Research:EBV in Animal Models

Chang RA, Miller SD, Longnecker R Epstein-Barr virus latent membrane protein 2A exacerbates experimental autoimmune encephalomyelitis and enhances antigen presentation function. Sci Rep. 2012;2:353. Epub 2012 Apr 3

Multiple sclerosis (MS) is an inflammatory, autoimmune disease of the central nervous system. The cause of MS is still unknown but epidemiological and immunological studies have implicated Epstein-Barr virus (EBV), which infects B cells, as a possible aetiological agent involved in disease. Of particular interest is EBV latent membrane protein 2A (LMP2A) because previous studies have demonstrated that LMP2A enhances the expansion and differentiation of B cells upon antigen stimulation, revealing a potential contribution of this protein in autoimmunity. Since B cells are thought to contribute to MS, we examined the role of LMP2A in the animal model experimental autoimmune encephalomyelitis (EAE). In this model, transgenic mice in which B cells express LMP2A show increased severity and incidence of disease. This difference was not due to lymphocyte recruitment into the CNS or differences in T cell activation, rather, we show that LMP2A enhances antigen presentation function

This report in scientific methods reports that a protein made by EBV augments neurological attack caused by  enhancement of antigen presentation by B cells. However, the evidence that B cells are that important in early stages of EAE is rather lacking. Indeed you can get normal EAE in the complete absence of B cells as shown previously , although it has been shown that B cell activity can augment T cell-mediated autoimmunity. 

This study reports on some odd findings and it would be a very surprsing that increases severity of disease are not associated with increased recruitment into the CNS. So when we look at the data, first thing to say they report using tests that are not correct for the data) and using the "smack you in the eye test", there looks to be no real difference.  On closer look at the data they compare a mean score on 2.7 verses 2.3 respectively , however with an incidence of 92% and 79%. This means the scores of the affected animals are 2.9 and 2.9. If the clinical scores are compared like for like you would not expect any difference. They see a small difference but is it simply skewed by the fact that less animals got disease in the transgenic than wild type-normal mouse. Abit of a Shania. Best stop there before I say too much.

Casiraghi C et al. Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis. PLoS Pathog. 2012 May;8(5):e1002715. 

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.

                             life cycle of gamma HV-68

This report talks about mice infected with a virus gamma-HV-68. It is suggested that this is a mouse equivalent of EBV, but does it cause lymphoma, B cell immortalisation etc, etc. However according to Wikipaedia, "MHV-68 is more closely related to the Kaposi's Sarcoma-associated herpesvirus (KSHV) than it is to the Epstein-Barr virus" If so the argument falls apart. So not so good EAE becomes good EAE when there is a viral infection. This latent virus does not re-activate and infect the CNS during EAE.

Just so you know there have been studies on viruses and EAE for many years including the first description of the use of the PL mouse strain. Unfortunately I can remember this paper from when it first came out...I am an old f**t :-)

Cross AH, McCarron R, McFarlin DE, Raine CS. Adoptively transferred acute and chronic relapsing autoimmune encephalomyelitis in the PL/J mouse and observations on altered pathology by intercurrent virus infection .Lab Invest. 1987;57(5):499-512.

PL/J mice developed chronic relapsing experimental allergic encephalomyelitis (EAE) after receiving syngeneic guinea pig basic protein (GPBP)-immune lymph node cells or spleen cells which were cultured in the presence of GPBP or the encephalitogenic N-terminal peptide of GPBP. The presence of CD4+ cells and in vitro proliferation in response to GPBP are required for the successful transfer. Pathologically, adoptively-(T cell) transferred EAE in the virus-free PL/J strain was characterized by an infiltration in the central nervous system by small lymphocytes, followed by the appearance of macrophages, and subsequently by primary demyelination. These findings were similar to those previously observed in chronic relapsing EAE in SJL/J mice. However, in some experiments pathologic examination of the spinal cord showed large demyelinating lesions which were necrotic and infiltrated with eosinophilic polymorphonuclear leucocytes. Sera from mice with this pathology contained antibodies to murine hepatitis virus and extensive search identified a few areas of coronavirus replication. The pathology of autoimmune mediated demyelination may be altered in the presence of coronavirus infection but the clinical pattern of EAE expression did not differ between virus-free and coronavirus-infected mice.