Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis
Shanzeh M. Ahmed, Nina L. Fransen, Hanane Touil, Iliana Michailidou, Inge Huitinga, Jennifer L. Gommerman, Amit Bar-Or, Valeria Ramaglia
Shanzeh M. Ahmed, Nina L. Fransen, Hanane Touil, Iliana Michailidou, Inge Huitinga, Jennifer L. Gommerman, Amit Bar-Or, Valeria Ramaglia
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Research Article Immunology

Accumulation of meningeal lymphocytes correlates with white matter lesion activity in progressive multiple sclerosis

Abstract

Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using postmortem FFPE tissue blocks (range, 5–72 blocks; median, 30 blocks) for each of 27 patients with progressive MS, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions, and greater immune cell accumulation was associated with larger subpial lesion areas. Patients with a higher extent of meningeal inflammation harbored a greater proportion of active and mixed active/inactive WM lesions and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury and point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical WM.

Authors

Shanzeh M. Ahmed, Nina L. Fransen, Hanane Touil, Iliana Michailidou, Inge Huitinga, Jennifer L. Gommerman, Amit Bar-Or, Valeria Ramaglia

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Figure 3

Meningeal myeloid cells are enriched in MS but not topographically linked to subpial demyelination or to the extent of cortical subpial demyelination or to subcortical white matter lesion activity.

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Meningeal myeloid cells are enriched in MS but not topographically linke...
(A) Quantification of meningeal IBA1+ myeloid cell count in MS donors and nonneurological controls (NNCs) showing enrichment in 27 MS donors compared with 9 NNCs. The median for meningeal IBA1+ myeloid cell count (shown by the dotted line) was used to stratify MS donors in high versus low meningeal myeloid cell count. (B) Quantification of meningeal IBA1+ myeloid cell count showing no significant changes in the number of meningeal myeloid cells adjacent to GML versus NAGM in MS donors with high (n = 14) or low (n = 13) meningeal myeloid cell count. (C) Quantification of the proportion of subpial gray matter that did not stain positive for myelin in MS donors with high versus low meningeal IBA1+ myeloid cell count. (D–G) Quantification of (D) proportion of active white matter lesions (WMLs), (E) mixed active/inactive WMLs, (F) number of inactive WMLs, and (G) number of remyelinated WMLs in MS donors with high versus low meningeal IBA1+ myeloid cell count. Each data point represents the proportion of WMLs in all tissue blocks analyzed per case (range 5–72 blocks, median: 30 blocks per donor). In A and C–G, statistically significant differences were determined by nonparametric Mann-Whitney test. In B, statistically significant differences were determined by nonparametric Kruskal-Wallis test followed by Dunn’s correction for multiple comparisons.