The Charcot Lecture | beating MS: a story of B cells, with twists and turns

Abstract

Autoimmune B cells play a major role in mediating tissue damage in multiple sclerosis (MS). In MS, B cells are believed to cross the blood-brain barrier and undergo stimulation, antigen-driven affinity maturation and clonal expansion within the supportive CNS environment. These highly restricted populations of clonally expanded B cells and plasma cells can be detected in MS lesions, in cerebrospinal fluid, and also in peripheral blood. In phase II trials in relapsing MS, monoclonal antibodies that target circulating CD20-positive B lymphocytes dramatically reduced disease activity. These beneficial effects occurred within weeks of treatment, indicating that a direct effect on B cells--and likely not on putative autoantibodies--was responsible. The discovery that depletion of B cells has an impact on MS biology enabled a paradigm shift in understanding how the inflammatory phase of MS develops, and will hopefully lead to development of increasingly selective therapies against culprit B cells and related humoral immune system pathways. More broadly, these studies illustrate how lessons learned from the bedside have unique power to inform translational research. They highlight the essential role of clinician scientists, currently endangered, who navigate the rocky and often unpredictable terrain between the worlds of clinical medicine and biomedical research.

Keywords: Charcot Lecture; Multiple sclerosis.

Figure 1

The phase IIB trial of RTX in relapsing MS. Patients were treated on day 0 and again on day 15 with either 1000 mg intravenous RTX or placebo. In the figure, the mean number of gadolinium (Gd)-enhancing lesions is shown by week for the RTX (blue) and placebo (black) groups. The primary endpoint was the total composite number of enhancing lesions detected at weeks 12, 16, 20, and 24. There was a 91% relative reduction in new enhancing lesions in the RTX group. Adapted from Hauser et al. RTX: rituximab; MS: multiple sclerosis.

Figure 2

Raymond D. Adams: Conventional wisdom can be wrong.

Figure 3

Ultrastructural features of C. Jacchus EAE. In (a), primary demyelination with preservation of axons, macrophage infiltration (macrophage nucleus visible at the top right), and astrogliosis is present. In the center, morphologic changes of myelin dissolution and fasciculation are visible. In (b), findings in chronic C. Jacchus EAE are shown, illustrating areas of thin, compact myelin-encircling axons, indicative of remyelination. C. Jacchus: Callithrix jacchus; EAE: experimental autoimmune encephalomyelitis.

Figure 4

An overview of the diverse functional roles of B cells. IL-interleukin; TNF-α: tumor necrosis factor alpha; LT-α: lymphotoxin-alpha; MHC: major histocompatibility complex; TCR: T cell receptor; DC: dendritic cell.

Figure 5

The effects of RTX on recirculating B cells. The top figure summarizes the life cycle of B cells destined for the CNS. The bottom highlights the effects of depletion of circulating B cells with anti-CD20 therapy; B cells residing in lymphoid tissues and the CNS are likely to be resistant to depletion with RTX. RTX: rituximab; CNS: central nervous system OCB: oligoclonal band; CSF: cerebrospinal fluid.

Figure 6

The genetic landscape of multiple sclerosis. More than 110 genetic variants have now been identified as conferring susceptibility to MS. Most are thought to have roles in adaptive immunity. This figure summarizes MS risk genes known to be expressed by human B cells. The distance from the center is inversely proportional to the odds ratio in the GWAS. The color is representative of the level of expression in B cells (red=high, blue=low, gray=intermediate); white means that no expression data are available. Some labels are drawn larger to emphasize the most highly expressed genes. Data courtesy of the International Multiple Sclerosis Genetics Consortium (IMSGC). MS: multiple sclerosis; GWAS: genome-wide association studies; HLA: human leukocyte antigen, equivalent to the MHC. See reference 34 for additional details.

Figure 7

Intimate connections between CNS and peripheral B cells in MS. Representative lineages of clonally related IgG-VH found in CSF (a), or in CSF and PBL ((b)–(d)) of MS patients as calculated by IgTree software and visualized in Cytoscape 3.1 (organic layout). Each round node represents at least one unique IgG-VH sequence ranging from at least the 5' end of H-CDR1 to the 3' end of H-CDR3; larger nodes represent up to hundreds of identical sequences. Blue nodes represent CSF-derived IgG-VH sequences, red nodes are PBL-derived, and green nodes represent identical sequences found in both compartments. Putative germline sequences represent the lineage root and are labeled black, hypothetical intermediates calculated by IgTree are beige. Triangular nodes contain two or more singleton sequences in leaves. In (a), intrathecal affinity maturation is represented; (b) represents an IgG-VH lineage with predominantly PBL-derived IgG-VH suggestive of B cell migration from the CNS to the PBL or seeding from the PBL into the CNS; (c) is suggestive of B cell migration from the PBL into the CNS, with traces of the clusters remaining in the PBL and with extensive intrathecal B cell SHM; D suggests ongoing B cell exchange across the BBB, or affinity-maturation occurring in both compartments in parallel. CNS: central nervous system; MS: multiple sclerosis; IgG: immunoglobulin G; VH: heavy chain variable region; CSF: cerebrospinal fluid; PBL: peripheral blood; SHM: somatic hypermutation; BBB: blood-brain barrier.