Aberrant Epstein-Barr Virus Response Associated With Schizophrenia

Investigators confirmed that people with schizophrenia have higher levels of antibodies to some but not all Epstein-Barr virus proteins, which indicates an aberrant response to Epstein-Barr virus infection that may be a factor in the immunopathology of schizophrenia and related disorders.

An aberrant response to Epstein-Barr virus (EBV) may contribute to the pathology of schizophrenia, according to study data published in Schizophrenia Bulletin.

Solid phase immunoassay techniques were used 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 psychiatric illness. Specifically, reactivity levels to EBV-viral capsid antibody (VCA), EBV nuclear antigen-1 (EBNA-1), and other human herpesviruses were compared among study participants. Further, quantitative Western blot testing was performed to identify reactivity to specific EBV proteins in 257 individuals (150 with schizophrenia; 107 control participants). Polygenic risk for schizophrenia was assessed according to the Illumina array, conducted using whole-blood DNA. Assay results were compared between individuals with schizophrenia and control participants, employing parametric and nonparametric regression models. Clinical, genetic, and demographic measures were also compared between groups.

Significantly elevated levels of IgG antibodies to EBV virions were observed in the schizophrenia group compared with the control group (P =.0002). Increased levels of IgG antibodies to VCA were also observed in the schizophrenia group (P =.025), although not increased levels of antibodies to EBNA-1. Investigators also measured antibodies to other human herpesviruses (herpes simplex virus 1 and 2, cytomegalovirus, vesicular stomatitis virus, and human herpesvirus 6) and found no significant between-group differences in antibody levels. Increased odds of IgG anti-EBV antibody levels were observed relative to cutoffs above the 50th (odds ratio [OR], 1.71 (95% CI, 1.18-2.48; P =.005), 75th (OR, 2.22; 95% CI, 1.50-3.28; P <.001), and 90th (OR, 2.31; 95% CI, 1.39-3.84; P =.001) percentiles of antibody levels in control participants. Increased odds of antibodies to VCA, although not EBNA-1, were also observed in the schizophrenia group compared with the control group for cutoffs above the 50th, 75th, and 90th percentiles.

According to Western blot assay results, schizophrenia diagnosis was associated with increased levels of antibodies to VCA p33 (P <.005), VCA p22 (P <.008), VCA p41 (P <.012), and viral protein p27 (P <.011). No schizophrenia-associated increases in antibodies to EBNA-1 p79 or other antigens were observed, however, which confirmed the lack of between-group difference in EBNA-1 reactivity levels. According to logistic regression models, elevated levels of anti-EBV virion antibodies were significantly associated with the presence of deficit syndrome and use of the medication valproate (both P <.005), although not other medications, body mass index, or Positive and Negative Syndrome Scale score. The polygenic risk score was associated with an increased risk for schizophrenia in the study population (P <.001). Investigators observed an additive effect of odds ratios associated with the polygenic risk score and EBV virion antibodies. Specifically, participants with exposure to both factors had 8.86-fold odds of a schizophrenia diagnosis (95% CI, 2.59-30.37; P <.001).

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According to these data, individuals with schizophrenia have significantly increased levels of IgG antibodies to EBV virions compared with control participants. These differences were independent of demographic variables known to affect EBV exposure. Given the elevated level of antibodies to EBV VCA, but not EBNA-1, researchers concluded that individuals with schizophrenia experienced an “aberrant immune response” to EBV. Future longitudinal research is necessary to explore the relationship between EBV response and schizophrenia. Investigators postulated that psychiatric symptoms may be related to the neuroinflammatory effects of EBV and aberrant response. In any case, understanding the role of antibodies against EBV and schizophrenia pathology may be illuminating for the prevention and treatment of this disease.


Dickerson F, Jones-Brando L, Ford G, et al. Schizophrenia is associated with an aberrant immune response to Epstein-Barr virus [published online November 20, 2018]. Schizophr Bull. doi: 10.1093/schbul/sby164