Multiple sclerosis: from basic immunopathology to immune intervention

Abstract

The clinical symptoms of multiple sclerosis (MS) reflect disturbances in the electrical signal transmission in the central nervous system (CNS) due to immunemediated damage to the myelin sheath and associated gray matter (axonal and neuronal) injury. The recent increase in our understanding of the immunopathogenesis of MS has made a great impact on the development of a number of new therapeutic strategies for this disease, some of which have already been approved while others are still under development. Among the important contributions to the understanding of the immunopathogenesis of MS is the availability of an animal model experimental autoimmune encephalomyelitis (EAE). Injecting a rat or mouse with myelin in an adjuvant leads to the development of an inflammatory CNS process manifested by paralysis. Most of the animals recover spontaneously. Re-injection of myelin in the recovered animals produces no disease, as they have developed immunological memory and thus acquired a tolerance to future exposures to the myelin antigens. However, injection of cells isolated from sick animals into naive animals elicits the disease (a phenomenon called adoptive or passive transfer of the disease). This suggests that EAE, and presumably MS, are cellmediated diseases, in contrast with diseases such as myasthenia gravis, which is an antibody-mediated autoimmune neurological condition. The cells involved in the pathogenesis of EAE and MS, are CD4 T cells of the TH1 subtype, characterized by the secretion of a specific profile of pro-inflammatory cytokines that includes interferon (IFN)-g, tumor necrosis factor (TNF)-a, and interleukin (IL)-2. In addition, MS is characterized by a decrease in regulatory or suppressor TH2/TH3 cells that secrete anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth factor (TGF)-b. Therefore, in MS there is an imbalance between the two arms of the immune response: an increase in TH1 concomitant with a reduction in TH2 cells and related cytokines. According to this paradigm, therapy might be achieved by correcting the basic disruption of the immune balance by ‘immune-deviation’, i.e. shifting the immune system from a TH1 to a TH2/TH3 profile. In other words, introducing a deviation in the immune response by changing it, from one characterized predominantly by cells that secrete proinflammatory cytokines to a response that will display mostly TH2 and TH3 cells, secreting the anti-inflammatory cytokines IL-4, IL-10, and TGF-b. The initial step in the pathogenesis of MS seems to be the aberrant activation of general populations of immune cells in the peripheral blood, including autoreactive, myelin-specific T-cells. When these T-cells are activated, they proliferate, circulate in the peripheral blood, express a variety of cell-surface adhesion molecules, and successively interact with the endothelium and transmigrate through the blood /brain barrier (BBB) into the CNS. Blocking any of these processes as early as possible may result in arrest or slowing of the pathological cascade in the periphery. As soon as the autoimmune cells have entered the CNS, they are reactivated by local antigen-presenting cells (APCs) and secrete the pro-inflammatory cytokines TNFa and IFNg. In parallel, the release of chemotactic factors leads to the recruitment of other arms of the immune response, including macrophages and B-cells, which together with auto-antibodies and complement, increase the damage to the CNS. The final result is an inflammatory process followed by demyelination and glial scar formation. * Corresponding author. Tel.: /972-4-8250-851; fax: /972-4-8250909 E-mail address: millera@tx.technion.ac.il (A. Miller). Clinical Neurology and Neurosurgery 104 (2002) 172 /176