The path to damage in multiple sclerosis

For several decades students of multiple sclerosis (MS) have generally accepted the cause of the MS lesion as being entirely T cell mediated. More recently, however, numerous reports of studies of the animal model, experimental allergic encephalomyelitis (EAE), and detailed analysis of the pathology of MS have indicated that the events involved in the MS lesion may be more complicated. In this issue of the Annals, Raine and his colleagues provide additional evidence that damage to the myelin sheath may, at least in some patients and in some animal models, result from an antibody-mediated step. The current article, which extends the recent report of these authors in Nature Medicine, provides important details of the pathological changes found in three cases of MS and in marmosets immunized with either myelin oligodendrocyte glycoprotein (MOG) or whole white matter. In both cases, the authors present evidence that an early event in the steps leading to destruction of the myelin sheath appears to be associated with antibody binding. Based on results obtained from eloquent studies using immunogold and silver staining, the authors report immunoglobulin (Ig) bound to the vesiculated myelin networks demonstrated by electron microscopy. Using gold-labeled MOG and myelin basic protein (MBP) peptides, the authors report that antibody to both MOG and MBP can be found in the MS cases. That antibody may have a role in demyelination seems increasingly likely. In 1988, Linington and colleagues demonstrated that when antibody to MOG, which is found on the outer lamella of the myelin sheath and which has extracellular domains, was administered to rats with EAE; it converted the disease to a more severe clinical form and produced more extensive demyelination. Generally, rats with EAE show only minimal myelin damage. These initial studies have been confirmed and extended by many investigators, and Genain and colleagues have shown that EAE induced in marmosets using MOG shows more extensive demyelination than that found in animals immunized with MBP. Further, a detailed study of the pathology of MS that examined a large number of samples obtained by biopsy or at autopsy showed that, although the pathology is heterogeneous, the most common finding was inflammation associated with Ig binding to myelin, suggesting an antibody-mediated process producing damage to myelin. In addition to Ig, deposits of complement components have also been demonstrated in regions of myelin destruction. The study reported in this issue and the previous report in Nature Medicine have extended these findings further, supporting a role for antibody in myelin damage. As Raine and colleagues note, an important question is whether antibody binding actually represents the initial step in myelin damage. They describe myelin vacuolization at the leading edge of active lesions in both marmosets and the MS cases. Bound antibody was not demonstrated at this step, so it is possible that other processes such as those mediated by cytokines could contribute to the initial step in myelin damage. Efforts to demonstrate antibody to MOG or other myelin components have been thus far unsuccessful in the model of relapsing EAE in the SJL mouse. Despite the lack of antibody, substantial demyelination is observed. One note of caution is also needed. Several investigators have shown that antibody to MOG or B cells specific for MOG can occur in controls as well as in patients with MS. The presence of the antibody in healthy controls indicates that caution must be used in interpreting the presence of the antibody in a lesion with an open blood-brain barrier. Although the immunohistochemical evidence presented in the current work, as well as that of others, strongly supports a role of antibody and specifically antibody to MOG in the myelin destructive process, it does not provide definitive proof. The ability of antibody to MOG to augment demyelination in various EAE models, however, provides additional circumstantial evidence in support of an antibody-mediated step. If antibodies contribute to the disease process, how does this fit with the notion that MS, and certainly EAE, is a T-cell–mediated disease? The evidence that T cells specific for an antigen found within the central nervous system are required to initiate the EAE lesion is without question. The ability to augment disease with antibody to MOG in some EAE models indicates that in these instances various steps are involved in the EAE lesion and, by extrapolation, in the MS lesion. It is not unreasonable to assume that a T-cell–mediated process initiates the lesion but that the effector mechanisms, which actually result in damage to the myelin sheath, are related to mechanisms that are immunologically distinct from those that initiate the lesion. The increasing evidence that some degree of axonal damage can occur even in relatively early lesions further complicates the development of the MS lesion. Finally, progression of damage may continue to occur even after the acute lesion has resolved and, as Raine and colleagues suggest, this may well be due to prolonged effects of cytokines or other mediators that result in prolonged tissue damage and destruction and contribute to progression of the lesion and of the disease. Understanding the events involved in the various stages EDITORIALS