Immunological and PCR Analyses for Borna Disease Virus in Psychiatric Patients and Blood Donors in Japan

Abstract

Borna disease virus (BDV) is the prototype of a new virus family, Bornaviridae, within the Mononegavirales order, which has a nonsegmented, negative-sense, single-stranded RNA genome (12,42). BDV is a noncytolytic neurotropic virus that infects a wide variety of animal species from birds to primates (7,17,26,36,51,52) and causes Borna disease (BD), which is characterized by central nervous system dysfunction with variable manifestations ranging from fatal neuronal damage to almost asymptomatic viral persistence (19,25,28,29). The wide host range of the virus and behavioral disturbances in animals with BD have suggested that BDV infection may be associated with human psychiatric disorders (5,8,9,15,23,33,40,48,49,53). Furthermore, seroepidemiological data and the detection of BDV RNA in peripheral blood mononuclear cells (PBMCs) by nested reverse transcriptase PCR (RT-PCR) have also suggested a possible involvement of BDV in human psychiatric disorders. However, there is controversy over the prevalence of BDV antibodies and BDV RNA in the PBMCs of patients with psychiatric disorders.In previous serological studies, the prevalence of anti-BDV antibodies in psychiatric patients varied from 0 to 30% in different laboratories. The differences in prevalence could be due to the use of different assay systems (immunofluorescence [IF] assay [4,5,37,38], Western blot [WB] analysis [8,14,15,21,23,24,40,47,50], enzyme-linked immunosorbent assay [14,20,24], and electrochemiluminescence immunoassay [ECLIA] [53]) with different sensitivities and specificities. Particularly, in most of the previous reports that examined BDV antibodies by WB analysis, the specificity for BDV has not been considered, giving rise to the possibility of false-positive results. One of the aims of the present study was to establish a WB analysis with specificity for the detection of BDV antibodies in human sera and to reevaluate the prevalence of BDV antibodies. Furthermore, we also tried to detect anti-BDV antibodies by ECLIA and IF assay to make elaborate inquires into the prevalence of anti-BDV antibodies. To our knowledge, this is the first report on the evaluation of the prevalence of anti-BDV antibodies examined by three different methods.Experimental animal models of BD demonstrated that BD is caused by T-cell-mediated immunopathology in the brain (1a, 2, 3, 16, 28, 31, 32, 35, 41, 43-45). The evidence has suggested that BDV-specific CD4 ϩ and CD8 ϩ T cells in the brain play an

Borna Disease Virus Infection, a Human Mental-Health Risk

“…Overall, the combined determination of CICs, plasma antigen, and antibodies represents a considerable step forward in BDV diagnosis. The discovery of CICs after years of controversy due to low antibody titers or "disappearing" antibodies explains many previous discrepancies (1,2,12,21,24,32,38,46,58). Moreover, the existence of BDV CICs and antigenemia has provided insight into the dynamics of a poorly understood equilibrium of plasma antigen, antibodies, and CICs during persistent BDV infection and its impact on clinical features (9).…”

“…The current focus on measurement of humoral infection markers seems likely to predominate over any diagnostic approaches using cell-mediated immunity parameters (24) in the future. Especially, because the experience with small-animal models cannot simply be superimposed on humans (9,31,43), the time has come to quantify the amount of native and antibody-complexed BDV antigen in blood plasma along with longitudinal monitoring.…”

“…However, all of these assays depend on subjective endpoint titration and are time-consuming. While electrochemiluminescence immunoassays (ECLIA) enabled the amount of antibodies to be determined more precisely, they did not provide any new insights into human BDV infections (24,58).…”

Detection by Radioligand Assay of Antibodies against Borna Disease Virus in Patients with Various Psychiatric Disorders

“…Since antibodies against Borna disease virus (BDV) were found in human mood disorders in 1985 (1,17), the role of BDV in human neuropsychiatric diseases has been investigated by means of seroprevalence (2,18), detection of viral RNA from peripheral blood (6,10), and examination of cerebrospinal fluids (3,8) or autopsied brains (7,14). However, such study has not yet established the role of BDV for human diseases (13,16).…”

“…One reason might be the lack of a reliable diagnostic system, because of the difficulty of detection of human anti-BDV antibodies compared to other animals (13), and the possible existence of the virus hidden in the central nervous system. To detect anti-BDV antibodies, indirect immunofluorescent antibody assay (2,4), Western blotting (9,15), enzyme-linked immunosorbent assay (5,11), electrochemiluminescence immunoassay (19), and T-cell proliferative response (10) have been employed, and yet disagreement remains to some extent among the results (10,13). On the other hand, detection of BDV RNA from peripheral blood has been reported to be unreliable unless contamination of cDNAs in the laboratory is strictly excluded (13).…”