Background
Immunological abnormalities involving the upregulation of endogenous retroviruses have been associated with schizophrenia in small studies.
Methods
Blood samples from 666 individuals (163 with recent onset psychosis, 268 with multi-episode schizophrenia, and 235 controls) were assayed for IgG antibodies to murine leukemia virus (MuLV), Mason-Pfizer monkey virus (MPMV), and feline immunodeficiency virus (FIV) by enzyme immunoassay utilizing whole virus and viral components. Antibody levels in the psychiatric groups were compared to controls by multivariate linear regression. Odds ratios associated with increased antibody levels were calculated based on values ≥ 75th percentile of the controls. Samples were also tested for antibodies to viral proteins by Western blotting and for DNA from infectious retroviruses by real time PCR. Homology between the target virus and the prototype human genome was determined using sequence analysis methods.
Results
Compared with controls, individuals with recent onset of psychosis had increased levels of antibodies to MPMV and MuLV (both p < .001 adjusted for covariates), and increased antibody levels for defined portions of the MPMV and MuLV gag, pol and env proteins. The specificity of these antibodies was confirmed by Western blotting. Individuals with multi-episode schizophrenia did not show elevated antibody levels to any of the retroviruses measured. Infectious retroviruses were not detected in the blood of any participants. Homology analyses indicated that there are multiple regions of the human genome homologous with MPMV and MuLV proteins, the highest being with the MuLV gag protein.
Conclusions
Antibodies to retroviral proteins are elevated in individuals with recent onset psychosis but not in individuals with multi-episode schizophrenia. The immunopathological consequences of this antibody response should be the subject of additional studies.
Schizophrenia is a pervasive neurodevelopmental disorder associated with excess morbidity and mortality throughout the world. Family and adoption studies have provided evidence for a genetic component for schizophrenia and genetic linkage studies have identified a number of chromosomal regions which are associated with the disorder. However, few specific genes have been found which confer a major risk for schizophrenia in different populations. Some of the genes which have been found are components of the immune response (Tiwari et al., 2010). In other studies, immunological and infectious factors have been identified which may contribute to the pathophysiology of schizophrenia in some individuals (Torrey and Yolken, 2001, Knight et al., 2007 and Patterson, 2009).
Endogenous retroviruses are elements of the human genome which arose from the retro-transposition of exogenous retroviruses following the infection of germ line cells in primate progenitors of modern humans (Bannert and Kurth, 2004). Endogenous retroviruses are present at multiple sites within the human genome. Furthermore, endogenous retroviruses are transcriptionally active during fetal development, a time critical for the formation of neural circuitry which can be disrupted in some individuals with schizophrenia. Previous studies have documented the aberrant expression of endogenous retroviruses in small numbers of individuals with persistent schizophrenia from blood samples (Perron et al., 2008), cerebrospinal fluid (Karlsson et al., 2001), and post-mortem brain tissue (Yolken et al., 2000 and Karlsson et al., 2001) and also in small numbers of individuals with recent onset schizophrenia from blood samples (Yao et al., 2008) and cerebrospinal fluid (Karlsson et al., 2001).
The measurement of antibodies to endogenous retroviruses would provide a method for the measurement of activation of retroviral proteins in a large number of individuals. While the measurement of antibodies to endogenous proteins is hampered by the lack of available reagents, there are a number of cultivable animal retroviruses which share homology to endogenous retroviruses and can thus be used for the measurement of antibodies. We measured antibody levels to antigens encoded by the gag, the pol and the env genes. These genes, which play essential roles in infection, replication and genome integration, are encoded by all retroviruses. The gag (which is an abbreviation for “group specific antigen”) gene encodes the structural protein of the retrovirus. The pol gene codes for the reverse transcriptase enzyme required for converting RNA back into DNA. In most retroviruses, this gene also encodes a viral protease required for the processing of viral proteins and efficient cellular infection as well as other proteins such as ribonuclease H and viral integrases. The env gene encodes the surface glycoprotein and the transmembrane domains of the virion. These glycoproteins interact with host receptors and facilitate infection ( Hughes and Varmus, 1997).
In this study we examine the levels of antibodies to three retroviruses, murine leukemia virus (MuLV), Mason-Pfizer monkey virus (MPMV), and feline immunodeficiency virus (FIV) and their components in a large group of individuals with recent onset of psychosis and with multi-episode schizophrenia. We compare the antibody levels in both psychiatric groups to the antibody levels in controls who do not have any history of psychiatric disorder.
