The genetic basis of a number of leukodystrophies has been firmly established. Of these disorders, the most common are adrenocortical leukodystrophy and metachromatic leukodystrophy. At one time both were considered to have some relationship to MS [2, 11]. Of some importance is Marburg’s disease, sometimes referred to as “acute multiple sclerosis,” which has been attributed to a defect in myelin basic protein (MBP) synthesis and structure . Work on alterations of the 3D structure of MBP and relationship to various demyelinating disease continues. Interestingly, several mutations of the proteolipid of myelin are causative of Pelizaeus-Merzbacher disease, another leukodystrophy, as well as several types of hereditary spastic paraparesis. These disorders ordinarily should not be confused with MS because of early age of presentation of the leukodystrophies, their inexorably progressive course, and their familial setting.
Multiple sclerosis is now generally accepted as an immune-mediated illness although its pathogenesis is incompletely understood. The occurrence of MS following about a third of cases of acute disseminated encephalomyelitis complicating infections [120-122] as well as after immunizations, including Semple vaccine (containing spinal cord and killed virus), suggested an autoimmune origin. Although EAE has been studied in animal models for decades, the primary impetus was to elucidate the nature of the immune response . These studies have also provided insight into the pathogenesis of MS as well. Transfer of EAE from immunized to naive animals was first successfully accomplished using lymph node cells but not antibody, thus pointing to a central role for lymphocytes . Nevertheless, antibody from immunized animals, and patients with MS, can induce demyelination in vitro [60, 61].
T cells play a primary role in the pathogenesis of EAE, irrespective of the nervous system antigen used to induce disease [124-127]. A consensus has developed that T cells are the primary effectors both in MS and in EAE . Nevertheless, B cells, plasma cells, and antibody can be found both in EAE pathology and in MS plaques [92, 93]. Despite their emphasis on other findings, these recent studies of pathology in MS show that the predominant cells in active lesions are lymphocytes, in particular CD3+ T cells, and macrophages .
Multiple injections of the whole spinal cord were used to induce EAE in early studies, but single immunizations of equivalent amounts of purified myelin or MBP combined with adjuvants were shown to be very effective in disease induction . Myelin proteins other than MBP have also been investigated, notably proteolipid and myelin oligodendrocyte glycoprotein (MOG). Proteolipid protein can induce forms of experimental disease in animal models and, although antibody as well as T cells reactive to this antigen may be present in plaques, no role for sensitization to this antigen has been established . However, an interesting EAE model in marmosets induced using MOG indicates that antibody may mediate demyelination [128, 129]. Passive transfer of the disease by serum from MOG- sensitized animals has been accomplished . However, T cells (CD4+ Th2, rather than CD4+ Th1 cells) may be the primary mediators of myelin damage in MOG-sensitized marmosets . The situation is complicated by the fact that CD4+ cells reactive to MBP, capable of inducing EAE, are present in naive animals as well as in these immunized animals coincidently with anti-MOG antibody . Anti-MOG antibody has been reported at the outset of MS and is common in RRMS [130, 131]. In contrast to anti-MOG antibody being limited to MS relapse, CD4+ cells reactive to MOG are ubiquitous .
Antigen presentation by MHC class I or MHC class II by antigen-presenting cells (APC) to T cells results in the initiation of immune responses: antibody production or a cellular immune response. Activated CD4+ T helper (Th) cells fall into three functionally distinct classes, Th1 and Th2, and Th17 with distinctive profiles of lymphokine production. Following antigenic stimulation CD4+ Th1 cells produce interleukin-1 (IL-1), IL-2, IFN-y, and tumor necrosis factor a (TNF-a) are postulated to mediate inflammatory pathological processes in immune-mediated tissue damage seen in MS and EAE . In contrast, Th2 cells produce IL-4, IL-5, IL-6, and IL-10 and induce upregulation of antibody production and downregula- tion of Th1 cellular responses (Fig. 2.4) . The observed failure of increased production of the regulatory cytokine IL-10, by myelin-reactive T cells in MS by Ozenci et al. in Sweden, has recently been confirmed by Cao et al. at MIT [134, 135]. More recently a role for Th17 helper cells in a large subpopulation of MS patients has been identified and characterized. Sera from interferon-p-1a treatment failure patients from Denmark were shown to contain IL-17F. Naive patients that had IL-17F and elevated levels of endogenous INF-p failed to respond to IFN-p-1a subsequently also. These IFN-p failure MS patients resemble EAE animals induced by Th17-polarized cells [136, 137].
Macrophages are the principal sources of IL-1, IL-12, and TNF-a, driven by IL-2 production from antigen-activated CD4+ cells. Importantly, IL-12 production is IFN-y dependent and TNF-a production is IL-12 dependent . Traditionally the macrophage was considered to be the principal APC, but B cells are now recognized as important in this task. However, macrophages are central effector cells in cell- mediated immunity. After antigen presentation, CD4+ cells respond by clonal proliferation and recruitment of other CD4+ cells to participate in the initiation of cellular immune responses. Cytotoxic CD8+ cells, driven by IL-12, may exert their effect directly or target antibody complexed with antigen on target tissue, i.e., antibody- dependent cytotoxicity [127, 139]. Macrophages may also target these complexes. The spectrum of CD4+ Th2 responses includes a regulatory role in switching of CD8+ cell cytotoxic function to active suppression of CD4 Th1 responses, suppressor T cells. In the CNS microglial cells can function as APC and exhibit certain other macrophage behaviors including an anti-inflammatory response.
The blood-brain barrier (BBB) is a physical barrier that prevents intravascular cellular elements, antibodies, and other proteins free access to the brain and spinal cord . The endothelial cells in the brain and spinal cord possess tight junctions
Fig. 2.4 A model of immunopathogenesis of multiple sclerosis. Following exposure to certain environmental antigen(s) in genetically susceptible individuals, myelin-reactive T cells migrate from peripheral circulation to the central nervous system. Interaction between activated T cell and cerebral endothelial cells leads to upregulation of the adhesion molecules (E-selectin, vascular cell adhesion molecule, intercellular adhesion molecule, mucosal addressin cell adhesion molecule, and platelet endothelial cells adhesion molecule). Transendothelial migration of reactive T cells is heralded by the disruption of the blood-brain barrier, which is in part mediated by the activities of the matrix metalloproteinases. Matrix metalloproteinases digest the activated T cells (such as TNF-a and IFN-y) and upregulate the expression of cell surface molecules on antigen-presenting cells (in this figure, glial cell). Binding of putative multiple sclerosis antigen (e.g., myelin basic protein and myelin oligodendrocyte glycoprotein) by the trimolecular complex T-cell receptor and class II major histocompatibility molecules on the antigen-presenting cells precipitates a massive inflammatory cascade, which leads to production of both pro- and anti-inflammatory cytokines. This inflammatory reaction ultimately results in loss of myelin-oligodendrocyte complexes
that are impervious to intravascular fluids as well as nonactivated cells. These endothelial cells are also surrounded by astrocytic foot processes that further support and maintain the integrity of the BBB. However, activated CD4+ cells do cross the BBB [140-145]. However, the BBB is an actual physical barrier which may be breached only in an organized and well-orchestrated fashion [140, 145, 146]. The mechanisms of cellular transmigration across the blood-brain barrier are now well understood [140-146].