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Published in final edited form as: J Affect Disord. 2019 Nov 30;264:221–226. doi: 10.1016/j.jad.2019.11.150

Atypical Immune Response to Epstein-Barr Virus in Major Depressive Disorder

Lorraine Jones-Brando 1,4,*, Faith Dickerson 2,4, Glen Ford 3, Cassie Stallings 2, Andrea Origoni 2, Emily Katsafanas 2, Kevin Sweeney 2, Amalia Squire 2, Sunil Khushalani 2, Robert Yolken 1
PMCID: PMC7025817  NIHMSID: NIHMS1547165  PMID: 32056754

Abstract

Background:

An atypical immune response to Epstein-Barr virus (EBV) infection has been associated with several complex diseases including schizophrenia. The etiology of MDD is unclear; host immune response to EBV infection could play a role.

Methods:

We utilized solid phase immunoassays and western blots to measure antibodies to EBV virions, specific viral proteins, and 5 other herpesviruses in 87 individuals with MDD and 312 control individuals.

Results:

Individuals with MDD had significantly reduced levels of reactivity to EBV Nuclear Antigen-1. Quantitative levels of antibodies to EBV virions and Viral Capsid Antigen did not differ between groups. Individuals with decreased levels of anti-Nuclear Antigen-1, or elevated levels of anti-virion had increased odds of being in the MDD group. The odds of MDD were elevated in individuals who had the combination of high levels of anti-virion and low levels of anti-Nuclear Antigen-1 (OR =13.6). Western blot analysis corroborated decreased reactivity to Nuclear Antigen-1 in the MDD group and revealed altered levels of antibodies to other EBV proteins. There was a trend towards decreased levels of antibodies to varicella virus in the groups of individuals with MDD.

Limitations:

The MDD sample size was relatively small. There could be unmeasured factors that account for the association between MDD and the immune response to EBV.

Conclusions:

Individuals with MDD have altered levels and patterns of antibodies to EBV antigens. This atypical response could contribute to the immunopathology of MDD. Therapeutic interventions available for treatment of EBV infection could potentially be of benefit in MDD.

Keywords: Major depressive disorder, Epstein-Barr virus, herpesvirus, infection, immune response

Introduction

Major depressive disorder (MDD) is a common and potentially debilitating psychiatric disorder of uncertain etiology with a lifetime prevalence of approximately 16% in the United States (de Melo et al., 2017; Levine et al., 2014). While MDD has genetic underpinnings, there are many genes of small effect and the polygenic risk score explains only 1–2 % of genetic risk (Lopizzo et al., 2015). Alternatively, it has been hypothesized that the etiology of depression is related to cell-mediated immune activation and inflammation and / or to an infectious disease exposure (Canli, 2014; de Melo et al., 2017).

Epstein Barr Virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing a persistent infection with associated immunomodulatory effects (Ambinder, 2003; Ambinder and Lin, 2005). Primary infection with EBV, historically acquired during childhood or adolescence, most often results in fever and lymphadenopathy of short duration but can be asymptomatic. During the course of the acute infection, the virus establishes a persistent infection in subsets of host B and T lymphocytes, monocytes, and epithelial cells; asymptomatic virus shedding from persistently-infected salivary glands can lead to transmission to new hosts (Dunmire et al., 2018; Niederman et al., 1976; Feinstein et al., 2014). Persistent EBV infection gradually develops into a quiescent, reactivatable latent infection that can be harbored in many body organs including the brain. Severe complications, including encephalitis (Martelius et al., 2011) and brain specific immune responses (Tzartos et al., 2012) result from reactivation of the latent infection. Serological tests can document the immune response to EBV infection by measuring levels of antibody directed at a complete set of viral antigens derived from whole virions as well as directed at subsets of purified viral proteins. Test panels typically include measurements of antibodies directed toward viral early antigen (EA), that rises early in the course of infection and then falls after 3–6 months, viral capsid antigen (VCA), that also rises early in infection but persists for years, and EB nuclear antigen (EBNA), that generally rises late in infection and persists for years (Andersson et al., 1994; Gulley and Tang, 2008; Middeldorp, 2015) (see Supplementary Fig. S1). Antibody recognition of specific EBV proteins can be measured and confirmed by western blotting techniques (Gulley and Tang, 2008; Lin et al., 1985) to more specifically define the immune response to infection.

Latent EBV infections reportedly are associated with a number of autoimmune disorders including rheumatoid arthritis, multiple sclerosis, systemic lupus, systemic sclerosis, autoimmune encephalitis, autoimmune thyroiditis, and fibromyalgia (de Almeida and Ward, 2019; Draborg et al., 2013; Farina et al., 2017; Hassani et al., 2018; Montoya et al., 2013). In a majority of cases the immune response to EBV in individuals with these disorders differs from that noted in otherwise healthy individuals in terms of the magnitude and timing of the antibody response to EA, VCA, EBNA antigens, and whole virions as well as in measures of innate immunity (Farina et al., 2014; Farina et al., 2017; Meszaros et al., 2012). Many individuals with these autoimmune diseases have psychiatric symptoms including depression and other mood symptoms (Feinstein et al., 2014) (Grafman et al., 1991; Murphy et al., 2017).

Exposure to EBV has also been associated with psychiatric complications or disorders in the absence of a defined autoimmune disease (Leavell et al., 1986). In a recent study we found that individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population (Dickerson et al., 2019). Further analyses indicated increased levels of reactivity to VCA but not to 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. Exposure to EBV has also been associated with attachment anxiety, psychotic experiences in adolescence, and cognitive impairments in some individuals. (Behr et al., 2006; Khandaker et al., 2014)

Only a few studies have examined the association between exposure to EBV and depression. In a community sample of adolescents, increasing depressive symptoms were significantly associated with salivary shedding of EBV DNA in females. Also in community samples of women, depressive symptoms in pregnancy were associated with Epstein-Barr virus reactivation (Ford and Stowe, 2017; Haeri et al., 2011; Zhu et al., 2013). To our knowledge, the comprehensive immune response to EBV proteins has not been studied in individuals with major depressive disorder ascertained in a psychiatric treatment setting.

The purpose of the current study was to measure the levels of antibodies to EBV virions and defined EBV proteins in a cohort of individuals with major depressive disorder and compare these to levels in a group of control individuals without a history of psychiatric symptoms.

Methods

Study population

The participants with major depressive disorder were recruited from acute hospital programs and affiliated outpatient settings at Sheppard Pratt for a study on the association between antibodies to infectious agents and psychiatric disorders (Dickerson et al., 2003). The control individuals without a history of psychiatric disorder were recruited from posted announcements at local health care facilities and universities in the same geographic area as the sites where the individuals with depression were drawn.

Individuals with major depressive disorder met the following criteria: age between 18–65 inclusive, diagnosis of major depressive disorder criteria in the Diagnostic and Statistical Manual of Mental Disorder Fourth Edition (DSM-IV). Individuals in the non-psychiatric control sample met the criteria: age between 18–60 inclusive, absence of a current or past psychiatric disorder as confirmed by screening with the Structured Clinical Interview for DSM-IV Axis I Disorders – Non-patient Edition (SCID-I/NP). The studies were approved by the Institutional Review Boards of the Sheppard Pratt Health System and the Johns Hopkins Medical Institutions following established guidelines. All participants provided written informed consent after the study procedures were explained.

Solid Phase Immunoassay Measurements

IgG antibodies to Epstein Barr Virus antigens derived from intact virions were measured by means of solid phase enzyme immunoassay as previously described (Dickerson et al., 2019). IgG antibodies to EBV-viral capsid antigen (VCA) and EBV Nuclear Antigen-1 (EBNA-1) were measured by solid phase immunoassay employing commercially available assay kits (IBL America, Minneapolis, MN.) (Dickerson et al., 2003). IgG antibodies to other human herpesviruses were measured by similar procedures (Dickerson et al., 2003; Severance et al., 2011). To allow for comparison across assays, the levels of antibodies were standardized to a control group employing mean value of 1 and a standard deviation of 1. Complete baseline sample sets consisting of individual blood samples for all participants were available for all of the solid phase immunoassay tests.

Western Blot Analysis

Samples were available for western blot from 239 individuals, 85 of whom are individuals with major depressive disorder and 154 controls. There were 2 individuals with major depressive disorder in which available samples were not adequate for Western Blot testing. The individuals from whom samples were available for western blot did not differ significantly from the overall study population in any demographic or clinical variable. Quantitative western blot assays were performed using previously described methods (Dickerson et al., 2019).

Demographic and Clinical Measures:

Demographic and background information was obtained by interview. A review of systems was conducted including a past history of immunological disorders. Body Mass Index (BMI) was calculated based on height and measured weight. Participants were also asked about current cigarette smoking status. All participants were individually administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (Randolph et al., 1998). The individuals with major depressive disorder were interviewed and rated on the Brief Psychiatric Rating Scale and the Hamilton Depression Rating Scale (Kay et al., 1987) and their medication data were recorded from the clinical chart. Maternal education was used a as a proxy for premorbid socioeconomic status.

Statistical Analyses.

The levels of antibodies to EBV virions and defined EBV proteins in individuals with depression and non-psychiatric controls were compared using linear regression models employing age, sex, and race as covariates. Logistic regression models were employed to calculate the odds ratios associated with increased or decreased levels of antibodies to the EBV proteins For these analyses, decreased levels of antibodies were defined as antibody levels that were ≤25th percentile of the control group and increased levels were defined as levels of antibody which were ≥75th percentile of the levels of the controls. Percentile cutoffs were employed to allow for the calculation of individual and combined adjusted odds ratios as well as to account for possible non-normal distribution of some of the data.

Within the depression group, the relationship between levels of EBV antibodies and demographic and clinical variables were explored using regression models. Variables measured included age, sex, race, place of birth, level of parental education, cigarette smoking, drug/alcohol abuse, medications, past medical history, RBANS cognitive scores, and BPRS and Hamilton Depression rating scales.

The results of the Western Blot analyses were analyzed using linear regression models with the covariates of age, sex, and race. In addition, total individual IgG levels were estimated by means of a control band located on each test strip. (see Supplementary Fig. S2) The resulting intensity values of reactivity were incorporated into the regression model.

In light of the performance of three sets of immunoassay measurements (EBV virions, VCA, EBNA-1) a critical value of p≤.05/3 = .016 was employed to indicate statistical significance for assays using these measures. A value of .016 ≤ p ≤ .05 was considered to represent a trend. In terms of the measurements of the other 5 human herpesviruses a value of p<.05/5 = .01 was employed to represent statistical significance and a value of .01 ≤ p ≤ .05 to represent a trend. These values were also employed for the determination of significance and trend in the Western blot measurements of reactivity to individual viral proteins. All statistical analyses were performed with STATA version 15, College Station, Texas.

Results

The demographic and clinical characteristics of the 399 individuals in the study, 87 individuals with major depressive disorder and 312 non-psychiatric controls, are presented in Table 1. All but three of the major depressive disorder participants had a diagnosis of recurrent major depressive disorder rather than a single episode. A total of 68 (78%) of the major depressive disorder participants were ascertained and evaluated when they were receiving treatment on an inpatient unit; the remainder were recruited from the day hospital setting (11, 13%) or other outpatient program (8, 9%). The following medications were the most commonly received at the time of the study assessment by the persons in the depression group: antidepressant (n=72, 83%); atypical antipsychotic (n=36, 41%); lithium (n=5, 6%).

Table 1.

Demographic and clinical characteristics of study populations1

MAJOR DEPRESSIVE DISORDER (N=87) NON-PSYCHIATRIC CONTROLS (N=312)
Age, years 35.2 (±13.8) 32.0 (±11.2)
Sex male 35 (40.2%) 122 (39.1%)
Race
 Caucasian 59 (67.8%) 153 (49.0%)
 African American 22 (25.2% 111 (35.6%)
 Asian 1 (1%) 30 (9.6%)
 Hispanic 3 (3.4%) 4 (1%)
 Other 2 (2.3%) 14 (4.5%)
Maternal education, years 13.8 (±2.4) 13.8 (±2.6)
Years education 12.3 (±2.2) 15.5 (±2.5)
Body Mass Index2 31.4 (±8.8) 27.5 (±6.9)
Current cigarette smoker 15 (17.2%) 46 (14.8%)
RBANS cognitive score3 80.8 (±13.7) 85.5 (±11.9)
BPRS symptom score4 48.1 (±7.5) ---
Ham-D symptom score5 29 (±10.2) ---
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1

Continuous variables expressed as mean (± sd) and dichotomous variables as number (percent). The groups differed significantly (p<.05) in variables except sex and maternal education [Stats below*]

2

n=253 in control group

3

RBANS, Repeatable Battery for the Assessment of Neuropsychological Status

4

BPRS, Brief Psychiatric Rating Scale

5

Ham-D, Hamilton Depression Rating Scale; n=79

*Age: F=4.81, p=.0289

*Years educ: F=31.64, p<.001

*RBANS F=10.14, p=.0016

*Race chi2=9.63, p=.002 (Caucasian vs. non-Caucasian)

*BMI: F=17.60, p<.001

Initial analyses were performed to compare the quantitative levels of individual EBV antibodies between the diagnostic groups adjusting for age, sex, and race. As shown in Figure 1, there were significantly decreased levels of antibodies to EBNA-1 (coefficient = −0.345, 95% CI −.570, −.121, p=.003) in the major depressive disorder group. The quantitative levels of whole virion antibodies and the levels of VCA antibodies did not differ between the groups (p>.05).

Figure 1.

Figure 1

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Coefficients of IgG antibody reactivity to EBV and other human herpesviruses by solid phase immunoassays in individuals with major depressive disorder as compared to controls calculated using logistic regression models adjusted for covariates. Red bars indicate EBV proteins, black bars indicate other herpesviruses. Error bars indicate 95% confidence intervals. * p=.003; # p=.013

We also calculated the odds ratios associated with levels of EBV antibodies which were above or below levels defined by the percentiles of the levels measured in the controls. As depicted in Figure 2, increased odds of major depressive disorder were associated with low levels of antibody to EBNA as defined by values ≤25th percentile of controls (OR 2.0, 95% CI, 1.2 −3.4, p<.01) and increased levels of antibodies to EBV virion proteins as defined by values ≥75th percentile of the controls (OR 2.3, 95% CI 1.3–3.9, p<.003). There were no significant differences associated with increased or decreased levels of VCA. Individuals who had the combination of levels of antibodies to whole virion ≥75th percentile and levels of anti-EBNA ≤25th percentile had significant odds of being in the major depressive disorder group of 13.6 (95% CI 4.0, 46.5, p<.0001) adjusted for age, sex, and race).

Figure 2.

Figure 2

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Odds ratios of a major depressive disorder diagnosis associated with values ≤25th percentile, ≥50th percentile, and ≥75th percentile of the indicated EBV proteins. Error bars indicate 95% confidence intervals. ** p<.003, *p<.01 adjusted for covariates.

We also measured antibodies to 5 other human herpesviruses HSV-1, HSV-2, CMV, VZV, and HHV6. There were no significant differences between the depression and the control groups in any of these antibody levels except for VZV which showed a trend towards reduction in the depression group (coefficient = −.305, 95% CI −.546, −.065, p=.013, adjusted for age, sex, and race). (Figure 1)

We further measured the immune reactivity of samples to specific EBV proteins employing a quantitative western blot assay system in 85 persons with major depressive disorder and 154 controls (Supplementary Fig. S2). As depicted in Figure 3, the individuals with major depressive disorder had a significant increase in antibody levels to VCA p42 (coefficient = 10.2, 95% CI 2.8, 17.6, p<.007), as well as a significant decrease in antibodies to the EBV early antigen EA-D p43 (coefficient = −13.9, 95% CI −22.0, −5.9, p<.001). Individuals with major depressive disorder also displayed trends of lower levels of reactivity to EBNA-1 p79 (coefficient = −11.7, 95% CI −21.6, −1.87, p<.02), VCA p22 (coefficient = −13.5, 95% CI −26.3, −.79, p<.037), and VCA p40 (coefficient = −9.2, 95% CI −18.5, −.002, p<.05) all adjusted for age, sex, race, and total IgG level.

Figure 3.

Figure 3

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Coefficients of IgG antibody reactivity to individual EBV proteins as measured by quantitative western blot comparing reactivity in individuals with major depressive disorder and controls. The effect sizes were calculated using logistic regression models employing covariates. Error bars indicate 95% confidence intervals. ***p<.001, ** p<.007, * p<.02. # p<.05

We examined the relationship between antibodies to EBNA and clinical and demographic variables within the group of individuals with depression. In terms of basic demographic variables, the levels of antibodies to EBNA, EBV virion proteins and VCA were positively associated with age and negatively associated with Caucasian race. The levels of antibodies to EBV virions and VCA were also positively associated with female sex (all p<.01). None of the antibody levels were significantly associated with cognitive scores, clinical ratings of depression or psychosis, cigarette smoking, drug/alcohol abuse, medications or a past history of immunological disorders when adjusted for age, sex, and race.

Discussion

We found that individuals with major depressive disorder had evidence of an altered immune response to EBV. This immune response was mainly characterized by relatively decreased levels of antibodies to the EBNA-1. While there were no significant differences in the quantitative levels of antibodies to EBV virions, we did detect an increased odds of major depressive disorder in individuals with values ≥75th percentile of the controls, suggesting a nonlinear association between antibody levels of major depressive disorder diagnosis. There were particularly high odds of a diagnosis of major depressive disorder in individuals with decreased levels of antibodies to EBNA-1 defined as levels ≤25th percentile of the controls combined with increased levels of antibodies to EBV virions ≥ 75th percentile suggesting that individuals with this pattern of response may be at particularly high risk of major depressive disorder. Recently, EBNA-1 peptides have been identified as the principal source of cross-reactivity with brain antigens such as myelin basic protein (Jog et al., 2019) and nuclear ribonucleoprotein L (Lindsey et al., 2016). It is thus plausible that individuals with low levels of immune response to EBNA-1 in the presence of increased reactivity to other EBV proteins might be of high risk for immune pathology within the central nervous system. Additional studies of EBNA-1 reactivity should be performed to further define immune phenotypes associated with decreased reactivity to EBNA proteins.

We have recently reported an aberrant response to EBV in individuals with schizophrenia (Dickerson et al., 2019). Both individuals with schizophrenia and individuals with major depressive disorder have increased levels of antibodies to EBV virions compared to controls. However the aberrant response to EBV in the former population differed from that in individuals with major depressive disorder in that individuals with schizophrenia have increased levels of antibodies to EBV VCA and virion proteins and levels of antibodies to EBNA which did not differ from that of controls. Also, individuals with schizophrenia and those with major depressive disorder differed in terms of the specific proteins recognized in Western blot measurements.

Western blot analyses of the current study cohort revealed alterations in the immune response to specific EBV proteins. The results confirm the findings from the solid phase immunoassay results in terms of the lower reactivity against EBNA-1. These assays also detected differences in reactivity to EBV early antigens (EAs) not measured by the solid phase immunoassays as well as among some of the VCA proteins. Specifically, individuals with major depressive disorder showed significantly higher reactivity to VCA p42. Although we do not know for certain the specific gene identity for VCA p42, we tentatively identify it as tegument protein BKRF4 (Johannsen et al., 2004). BKRF4 reportedly is present in both lytic and latent infections. Thus this protein is expressed early in the process of producing progeny virions during initial and reactivation lytic infection (Ho et al., 2018; Masud et al., 2017). It is not clear if the increased reactivity seen here could be at least partially responsible for the increased OR of major depressive disorder associated with higher levels of antibody against EBV virions. The proteins that elicited diminished western blot responses are markers of very early infection (EA-D p43), late progeny lytic phase (VCA p40) and late phase infection (VCA p22, EBNA-1) (Middeldorp, 2015). Thus with the exception of early progeny production, it appears that individuals with major depressive disorder do not mount a typical response to EBV infection. Reportedly the gene product of BKRF4 does not elicit a strong antibody response in healthy EBV virus carriers (Goswami et al., 2017; Liu et al., 2018) suggesting that the increased response seen here in individuals with major depressive disorder could be a marker of increased risk of diagnosis. The combination of reduced reactivity to EA-D p43 with increased reactivity to VCA p42 could be indicative of reactivation of latent EBV. Together with the decreased reactivity to markers of late phase infection the overall pattern is consistent with an abortive reactivation (Guo et al., 2019; Murata and Tsurumi, 2014). Additional studies should focus on the further identification of the specific reactive proteins on the western blot as well as timing of the immune response to these and other EBV proteins in individuals with major depressive disorder and related conditions.

There have been several previous reports of increased levels of EBV infections in individuals with major depressive disorder and other mood disorders. For example, the salivary shedding of EBV in adolescent females was associated with symptoms of depression (Ford and Stowe, 2017). The reactivation of EBV was associated with increased rates of maternal depression during both the early and late stages of pregnancy (Haeri et al., 2011; Zhu et al., 2013). Two previous studies reported no differences in levels of antibodies to EBV (Amsterdam et al., 1986; Maes et al., 1991). Both studies measured antibodies to VCA and hence the results were consistent with ours in not showing a difference in antibodies to VCA in individuals with major depressive disorder as compared to controls. Further studies relating EBV to major depressive disorder and psychiatric disorders should include tests for a wide range of EBV antigens in order to provide a detailed classification of the immune response to infection.

We also found a trend towards decreased levels of antibodies to VZV in the individuals with major depressive disorder. As most of the individuals were not children when varicella immunization was widely employed it is likely that these levels represent a decreased response to natural infection. However future studies should employ varicella vaccination histories in studies of these antibodies. The fact that we did not find differences in the levels of antibodies to the other herpesviruses indicates that our results are not related to an overall immune deficiency or to a general level of differential exposure to herpesviruses due to geographic or demographic factors.

Limitations of the study include the relatively small sample size of persons with major depressive disorder, most of whom were ascertained in a tertiary care psychiatric hospital setting. Also, we cannot rule out other factors, not measured in our study, that may account for the association between major depression and the EBV markers

Conclusion

Individuals with major depressive disorder have evidence of an atypical immune response to EBV infection. This response differs from the immune response measured in individuals with schizophrenia and may be indicative of an altered immune state. The possible role of an altered immune response to EBV in the pathogenesis of major depressive disorder and other psychiatric disorders is worthy of further investigation with the goal of identifying specific interventions.

Supplementary Material

1
2

Highlights.

  • Epstein Barr Virus (EBV) infection leads to an immune response to EBV proteins

  • Individuals with Major Depressive Disorder (MDD) have an altered response to EBV

  • EBV infections and immune response may play a role in MDD pathogenesis

Acknowledgements

The authors thank C. Bordón, A. Cusic, R. Mason, and S. Yang for administrative and technical assistance.

The research was funded by the Stanley Medical Research Institute and NIMH grant MH-94268.

The funding agencies did not participate in the design or performance of the research.

Footnotes

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Author Statement

We certify that this article is not under consideration for publication elsewhere, and its publication is approved by all authors. If accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder.

Conflict of Interest

The authors have no conflict of interest to report.

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