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 post-mortem formalin-fixed paraffinembedded tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 progressive MS patients, 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 higher subpial lesion numbers. Patients with a higher extent of meningeal inflammation harboured 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 also point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical white matter.

Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation

“…This apparent discrepancy may be due to the fact that the human tissue analyzed in this study is from a cohort of PMS patients with long-standing disease (>20 years) as opposed to the EAE model herein, which captures acute inflammatory changes at peak disease. Indeed, although present, the neutrophils in the PMS postmortem brains were rare, and B cells showed a diffuse localization throughout the leptomeninges as described in other donor cohorts ( 31 ). The effects of neutrophil depletion in our EAE model are currently under investigation and will be an important follow-up to this study.…”

“…Neutrophils have been implicated in demyelination and axonal degeneration during the acute phase of EAE in C57BL/6 mice ( 30 ), but little is known about their presence in the MS brain. We therefore examined previously characterized postmortem MS brains, which showed a range of subpial demyelination and meningeal inflammation compared with age-matched non-neurological controls ( 31 ), for the presence of neutrophils in the leptomeningeal compartment using high-magnification microscopy on H&E-stained samples. Neutrophils were identified based on their multilobular nuclei.…”

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

“…Relapsing MS is pathophysiologically characterized by periods of peripheral activation of the immune cells and their infiltration to the CNS, resulting in focal injury of the white matter. However, progressive MS is considered to be caused by low-grade, chronic and rather multifocal neuroinflammation in the CNS regions, including in the leptomeninges and Virchow-Robin spaces, progressively leading to neuronal injury and possibly, neurodegeneration [ 85 ].…”

Single-Cell Analysis to Better Understand the Mechanisms Involved in MS

“…It is now clearly established that the mechanisms involved in early and progressive MS are different. with less immune cell infiltration at the lesion site [ 72 , 73 ] and a lack of a response to immunomodulatory treatments in PMS [ 74 ]. This study was conducted to partially elucidate the mechanisms and cells involved in the progressive form of MS, as very little is currently known.…”