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

• DOI: 10.1073/pnas.1909098116
• Publication Date: 2019-11-08T00:35:16Z
• Authors: Chelsea R. Parker...; Angela S. Archamb...; Matthew Cheung; Jesse W. Williams; Rafael S. Czepiel...; Patrick C. Duncker; Aaron J. Kilgore; Aidan T. Miller; Benjamin M. Segal; Alfred H. J. Kim; Gwendalyn J. Rand...; Gregory F. Wu
• Keywords: Male; 0301 basic medicine; Antigen Presentation; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Lymphoid Tissue; Neutrophils; Integrin alpha4beta1; Receptors, Interleukin-8B; Subarachnoid Space; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Meninges; PNAS Plus; Animals; Female; Meningitis; Myeloid Cells; Rabbits; Chemokines

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.