# B-cell abundance in perivascular cuffs associates with local lesion activity in multiple sclerosis

## TL;DR

B cells in perivascular cuffs are linked to active lesions in multiple sclerosis brains, suggesting a role in disease progression.

## Contribution

Identifies B-cell enrichment in perivascular cuffs as a marker of lesion activity in progressive MS.

## Key findings

- Perivascular cuffs with higher B-cell abundance are associated with active or mixed MS lesions.
- CD4+ T cells correlate with antibody-secreting cells in perivascular cuffs.
- BTK is abundantly expressed in B cells and macrophages within cuffs, suggesting therapeutic targeting potential.

## Abstract

Perivascular aggregations of leukocytes, referred to as perivascular cuffs, are a pathological phenomenon in progressive multiple sclerosis (MS). Perivascular cuffing is an exaggerated form of compartmentalized inflammation present in progressive disease. By studying traits of perivascular cuffs, this study aims to elucidate processes within the perivascular niche of the MS brain. We characterized n = 255 MS donors from the Netherlands Brain Bank for the presence of perivascular cuffs and investigated their association with clinical and pathological donor characteristics. Furthermore, we examined the proportional abundance of different cell types and functional markers in n = 457 perivascular cuffs present in different lesion stages within a cohort of n = 18 MS brain donors. MS donors with detected perivascular cuffs (25.5%) showed a higher brainstem lesion count. Within these cuffs, there was a relative increase of CD4+ compared to CD8+ T cells, and a higher B-cell abundance in active and mixed active/inactive MS lesions specifically. All perivascular cuffs were inflammatory active (TNF, PCNA, HLA) and contained antibody-secreting cells, which correlated with the presence of CD4+ T cells. In a different cohort, CNS-isolated viable B cells tested positive for EBV with qPCR (6/6 MS donors). In these donors, EBV/LMP-1+ B cells were detected in the meninges. In the cuffing cohort, LMP-1+ B cells were only present sparsely (13/122 perivascular cuffs of 6/11 donors). Lastly, Bruton’s tyrosine kinase (BTK) was abundant in B cells and macrophages within all perivascular cuffs. Our comprehensive characterization of perivascular cuffs in advanced MS links them with disease severity and supports a local interaction between CD4+ T and B cells to be associated with lesion presence. Our data indicate that this can happen irrespective of local EBV presence, and supports the targetability of perivascular cuffs by brain-penetrating BTK inhibitors.

The online version contains supplementary material available at 10.1186/s40478-025-02208-4.