Stress proteins: their role in the normal central nervous system and in disease states, especially multiple sclerosis.

Stress proteins are constitutively expressed in normal CNS tissues, in a variety of cell types (oligodendrocytes, astrocytes and neurons). Their function is uncertain but they may be critical during nervous system development and may protect cells from various stresses, such as hypoxia, anoxia, and excessive excitatory stimulation. Increased amounts of stress proteins are expressed in various cells of the CNS during acute toxic-metabolic states and in more chronic degenerative diseases. Increased expression of stress proteins may constitute a sensitive marker of cell injury. Antibodies to mycobacterial stress proteins bind to normal human myelin and to oligodendrocytes in regions of MS demyelination. Cellular immune responses to stress proteins occur with increased frequency and magnitude in persons with MS, especially those with recent onset of disease. In addition, there are populations of T cells expressing gamma/delta T cells in the brains and CSF of persons with MS, suggesting an in situ immune response to hsp. Humoral immune responses to stress proteins are found in CSF, but no disease specificity has been documented. Some myelin proteins have sequence homology with particular stress proteins. One instance is the homology between a peptide of mycobacterial hsp65 and the myelin protein CNP. Preliminary observations suggest that immune responses to such cross-reactive epitopes modify the course of EAE. All in all, these data support the hypothesis that an immune response to the stress proteins of an infectious agent could result in a cross-reactive immune response to CNS myelin, resulting in demyelination. This may be an especially important mechanism in MS.