Immunology

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Most authorities believe the inflammatory, demyeli-nating disease process is immunemediated, even though the cause remains unknown. The target of inflammation may be a component of myelin. The process most likely begins with the T cell. Antimyelin T cells are recognized in the normal adult peripheral blood, but in MS these cells migrate to the central nervous system. Humeral immune responses are also likely, based on the intrathecal presence of immuno-globulins. The antigen recognized by these antibodies has not been determined. Myelin basic protein (MBP) and proteolipid protein make up 30-50% of myelin protein. Myelin oligodendroglia protein (MOG) makes up 50% of central nervous system myelin. This protein is not present in the peripheral nervous system and may be the antigen in this exclusively central nervous system disease. MOG is located on the oligodendroglia surface of the outer lamella of the myelin sheath and is thus accessible to attack. Other possible targets include myelin-associated glycoprotein, aß crystalline, 2-3-cyclic nucleotide, 30-phosphodiesterase, and viral antigens.

The marmoset model of relapsing experimental allergic encephalomyelitis, which is histologically similar to MS, has demonstrated that T cells recognize MBP and MOG. These T cells induce inflammation, but demyelination does not occur unless the MOG antibody is present. Although MOG may be the initial antigen and inciting factor, exposure as a result of inflammation induces new antigens and epitope shifting. The antigen for this disease is difficult to identify possibly because there are multiple antigens.

Figure 1 illustrates the proposed mechanisms for the immune-mediated injury in MS. Genetic or environmental factors (viruses, bacteria, or superantigens) cause activation of circulating T cells. Adhesion molecules on the circulating T cell surface, very late

Figure 1 Proposed mechanisms for immune-mediated injury in MS.

antigen (VLA-4) and lymphocyte function associated antigen (LFA-1), bind complementary receptors on the endothelium, intracellular cell adhesion molecule-1, and vascular cell adhesion molecule-1. Once in the central nervous system, the activated T cell secretes cytokines, including tumor necrosis factor-b (TNF-b) and interferon-g (IFN-g), which in turn activate antigen presenting cells (APCs) including astrocytes, macrophages, and microglia. Class II MCH molecules on APCs and T cells interact in the presence of central nervous system antigen. Costimulating molecules on the APC and T lymphocytes are necessary for activation of T cells. CD4+ cells differentiate into proinflammatory cells (CD4 + Th1) or antiinflammatory (CD4+Th2) cells. Proinflammatory cells (Th1) secrete cytokines such as TNF-a or -b or IFN-g. The result is activation of various process, that cause injury to myelin or oligodendrocytes. Antibody-mediated injury may be cell dependent or occur via complement activation. Cell-mediated injury induces damage by further release of proinflammatory cytokines. Binding between FAS-ligand and FAS or binding of ab crystallin will result in apoptosis or programmed cell death. Macrophages induce myelin injury by phagocytosis and secretion of toxic substances, such as proteases, nitric oxide, oxygen radicals, and proin-flammatory cytokines. Apoptosis may occur via the FAS-ligand interaction.

In some cases, cytotoxic CD8+ autoreactive T cells may be the primary cause of injury by binding class I MHC antigens on oligodendrocytes. They may also bind via FAS and induce apoptosis. In addition, these cells may release perforins, which create membrane pores and kill cells. Finally, other factors may lead to injury of the oligodendroglia, resulting in "dying back oligodendrogliopathy.'' The result is varying degrees of demyelination and axonal destruction.

Even as some areas are damaged, others are in various stages of repair. An antiinflammatory process activated via the CD4 Th2 cells, which secrete cytokines such as IL-4, -10, and -13, decreases inflammation and downregulates the immune response. This process occurs simultaneous to the inflammatory response.

Thinly myelinated axons in pathologic specimens indicate that remyelination occurs in patients with MS. Repair likely begins with resolution of inflammation and edema. New sodium channels may develop in a demyelinated axon to allow for propagation of active potential. It is not known if these sodium channels develop from the neuron or surrounding glial cells. Oligodendroglia progenitors capable of proliferation have been identified but the specific role of these cells is not clear. It is known that remyelination can occur if inflammation is controlled.

The final result of this inflammatory process, irreversible axonal injury, is known to occur early in the disease. These findings suggest that early intervention of the disease course, which prevents or decreases inflammation, may prevent axonal injury and allow for remyelination. Multiple potential sites for therapeutic interventions can be considered including blockage of adhesion or co stimulating molecules, cytokine therapy, or modulation of the T cells via vaccination.

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