The role of myelin antigen transfer in the CNS in the etiology of multiple sclerosis
Multiple Sclerosis (MS) is a debilitating autoimmune disease that is characterized by demyelination and inflammatory lesions of the central nervous system. The axonal damage and impairment of motor, autonomic and cognitive function lead to significant disability. It is well known that the acute lesions are mediated by CD4+ T helper type cells and CD8+ cytotoxic T cells. Myelin antigen is presented to T cells under inflammatory conditions but it remains unknown whether antigen is presented constitutively at low levels under conditions of non-inflammation in the CNS. Our data show that in the naive brain, the only antigen presenting cells (APC) present in sufficient quantity and capable of presenting antigen to T cells are microglia. We demonstrate that microglia are loaded with myelin antigen in the naive brain and after immunization are able to present antigen immediately for T cell activation.
Furthermore, inflammatory mediators such as cytokines have been shown to play a major role in the pathology and tissue damage associated with MS. It remains to be proven which pro-inflammatory cytokines are critical for the ensuing inflammation and tissue damage. Our research shows that when IFN-gamma is removed either though gene knockout mice or neutralizing antibody, that experimental autoimmune encephalomyelitis (EAE) is exacerbated in the mouse model of MS. Interesting, we found an inverse correlation with the presence of IFN-gamma and myelin antigen loading and disease severity. Collectively these data show that microglia may be the first cell type to activate CD4+ T cells and that IFN-gamma may play a protective role in EAE.
Our long term goal is to better understand the mechanism of neuroantigen transfer and the requisite inflammatory mediators in order to facilitate the development of therapeutic agents for treatment of this disease.