Pathogenesis of MS from a Neuropathologist�s Vista

Abstract

AbstractImmunoperoxidase study for tissue-bound immunoglobulins (IgG, IgA, IgM, and light chains) was performed in the formalin-fixed paraffinembedded sections from 11 MS cases (3 acute, 2 incidental and 6 chronic). Histopathologically, 7 distinct but interrelated processes were subdivided into acute monophasic, chronic monophasic, and polyphasic types. The earliest acute monophasic lesion was identified as hypertophic astrocytosis in the intact white matter. EM was done on a biopsy specimen with such an acute lesion. The IP study demonstrated heavily IgG labeled astrocytes in the normal white and gray matter of MS brains, but to a much lesser extent of the controls also. In acute lesions reactive astrocytes were heavily IgG-labeled with light chains but not with IgA or IgM. In actively demyelinating foci, phagocytes contained IgG-bound myelin breakdown products while the hypertrophic astrocytes and their glial bundles lost their IgG labeling. Old MS plaques were virtually devoid of IgG positivity saving for the margin, suggesting a shedding of previously bound IgG. EM of the reactive astrocytes revealed numerous osmophilic particles resembling those of togavirus group, with the cores measuring 35 nm in average diameter; some of them were considered as the defective interferring (DI) particles. The bordering myelin sheaths were often destroyed by cytolytic activity of such activated astrocytes, and around them were the monocytes apparently attracted to the degraded myelin proteins. The following sequence of immunopathologic events may be postulated: 1) previously IgG-coated astrocytes harbor a persistent togavirus infection with the standard and DI particles, 2) the IgG-coated astrocytes are protected from oligoclonal response and active viral replication, 3) nonimmune IgG shedding of astrocytes is brought about by many nonspecific events to activate an oligoclonal response specific to the virus, 4) upset in the balance between DI and standard virus replication as well as the oligoclonal response is accountable of the clinical exacerbation, 5) activated astrocytes (? by complements) become cytotoxic to the bordering myelin sheaths by liberating lysosomal enzymes and degrade myelin proteins, 6) degraded myelin proteins trigger the antibody-dependent cell-mediated cytotoxicity (ADCC) against the CNS myelin but not against the PNS, 7) ADCC-dependent shedding of IgG previously bound to CNS myelin follows. Thus, CSF IgG elevation ensues along with an oligoclonal response, providing an alternative explanation for the previously held view of de novo IgG synthesis in MS brains.