a group of control individuals without a history of psychiatric symptoms.