Neutrophils promote VLA-4–dependent B cell antigen presentation and accumulation within the meninges during neuroinflammation

Significance A distinct murine model of multiple sclerosis used to examine factors involved in ectopic lymphoid tissue formation during central nervous system autoimmunity reveals that infiltration and aggregation of B cells within the leptomeninges is dependent upon B cell expression of VLA-4 and is preceded by neutrophil migration. This finding establishes the early mechanisms involved in the establishment of chronic inflammatory changes within the meninges during autoimmune inflammation that promote the formation of ectopic lymphoid tissue associated with disease progression and disability in multiple sclerosis.
The success of B cell depletion therapies and identification of leptomeningeal ectopic lymphoid tissue (ELT) in patients with multiple sclerosis (MS) has renewed interest in the antibody-independent pathogenic functions of B cells during neuroinflammation. The timing and location of B cell antigen presentation during MS and its animal model experimental autoimmune encephalomyelitis (EAE) remain undefined. Using a new EAE system that incorporates temporal regulation of MHCII expression by myelin-specific B cells, we observed the rapid formation of large B cell clusters in the spinal cord subarachnoid space. Neutrophils preceded the accumulation of meningeal B cell clusters, and inhibition of CXCR2-mediated granulocyte trafficking to the central nervous system reduced pathogenic B cell clusters and disease severity. Further, B cell-restricted very late antigen-4 (VLA-4) deficiency abrogated EAE dependent on B cell antigen presentation. Together, our findings demonstrate that neutrophils coordinate VLA-4–dependent B cell accumulation within the meninges during neuroinflammation, a key early step in the formation of ELT observed in MS.