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Figure 4 MRI scan of a 25-year-old woman with multiple sclerosis, which was diagnosed at age 22. Note the hyperintense pericallosal white matter lesions.

2. Late developing lesions (marked breakdown of the myelin in the absence of myeline oligodendrocyte glycoproteins or CNPase)

3. Inactive demyelinated lesions

Comparison of histological findings with those from magnetic resonance neuroimaging have shown that due to an impaired blood-brain barrier, the lesions in their early stages can take up much gadolinium. However, surprisingly, T2-weighted images show a remarkably weak signal intensity. Rather, the late developing or old lesions show areas of hyperintensity and a more homogeneous uptake of gadolinium. In contrast, axonal lesions can be shown to be associated more with hypointensities in T1-weighted images.

It is clear that the key immunological role in the development of the illness is played by activated T cells. Activated T helper cells interact with specific proinflammatory cytokines, particularly tumor necrosis factor-a, lymphotoxin, interferon-g (IFN-g), and interleukin-2 (IL-2). They can thus activate macrophages and damage the target tissue. Whereas in the peripheral circulation monocytes and macrophages can take up an antigen once detected, T cells are available, and phagocytosis can occur, in the CNS such activities are directed against the microglia, astrocytes, oligodendrocytes, and the myelin they synthesize. The most important target candidates include proteolipid protein (which that makes up about 50% of the protein content of the myelin sheath), basic myeloprotein, myelin-associated glyco-protein, and myelin oligodendrocyte glycoprotein. T2 helper cells destroy the antiinflammatory cytokines such as IL-4 and IL-10 that would otherwise keep the functions of the inflammatory T cells in check. During restitution, this type of cell shows a higher level of activity. Nevertheless, this subtype of helper cell supports antibody synthesis in the b-lymphocytes with the result that the inflammatory process and the underlying mechanisms are perpetuated and the damage becomes chronic.

The course of the inflammatory process may occur as follows: T cells are activated by an unknown antigen in the periphery. This activation is followed by the release of specific cytokines (e.g., the expression of integrins and the intracellular cell adhesion molecule-1 from the superfamily of immunoglobulins) that promote the binding of the activated T cells to the endothelium of the blood vessels. By way of the release of the proinflammatory cytokines, the structure of the blood vessels in the blood-brain barrier disintegrates.

This enables the migration of T cells to the structures that would otherwise have been protected. During the course of this migration, mediators of the toxic effect on myelin are released, edemas form, and the constituents of myelin are affected in their function and eventually destroyed. The cytokines of the T2 helper cells (IL-4 and IL-10) are modulators of this process. They help reduce the extent of the inflammation and may even increase in number during the more stable phases of the illness. The extent to which apoptosis (programmed cell death) of the T cells actually influences this process cannot be determined with confidence.

The mainstays of therapy constitute neurophysio-logically based practice, ergotherapy, and various measures for support and rehabilitation: the latter include psychotherapy, pharmacotherapy directed toward symptom relief, as well as the putative causes (immunomodulation, inhibition of glial scar formation, and the promotion of remyelination). High-dose corticosteroid therapy in the acute phase can help inhibit inflammation and can stabilize the blood-brain barrier, and it can be directed toward T cell apoptosis. In the form of illness with an episodic course, immunomodulators may also be applied. Thus, recombination IFN-b can antagonize the effects of IFN-g and the induced suppressor activity, and it can stabilize the blood-brain barrier. Glatirameracetate, a synthetic polypeptide, can promote T cell activation and reintroduction of the disturbed TH1-TH2 balance. Other therapeutic options include the use of mitoxantron, azathioprin, and methotrexate, which can inhibit global proliferation and inflammation.

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