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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

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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 1

Meningeal T cells and B cells are enriched in MS and topographically linked to cortical subpial demyelination.

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Meningeal T cells and B cells are enriched in MS and topographically lin...
(A) Quantification of meningeal CD20+ B cell count and CD3+ T cell count in 27 MS donors and 9 nonneurological controls (NNCs) showing enrichment in MS donors versus NNCs. The median for meningeal CD20+ B cell count (orange dotted line) and meningeal CD3+ T cell count (blue dotted line) was used to stratify MS donors in high versus low meningeal B or T cell count. (B) Quantification of meningeal CD3+ T cell count showing significant enrichment of T cells in meninges adjacent to GML versus NAGM in MS donors with high (n = 14) but not low (n = 13) meningeal T cell count. (C) Quantification of meningeal CD20+ B cell count showing significant enrichment of B cells in meninges adjacent to GML versus NAGM in MS donors with high (n = 14) but not low (n = 13) meningeal T cell count. (D–G) Representative immunohistochemical staining for CD3 (D and E, arrows) and CD20 (F and G, arrows) in meninges adjacent to subpial GML or NAGM in MS donors with high CD3+ or CD20+ meningeal cell count. (H) Quantification of the proportion of subpial gray matter that did not stain positive for myelin in MS donors with high versus low CD3+ T cell meningeal count. (I) Spearman’s correlation coefficient between meningeal CD3+ T cell count and the proportion of subpial gray matter that did not stain positive for myelin. (J) Quantification of the proportion of subpial gray matter that did not stain positive for myelin in MS donors with high versus low CD20+ B cell meningeal count. (K) Spearman’s correlation coefficient between meningeal CD20+ B cell count and the proportion of subpial gray matter that did not stain positive for myelin. In A–C each data point represents mean cell count (mean ± SD) in all fields analyzed per case. Statistically significant differences determined by nonparametric Mann-Whitney test (A, H, and J) or nonparametric Kruskal-Wallis test followed by Dunn’s correction for multiple comparisons (B and C). Scale bars: 100 μm (D–G).

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