B Cells in the Multiple Sclerosis Central Nervous System: Trafficking and Contribution to CNS-Compartmentalized Inflammation

Abstract

Clinical trial results of peripheral B cell depletion indicate abnormal proinflammatory B cell properties, and particularly antibody-independent functions, contribute to relapsing MS disease activity. However, potential roles of B cells in progressive forms of disease continue to be debated. Prior work indicates that presence of B cells is fostered within the inflamed MS central nervous system (CNS) environment, and that B cell-rich immune cell collections may be present within the meninges of patients. A potential association is reported between such meningeal immune cell collections and the subpial pattern of cortical injury that is now considered important in progressive disease. Elucidating the characteristics of B cells that populate the MS CNS, how they traffic into the CNS and how they may contribute to progressive forms of the disease has become of considerable interest. Here, we will review characteristics of human B cells identified within distinct CNS subcompartments of patients with MS, including the cerebrospinal fluid, parenchymal lesions, and meninges, as well as the relationship between B cell populations identified in these subcompartments and the periphery. We will further describe the different barriers of the CNS and the possible mechanisms of migration of B cells across these barriers. Finally, we will consider the range of human B cell responses (including potential for antibody production, cytokine secretion, and antigen presentation) that may contribute to propagating inflammation and injury cascades thought to underlie MS progression.

Induction of brain‐infiltrating T‐bet–expressing B cells in multiple sclerosis

“…11 Production of the chemoattractants CXCL10, CXCL13, and CCL20 in the CNS has been associated with B-cell recruitment, distribution, and reactivity in MS. [24][25][26] We compared the presence of B cells that express the chemokine receptors that correspond to these ligands, CXCR3 + (CXCL10), CXCR5 + (CXCL13), and CCR6 + (CCL20), between paired blood, CSF, and meningeal and brain tissues from 10 MS patients (see Table 1). 11 Production of the chemoattractants CXCL10, CXCL13, and CCL20 in the CNS has been associated with B-cell recruitment, distribution, and reactivity in MS. [24][25][26] We compared the presence of B cells that express the chemokine receptors that correspond to these ligands, CXCR3 + (CXCL10), CXCR5 + (CXCL13), and CCR6 + (CCL20), between paired blood, CSF, and meningeal and brain tissues from 10 MS patients (see Table 1).…”

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

“…B cells may contribute to disease in several ways, including antigen presentation, cytokine secretion, and antibody production 2. Intrathecal production of immunoglobulin G (IgG), which was demonstrated for more than half a century ago,3 is considered a hallmark of the disease and can be visualized as oligoclonal bands (OCBs) by electrophoresis or isoelectric focusing of cerebrospinal fluid (CSF) in most patients 4…”

Natalizumab treatment leads to an increase in circulating CXCR3-expressing B cells

“…B cells are increasingly recognized as active players in the pathogenesis of MS. They are found within the active lesions in MS brain, 2 but it is not well known how natalizumab affects B cell trafficking into the CNS. However, VLA-4 is known to be expressed on B cells, 3 and selective elimination of VLA-4 from B cells reduced leukocyte recruitment and susceptibility to CNS autoimmunity in an animal model of MS, thus providing mechanistic proof for the role of VLA-4 in B cell trafficking into the CNS.…”