Presenter of 1 Presentation
IS028 - THE ROLE OF B CELLS IN MULTIPLE SCLEROSIS (ID 868)
Abstract
Abstract Body
Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS). Traditionally, B cells were considered to be passively involved in MS pathogenesis by the production of autoantibodies. However, the success of B cell depleting strategies in MS treatment has emphasized the more central role of B cells in MS pathology with an emphasis on antibody-independent functions such as cytokine secretion and stimulation of T cell responses by antigen presentation and costimulation.
B cell biology is highly complex, as different B cell subsets exist depending on their maturation state. Transitional B cells enter the circulation following development in the bone marrow. After antigen recognition, immunoglobulin (Ig)D+CD27- naive B cells mature into memory B cells which further optimize antigen binding. The population of memory B cells consists of IgD+CD27+ non class-switched memory (NCSM) B cells and IgD-CD27+ class-switched memory (CSM) B cells. IgD-CD27- double negative (DN) B cells are also mostly mature antigen-experienced cells with a pro-inflammatory function.
An important focus of our current research is unravelling the pro-inflammatory phenotype and function of DN B cells in MS patients. Previously, we reported abnormally elevated frequencies of DN B cells in the peripheral blood and cerebrospinal fluid (CSF) of MS patients. Expression of antigen presentation and costimulatory molecules on DN B cells indicated their potential to induce T cell responses. Further, DN B cells produced the pro-inflammatory cytokines lymphotoxin-α and tumor necrosis factor-α and the cytotoxic molecule granzyme B following ex vivo stimulation. In addition, we reported that DN B cells resemble mature CSM B cells based on the expression of developmental markers (CD5, CD10, CD38) and Ig isotypes (IgM, IgA, IgG). Preliminary data showed that DN B cells expressed cell adhesion molecules (lymphocyte function-associated antigen 1 (LFA-1), very late antigen 4 (VLA-4), activated leukocyte cell adhesion molecule (ALCAM)) and pro-inflammatory chemokine receptors (C-X-C chemokine receptor (CXCR)3 and CXCR5), all involved in B cell migration towards the CNS. In addition, DN B cells demonstrated a high migration capacity towards the pro-inflammatory chemokines C-X-C chemokine ligand (CXCL)10 (CXCR3 ligand) and CXCL13 (CXCR5 ligand). The expression of the T-box transcription factor T-bet, previously described in a pathological age-associated B cell subset, was found in 22 [3.3, 52.0]% of MS DN B cells.
Thus, DN B cells are abnormally elevated in MS patients and could migrate into the CNS. They could contribute to inflammation by induction of T cell responses and pro-inflammatory cytokine production. Further research on DN B cells could lead to novel targets for more specific MS therapies as well as increase our insight into the involvement of B cells in MS pathogenesis.