Immunopathology of secondary‐progressive multiple sclerosis

TLDR

The study examined 23 plaques from two secondary‑progressive MS patients using immunohistochemistry to identify microglia/macrophages, immunoglobulins, and activated complement components. The analysis revealed low‑grade active demyelination characterized by frustrated phagocytosis and microglia–C3d–myelin complexes in periplaque white matter, a pattern absent in acute MS lesions, indicating that ongoing myelin breakdown in old plaques—without overt inflammation—may drive progression in secondary‑progressive MS.

Abstract

Abstract Twenty‐three plaques obtained at early autopsy from 2 patients with secondary‐progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low‐grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary‐progressive multiple sclerosis.