| Demyelination in the CNS is the hallmark of MS and myelin specific autoimmune responses are believed to play a crucial role in the pathogenesis of MS and in myelin damage. However, axonal damage and/or loss as identified by MRI and histopathological studies may also play an important role in both the early changes of disease as well as in the progressive phase of MS when cumulated axonal loss is reached. Whatever the timing of such axonal degeneration and loss, the exact role of such damage in clinical disease and the mechanism of axonal damage is unclear. In this project we aim to: a) Investigate the relationship between axonal loss and demyelination and inflammation in two major experimental demyelinating diseases in mice, namely chronic relapsing experimental allergic encephalomyelitis (CREAE) and Semliki Forest virus (SFV) infection in mice. In contrast to the clinical relapses and remissions in CREAE in which demyelination is prominent in the relapse phase, SFV induces large lesions of demyelination in the absence of clinical disease. Histochemical methods will be used to examine the level of axonal suffering and transsection as assessed by the accumulation of amyloid precursor protein (APP) and the relationship and density of non-phosphorylated compared to phosphorylated neurofilaments with demyelination. b) Determine whether immunity to axonal components play a role in disease using ELISA, immunoblotting techniques and T cell assays to examine autoimmunity to axonal components during disease in CREAE and SFV infection in ABH mice and assays to assess humoral responses in MS patients. c) Examine the pathogenic significance of immunity to axons as judged by the ability of axon preparations and/or axonal proteins to induce CNS disease or exacerbate existing disease in mice. The use of both the viral and CREAE models of MS will allow the examination of the relative contribution of axonal suffering and axonal loss to the different stages of neurological disease and assess whether the transition from subclinical demyelination (SFV) to inflammation (acute and CREAE) and finally to secondary progressive disease (later stages of CREAE) is dependent on axonal damage and or development of autoimmunity to axonal components and disease status. These studies will clarify the importance of axonal damage itself and the presence of (auto)immunity to axons in the experimental animal models and also in MS patients. The realisation that axonal degeneration is a fundamental component in inflammatory and demyelinating neurological disease may help the approach to management and be relevant to a more targeted immunotherapy aimed at reducing the progression to disability. |
