B lymphocytes in neuromyelitis optica

Abstract

Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predominantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with NMO are seropositive for autoantibodies against the astrocyte water channel aquaporin-4 (AQP4). These autoantibodies are predominantly IgG1, and considerable evidence supports their pathogenicity, presumably by binding to AQP4 on CNS astrocytes, resulting in astrocyte injury and inflammation. Convergent clinical and laboratory-based investigations have indicated that B cells play a fundamental role in NMO immunopathology. Multiple mechanisms have been hypothesized: AQP4 autoantibody production, enhanced proinflammatory B cell and plasmablast activity, aberrant B cell tolerance checkpoints, diminished B cell regulatory function, and loss of B cell anergy. Accordingly, many current off-label therapies for NMO deplete B cells or modulate their activity. Understanding the role and mechanisms whereby B cells contribute to initiation, maintenance, and propagation of disease activity is important to advancing our understanding of NMO pathogenesis and developing effective disease-specific therapies.

Figure 1. Potential roles of B cells in neuromyelitis optica pathogenesis

B cells may play proinflammatory and anti-inflammatory roles in neuromyelitis optica pathogenesis through various mechanisms. Autoreactive B cells may be generated by defective central tolerance (CT; primary checkpoint in bone marrow) or peripheral tolerance (PT; secondary checkpoint in secondary lymphoid tissue). Stimulated B cells leaving germinal centers may differentiate into memory B cells or antibody-producing plasmablasts and plasma cells. In addition to the production of aquaporin-4 (AQP4)-IgG in the bone marrow and CNS, plasma cells and plasmablasts may have additional proinflammatory and anti-inflammatory functions. Plasmablasts may secrete factors such as interleukin (IL)-17, tumor necrosis factor α (TNF-α)/nitrous oxide (NO), and granulocyte-macrophage colony-stimulating factor (GM-CSF), facilitating neutrophil and macrophage CNS infiltration and heightening proinflammatory immune cell activity through modulation of gut microbiota. Alternatively, anti-inflammatory plasma cells (Pregs) may suppress disease activity in part through the production of IL-10 or IL-35. Memory B cells may further promote disease activity by antigen (Ag) presentation, secretion of the proinflammatory cytokines lymphotoxin (LT) and TNF-α, or facilitation of Th17 differentiation (IL-6 production). IL-10-producing B regulatory cells may limit the immune response through antigen-specific or bystander suppression of proinflammatory T cell function. Circulating AQP4-specific anergic B cells may provide a pool of autoreactive disease-relevant B cells that contribute to disease activity. The pool of anergic B cells may be enhanced by deficient B cell tolerance; release of anergic B cells may be enhanced by antigen-complement adducts or decreased levels of IL-6. The location of germinal centers producing AQP4-reactive memory cells and plasmablasts remains unknown (asterisk). Blue arrows: developmental pathways; dashed green arrows and boxes: stimulatory cytokines; dashed red arrows and boxes: inhibitory cytokines. APRIL = a proliferation-inducing ligand; BAFF = B cell-activating factor.

Figure 2. B cell development, tolerance checkpoints, and neuromyelitis optica immunotherapy

Antibodies are generated during early B cell development by random joining of immunoglobulin gene segments. The arbitrary joining is the basis for the vast diversity of the B cell repertoire needed for complete immunity, but this comes at a price: the developing B cell repertoire includes autoreactive antibodies. B cell tolerance ensures that potentially detrimental autoreactive B cells are cleared from the B cell repertoire. During B cell development, autoreactive B cells are removed at 2 separate steps. In the first, a central checkpoint in the bone marrow prior to the transition to immature B cells removes the large portion of developing B cells that express polyreactive antibodies, leaving a smaller fraction of clones with low levels of polyreactivity to migrate from the bone marrow to the periphery. The second tolerance checkpoint, residing in the periphery, further counterselects autoreactive new emigrant B cells before they differentiate into mature naïve B cells. B cell lineages that may be directly affected by potential neuromyelitis optica treatment modalities are shown in the row below the schematic. Surface markers indicated in the bottom part of the schematic are not intended to be comprehensive and do not include all reported subsets. Adapted by permission from Macmillan Publishers Ltd: Nature Immunology (Meffre E, Casellas R, Nussenzweig MC. Antibody regulation of B cell development. 2000;1:379–385).