Immunopathology of secondary‐progressive multiple sclerosis

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.

C3-dependent mechanism of microglial priming relevant to multiple sclerosis

“…Double-immunostaining for microglial markers and C3b/iC3b showed colocalization, similar to our findings in Crry −/− mice, suggesting an interaction between axonal C3b/iC3b and its receptor on microglia. Activated C3 was independently identified in association with ramified microglia in perilesional white matter bordering plaques (19,20), IL-1β was up-regulated in the rim but not the perilesional white matter, whereas C3 was up-regulated in the rim and the perilesional white matter of chronic active lesions (18). Complement activation in MS suggests local dysregulation; in support of this, we have recently shown that plasma fH levels predict the clinical course of MS (34).…”

“…(17) and may range from quiescent to highly activated morphology. Microglial expression of IL-1β (18) and deposition of activated C3 (C3d) (19,20) have been independently reported but no account has been published of an investigation in the same lesion/patient or analysis in the context of microglial priming. MS brain tissue and white matter from nondemented controls (Table S1) were examined for evidence of microglial priming by morphology, staining for all three subunits (HLA-DP, HLA-DQ, and HLA-DR) of the HLA (HLA-DP-DQ-DR), IL-1β, and C3 fragment (C3b/iC3b) deposition (Table S2 and Fig.…”

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

“…45,46 Many reported histological patterns are reflective of different evolution stages: from acute active plaques with abundant macrophages and myelin breakdown, to active (smoldering) rim lesions with macrophage presence concentrated at the rim, to inactive plaques without myelin breakdown. 4 Recent studies also showed remyelination to be more extensive than previously assumed, 47 giving new impetus to the search for an in vivo marker of repair and calling for new paraclinical markers of how tissue destruction occurs in vivo. 48 The residual heterogeneity of lesion patterns observed in time-series analysis studies implies similar variability in progression and destructive nature of lesion formation.…”

“…4 An altered role of inflammation in SPMS is documented also from multiple treatment trials in which inflammation was effectively suppressed but accrual of atrophy remained unaltered. [5][6][7] …”

“…4 An altered role of inflammation in SPMS is documented also from multiple treatment trials in which inflammation was effectively suppressed but accrual of atrophy remained unaltered. [5][6][7] Both clinical characteristics and MRI findings point to a similar picture of slow but accelerated accrual of damage that eventually dissociates from baseline predictors, such as the load of gadolinium-enhancing lesions.…”