T cells and microglia as drivers of multiple sclerosis pathology

One of the many open questions in multiple sclerosis research is whether inflammation in the CNS is initiated by an autoimmune attack, triggered by unidentified environmental factors, or represents a response to axonal degeneration and myelin degradation secondary to processes that are intrinsic to the CNS.The autoimmune hypothesis is supported by the recently well-established disease association with genes in the HLA region which encode proteins that are functionally relevant for initiating immune responses by presenting peptides to CD4+ and CD8+ T cells (Lincoln et al. , 2005; Oksenberg et al. , 2004). Functional evidence was provided initially by the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which showed that the minimal requirement to trigger disease is activated T cells (Ben-Nun et al. , 1981; Madsen et al. , 1999). More recently, clinical trials of immune modifying drugs have also provided evidence that T cells play a role in the pathogenesis of multiple sclerosis (McFarland and Martin, 2007). In this context, the universal importance of T cells has, however, been questioned in at least one study, in which almost no T cells in plaques from patients studied early in the course were detected, but with microglial activation and apoptosis of oligodendrocytes (Barnett and Prineas, 2004).New genetic studies have provided further support for the role of autoimmune mechanisms in the pathogenesis of multiple sclerosis. Genome wide association studies have identified several new susceptibility genes, each of which is involved in controlling immune responses. In contrast, no genes have yet been found …