Autoantibodies to neurofilaments in the pathogenesis of axonal damage and grey matter pathology in MS
07 / 2008 - 07 / 2012
Stichting MS Research
Axonal damage is considered as the major cause of chronic disability in MS but the underlying pathological mechanisms are poorly understood. Similar to immune-mediated myelin destruction, autoimmunity to neuronal/axonal antigens may play an important role in axonal damage. Our recent studies in mice have revealed that experimental autoimmunity to the axonal protein neurofilament light (NF-L) induces spastic paresis, axonal damage and neurodegeneration [Huizinga et al 2007]. In this model grey matter lesions are frequently observed as they are in MS and, interestingly, immunoglobulin (Ig) deposits occur inside neurons and axons. Like in MS grey matter lesions, T cell infiltrates in the CNS of NF-L immunised mice are rare. Also since NF-L-reactive T cells are unable to transfer disease in mice, we therefore hypothesize that auto-antibodies to neurofilaments play a crucial role in mediating the axonal damage observed. In this project we aim to: ? determine the presence of antibodies and complement in neurons and axons in MS lesions, their reactivity to neurofilaments and evaluate the relationship between serum antibodies to neurofilaments and subtype of MS. Also, the presence of neuronal antigens inside macrophages will be compared with the extent of axonal/neuronal damage. ? investigate the pathogenicity of human anti-NF antibodies in mouse models. Ig from MS and controls will be co-injected into mice with myelin-specific T cells (to disrupt the BBB) and deposition of human Ig in the CNS of these mice will be evaluated and correlated with clinical disease and neuronal damage. Such antibodies will also be examined for disruptive effects in murine neuronal cultures and in neurofilament assembly assays. ? determine the mechanisms underlying experimental NF-L-induced axonal damage by comparing such damage in wild-type mice with B-cell- and FcR-deficient mice. These studies should reveal the extent to which autoantibodies neurofilaments may actively contribute to axonal damage in MS as well as in animal models, and clarify whether they are an active part of the pathogenic process rather than merely surrogate markers of disease.