Background to MS
The hallmark of multiple sclerosis (MS) as revealed by magnetic resonance imaging (MRI) is the white matter plaque, which represents an area of demyelination and axonal loss. MS can produce lesions throughout the central nervous system (CNS), but certain sites appear to be especially vulnerable, such as the optic nerve, brain stem, spinal cord and periventricular regions. Involvement is often bilateral and symmetrical. Lesions are broadly divided into two types: acute and chronic.
Acute lesions are inflammatory in nature and exhibit infiltration by T-lymphocytes, B-lymphocytes and macrophages, which may be filled with myelin debris from the breakdown of myelin sheaths. Proliferation of astrocytes is also usually evident, accompanied by oligodendrocyte loss. There may also be a selective decrease in the number and function of T-suppressor cells circulating peripherally.1,2 Ferguson et al. and Trapp et al.3,4 have also shown that the degree of inflammation correlates strongly with the extent of axonal loss.
Chronic lesions, by contrast, show few inflammatory characteristics, and oligodendrocytes are absent. Demyelinated axons are present, however, separated by a dense network of astrocyte processes.
It is believed that one of the first events to occur in the pathology of MS is a dysregulation of the immune system, which allows T-cells specific for myelin basic protein (MBP) to be activated in the periphery. If these cells manage to enter the CNS then they are able to attack the MBP and cause damage and demyelination.5,6 The initial activation may not have a single cause but rather could be triggered by a variety of factors, some of which have yet to be identified. It is also possible that different triggers may be successively involved at different stages of the disease.7
MS is characterized by a range of dysfunctions of the immune system in both the CNS and the periphery. It has been demonstrated experimentally that T-cells alone cause inflammatory responses, but that demyelinating lesions only develop in the presence of antibodies. This has led to the theory that T-cells specific for various CNS autoantigens initiate the inflammatory process and breach the BBB, whereas antibodies acting against surface antigens of myelin or oligodendrocytes are necessary for demyelination to occur.8
1. Dhib-Jalbet S, McFarlin DE. Immunology of multiple sclerosis. Ann Allergy 1990; 64: 433-44.
2. French-Constant C. Pathogenesis of multiple sclerosis. Lancet 1994.; 343(8892): 271-5.
3. Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120(Pt 3): 393-9.
4. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338(5): 278-85.
5. Hafler DA, Weiner HL. MS: a CNS and systemic autoimmune disease. Immunol Today 1989; 10(3): 104-7.
6. Steinmann L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 1996; 85: 299-302.
7. Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 1997; 120: 865-916.
8. Wekerle H, Linington C, Lassmann H, et al. Cellular immune reactivity within the CNS. Trends Neurosci 1986; 9: 271-7.