Contributions
Abstract: 149
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
While subpial (type III) cortical involvement has emerged as an important component of multiple sclerosis (MS) pathology and a likely substrate of progressive disease, its pathogenesis remains unclear. It has been suggested that this subpial injury may be driven by an immune response in the inflamed meninges. However, pathologic studies into the relationship between meningeal inflammation and underlying cortical pathology have yielded conflicting results, with some reports identifying a strong association, whereas other work reporting relative paucity of meningeal immune cells and lack of correlation with cortical injury.
We considered that a relationship between meningeal inflammation and subpial cortical demyelination may be related to the degree of ongoing deep white matter (WM) demyelinating disease activity. Using rapid-autopsy post-mortem brain tissue, we analyzed for the presence and extent of meningeal inflammation and its topographic association with subpial demyelination in 14 progressive MS donors, stratified based on having either smoldering WM lesions (ongoing myelin phagocytosis), or inactive WM lesions. Numbers of meningeal T cells (CD3+), B cells (CD20+) and macrophages (CD68+) were quantified in areas adjacent to subpial grey matter lesions (GML) or to normal appearing grey matter (NAGM), and compared to non-neurological controls.
Meningeal immune cells were observed in all samples, though to a variable degree. Meninges adjacent to GML showed a 50-75% higher density of CD3+ and CD20+ cells, but only in donors with smoldering WM lesions, compared to both donors with inactive WM lesions, and compared to meninges adjacent to NAGM. Further, in cases with smoldering WM lesions, subpial GML were prominent, accounting for 68% of all grey matter lesions and the number of meningeal immune cells was strongly associated with the extent of subpial cortical demyelination (Spearman's correlation coefficient, r=0.9; p=0.003).
Our data in MS patients indicate that meningeal immune cells are enriched and linked to subpial cortical demyelination in brains of progressive MS donors with ongoing white matter demyelination, but not in those donors in whom white matter demyelination is no longer active.
We further present a mouse model which recapitulates both meningeal aggregates and subpial cortical injury, providing a tool to study dynamics involved in both development of meningeal inflammation and its potential role in subpial cortical injury.
Disclosure: Valeria Ramaglia: nothing to disclose
Iliana Michailidou: nothing to disclose
Hanane Touil: nothing to disclose
Corbert van Eden: nothing to disclose
Inge Huitinga: nothing to disclose
Jennifer L Gommerman: nothing to disclose
Amit Bar-Or: nothing to disclose
Abstract: 149
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
While subpial (type III) cortical involvement has emerged as an important component of multiple sclerosis (MS) pathology and a likely substrate of progressive disease, its pathogenesis remains unclear. It has been suggested that this subpial injury may be driven by an immune response in the inflamed meninges. However, pathologic studies into the relationship between meningeal inflammation and underlying cortical pathology have yielded conflicting results, with some reports identifying a strong association, whereas other work reporting relative paucity of meningeal immune cells and lack of correlation with cortical injury.
We considered that a relationship between meningeal inflammation and subpial cortical demyelination may be related to the degree of ongoing deep white matter (WM) demyelinating disease activity. Using rapid-autopsy post-mortem brain tissue, we analyzed for the presence and extent of meningeal inflammation and its topographic association with subpial demyelination in 14 progressive MS donors, stratified based on having either smoldering WM lesions (ongoing myelin phagocytosis), or inactive WM lesions. Numbers of meningeal T cells (CD3+), B cells (CD20+) and macrophages (CD68+) were quantified in areas adjacent to subpial grey matter lesions (GML) or to normal appearing grey matter (NAGM), and compared to non-neurological controls.
Meningeal immune cells were observed in all samples, though to a variable degree. Meninges adjacent to GML showed a 50-75% higher density of CD3+ and CD20+ cells, but only in donors with smoldering WM lesions, compared to both donors with inactive WM lesions, and compared to meninges adjacent to NAGM. Further, in cases with smoldering WM lesions, subpial GML were prominent, accounting for 68% of all grey matter lesions and the number of meningeal immune cells was strongly associated with the extent of subpial cortical demyelination (Spearman's correlation coefficient, r=0.9; p=0.003).
Our data in MS patients indicate that meningeal immune cells are enriched and linked to subpial cortical demyelination in brains of progressive MS donors with ongoing white matter demyelination, but not in those donors in whom white matter demyelination is no longer active.
We further present a mouse model which recapitulates both meningeal aggregates and subpial cortical injury, providing a tool to study dynamics involved in both development of meningeal inflammation and its potential role in subpial cortical injury.
Disclosure: Valeria Ramaglia: nothing to disclose
Iliana Michailidou: nothing to disclose
Hanane Touil: nothing to disclose
Corbert van Eden: nothing to disclose
Inge Huitinga: nothing to disclose
Jennifer L Gommerman: nothing to disclose
Amit Bar-Or: nothing to disclose