key: cord-0882816-snzmb0yn
authors: Burrer, Renaud; von Herrath, Matthias G.; Wolfe, Tom; Rempel, Julia D.; Iglesias, Antonio; Buchmeier, Michael J.
title: Autoantibodies Exacerbate the Severity of MHV-Induced Encephalitis
date: 2006
journal: The Nidoviruses
DOI: 10.1007/978-0-387-33012-9_71
sha: 38fd5e2ca48ac19cbaa14f8d985708559de5c694
doc_id: 882816
cord_uid: snzmb0yn

nan

complex. Infectious agents can initiate autoimmune responses by mechanisms such as molecular mimicry or bystander activation (reviewed in Ref. 1 ). In addition, pathogens might also provoke relapses or worsen preexisting autoimmune pathologies. For example, common infections augment both the risk and the severity of relapses in multiple sclerosis (MS) patients. 2 To study the effects of a viral infection on a preexisting autoimmune background, we have combined the neurotropic strain of mouse hepatitis virus (MHV) and mice that express auto-antibodies to a CNS antigen. MHV A59 provokes acute encephalitis, which is followed in a proportion of the surviving mice by a demyelinating disease that shares several features with MS. 3, 4 Litzenburger and colleagues have generated transgenic mice (referred here as anti-MOG Ig mice) that constitutively express auto-antibodies specific of the myelin oligodendrocyte glycoprotein (MOG). These mice show an exacerbated version of experimental autoimmune encephalomyelitis (EAE), but do not develop any spontaneous disease. 5

Intracranial injection of a sublethal dose of MHV A59 resulted in an exacerbation of the clinical disease in mice with MOG-specific antibodies compared with controls ( Figure 1, A) survival test). In addition to the increased clinical scores and mortality, clinical signs were also detected 2 days earlier in the autoantibody transgenic mice than in the controls when a dose of 100 or 1000 pfu was used (data not shown). Injection of UV-inactivated virus (1000 pfu-equivalent) did not trigger any clinical signs in anti-MOG Ig mice, sufficient to trigger the pathogenicity of the autoantibodies, and that viral replication was required.

We found no significant difference between the viral titers in the CNS of control and MOG-Ig transgenic mice (Table 1) , showing that the exacerbated disease could not be attributed to a difference in viral replication. Transfer of a single dose of serum from anti-MOG Ig mice to C57Bl/6 at the time of infection was sufficient to reproduce the clinical disease that was observed in the transgenic animals ( Figure 1B) , and resulted in a comparable increase of the mortality (13% survival at day 21 in recipients of anti-MOG Ig serum vs. 85% in controls, p<0.01). These results confirm that the anti-MOG autoantibodies account for the exacerbation of the virally-induced CNS disease in our model. 6.5*10 4 ±5.8*10 4 a 5.9*10 5 ±1.5*10 5 2.2*10 7 ±7.5*10 6

Anti-MOG Ig 1.1*10 5 ±4.3*10 4 6.6*10 5 ±1.7*10 5 2.3*10 7 ±9.6*10 6 a PFU/g, average±SE, n=3 to 6.

indicating that breaking the blood-brain barrier or the presence of viral antigens was not Table 2 . Demyelination score in lesions in the brains of anti-MOG Ig and WT mice at day 9 postinfection. 

In the MHV A59 model, demyelination can be detected as early as day 7 post-infection in the brains of a subset of mice. As anti-MOG antibodies have been shown to exacerbate demyelination in EAE 5, 6 or in MS, 6 we have examined luxol fast blue-stained brain sections obtained from anti-MOG Ig and control mice. Preliminary results do not show any significant difference between the number or importance of demyelinating lesions in the brains of transgenic and control animals ( Table 2 ). The mechanisms responsible for the augmented virus-induced pathology in mice with CNS auto-antibodies are currently under investigation. We are also trying to determine if the ability to trigger the auto-aggressivity of the auto-antibodies is limited to MHV, or a more general feature of viral infections of the CNS.

Our study illustrates the additive effects of the concomitant presence of autoantibodies to a CNS antigen and a viral CNS infection, each of which, by themselves, support the concept that infectious and autoimmune components can act in synergy leading to enhanced disease. 

Viruses as triggers of autoimmunity -making the barren field fertile

Prospective study on the relationship between infections and multiple sclerosis exacerbations

Murine coronavirus infection: a paradigm for virus-induced demyelinating disease

Murine hepatitis virus-a model for virus-induced CNS demyelination

B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice

Identification of autoantibodies associated with myelin damage in multiple sclerosis

is relatively harmless or leads to milder disease (Figure 1 ), respectively. These findings