Evidence for Immunopathogenesis (2001)

I. INTRODUCTION Although the clinical and pathological features of multiple sclerosis (MS) were described in detail by Charcot as early as 1868 (1), the etiology of this primary demyelinating disease of the central nervous system (CNS) remains largely unknown. In recent years, the application of highly sophisticated techniques has greatly facilitated the understanding of the complex mechanisms that lead to lesion formation in MS (2). In accord with the current concept on the pathogenesis of autoimmune diseases in general (3), in MS, it is proposed that in genetically predisposed individuals, viral or other infections can trigger a pathological white matter-specific cell-mediated immune response that, together with antibodies and complement, leads to selective destruction of myelin and oligodendrocytes and to some axonal damage. Immunological tolerance, which is normally maintained by various mechanisms such as suppressor cells and clonal deletion of T cells, can be overcome when activation of physiological low-affinity binding of autoreactive T cells by myelin antigen cross-reactive pathogens or by release of sequestered antigens leads to the generation of high-affinity binding of pathological autoreactive T cells, which can cause tissue damage. Polyclonal activation of T cells by proinflammatory cytokines produced during unrelated immune responses or by superantigens can also lead to high affinity-binding of autoreactive T cells (3). Proinflammatory cytokines can contribute to extravasation of leukocytes and to the development of inflammatory lesions in target organs by upregulating adhesion molecules, vascular addressins, chemokines, and matrix metalloproteases (MMP) and by inducing aberrant class II major histocompatibility complex (MHC) expression on endothelial cells and glial elements (4,5). Disease activation by cytokines in MS is strongly supported by the previously reported increased exacerbation rate following intercurrentviral infections (6) and after systemic administration of interferon (IFN)-γ (7). The specificity of the disease process for myelin and oligodendrocytes, the type IV delayed type hypersensitivity (DTH)-like features of inflammatory lesions, the presence of myelinspecific antibodies, the wide spectrum of immunological abnormalities in both blood and cerebrospinal fluid (CSF), and the similarities of these changes with those observed in other human autoimmune diseases and in the animal model experimental autoimmune encephalomyelitis (EAE) have provided strong support for the conclusion that MS is an immune-mediated disease. Classification of MS as an autoimmune disease may be possible according to criteria used in clinical settings, which require (a) presence of other autoimmune diseases in patients or their family members; (b) presence of lymphocytic infiltrates in the target organ;(c) statistical association with certain MHC haplotypes; and (d) a favorable response to immunosuppressive medications (8). Direct proof, as can be obtained for myasthenia gravis by passive transfer of the disease-mediating antibodies from a pregnant woman to her fetus, is difficult to obtain for T cell-mediated diseases due to the MHC restriction of T-cell functions (3,8). The following sections summarize immunological abnormalities in blood and CSF, report on the effect of cytokines on endothelial cells and glial elements in vitro, provide a detailed description of the lesion immunopathology, and discuss the findings as they relate to a possible autoimmune pathogenesis of MS.