Schizophrenia is Associated With an Aberrant Immune Response to Epstein-Barr Virus

Abstract

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.

Keywords: Epstein–Barr virus; herpes virus; infection; schizophrenia.

Fig. 1.

Effect sizes of immunoglobulin G (IgG) antibody reactivity to Epstein–Barr virus (EBV) and other human herpesviruses by solid phase immunoassays in individuals with schizophrenia as compared to controls calculated using logistic regression models. **P < .001; #P < .05.

Fig. 2.

Odds ratios of immunoglobulin G (IgG) anti-EBV antibody levels in schizophrenia as compared to controls by percentile values of IgG antibodies to Epstein–Barr virus (EBV) virions, EBV Viral Capsid Antigen (VCA) and EBV nuclear antigen (NA). The odds ratios were calculated by the use of logistic regression models **P < .001, *P < .012, #P < .05.

Fig. 3.

Effect sizes of immunoglobulin G (IgG) antibody reactivity to individual Epstein–Barr virus (EBV) proteins as measured by quantitative western blot comparing reactivity in individuals with schizophrenia and controls. The effect sizes were calculated using logistic regression models employing *P < .012; #P < .05.