Heat shock or stress proteins and their role as autoantigens in multiple sclerosis

Stress or heat shock proteins are constitutively expressed in normal CNS tissues, in a variety of cell types (oligodendrocytes, astrocytes, and neurons). Their presence may protect cells from various stresses, such as hypoxia, anoxia, and excessive excitatory stimulation. Increased amounts of hsp are expressed in various cells of the CNS during acute toxic-metabolic states and in chronic degenerative and inflammatory diseases. Increased expression of hsp may lead to immune responses to these proteins. Antibodies to mycobacterial hsp bind to normal human myelin and to oligodendrocytes in regions of MS demyelination. Cellular immune responses to hsp 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 antigen receptors in the brains and spinal fluids of persons with MS, suggesting an in situ immune response to hsp. Humoral immune responses to hsp are found in CSF, but no disease specificity has been documented. Some myelin proteins have sequence homology with particular hsp. One instance is the homology between a peptide of mycobacterial HSP 65 and the myelin protein CNP. Our data in EAE suggest that immune responses to either cross-reactive epitopes or whole hsp can modify the course of both acute and chronic relapsing EAE. These data support the hypothesis that an immune response to an infectious agent's hsp could result in a cross-reactive immune response to CNS myelin, or to responses to endogenous, CNS-expressed hsp, resulting in demyelination. This may be an important mechanism in the pathogenesis of MS.