B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis

Abstract

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterized in the presence (F+) or absence (F−) of lymphoid-like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and five control cases were analyzed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA-1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament-H+). Lymphoid-like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of 3 out of 11 F+ SPMS cases. CD4+ and CD20+ cell counts were increased in F+ SPMS compared to F− SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+ SPMS cases (P < 0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (P < 0.05); with white matter lesion area (P < 0.05); and the extent of axon loss (P < 0.05) in F+ SPMS cases only. We show that the presence of lymphoid-like structures in the forebrain is associated with a profound spinal cord pathology and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

“…As B cells are most prominent in the meninges of both MS2 patients and 2 month CMI animals, this would suggest that at first T cells and myeloid cells populate the MS meninges, with the amount of meningeal B cells rising over time. This also fits with the finding that the amount of B cells in meninges and B-cell related cytokines in the CSF associate with disease progression 17,28,33 . Furthermore, the extent of meningeal inflammation in MS patients, and more specifically the amount of meningeal B cells, has been strongly linked to the presence of tertiary lymphoid-like follicles 15,28 .…”

Synaptic Loss in Multiple Sclerosis Spinal Cord

“…A cellular infiltrate suggestive of inflammatory activity was only detected in 3 of 154 blocks of our sample. Evidence suggests the main signature of inflammation in the spinal cord may be located in the meninges, 33 which were not examined in this study. Although inflammation may contribute to synaptic damage/loss in the course of MS, it may not necessarily be involved in the initiation of the processes leading to connectivity breakdown in the spinal cord.…”

An “Outside-In” and “Inside-Out” Consideration of Complement in the Multiple Sclerosis Brain: Lessons From Development and Neurodegenerative Diseases

“…One theory supporting a key role of inflammation in subpial cortical pathology, while reconciling pathological and clinical findings of progressive MS, proposes that this injury may be driven by a compartmentalized immune response involving the inflamed leptomeninges within brains that have a relatively intact BBB (Serafini et al, 2004;Lassmann et al, 2007;Magliozzi et al, 2007Magliozzi et al, , 2010Howell O. W. et al, 2011;Lucchinetti et al, 2011;Popescu et al, 2011;Choi et al, 2012;Absinta et al, 2015;Howell et al, 2015;Haider et al, 2016). Histological examination of autopsy CNS tissue from progressive MS cases have shown evidence of Tertiary Lymphoid Tissues (TLT) in the leptomeninges lining the forebrain (Serafini et al, 2004;Magliozzi et al, 2007), the cerebellum (Howell et al, 2015) and to a lesser extent the spinal cord (Reali et al, 2020). MRI studies have also confirmed the presence of meningeal TLT in the MS brain (Absinta et al, 2015).…”