Report from a Satellite Symposium held at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis in Barcelona, Spain, 9 October 2015
The role of B cells in the pathogenesis of multiple sclerosis (MS) may not be simply related to their ability to produce antibodies. They are highly efficient antigen-presenting cells, producing cytokines that can change the microenvironment and can mediate negative effects through astrocyte populations. Furthermore, as well as producing antibodies, B cells produce ectopic lymphoid follicle-like aggregates that persist in the brains of MS patients. This improved understanding of the centrality of the B cell in the biology of MS presents greater opportunities for developing effective therapies. The lymphocyte antigen CD20 is not expressed at early stem and pro B cell stages, nor on most short- or long-lived plasma cells. This presents the possibility that anti-CD20 treatment could deplete the intermediate stage of B-cell development while preserving the ability of stem cells to repopulate and protecting pre-existing humoural immunity. Ocrelizumab is a humanised monoclonal antibody that depletes CD20+ B cells via multiple mechanisms. In the OPERA I and OPERA II trials, compared with interferon beta-1a (IFNβ-1a) treatment over 96 months, ocrelizumab significantly reduced: the annualised relapse rate, 12- and 24-week confirmed disease progression, T1 gadolinium-enhancing lesions and new and/or enlarging T2 lesions. Overall, in OPERA I and OPERA II, ocrelizumab had a similar safety profile to that of IFNβ-1a over the study period. The OPERA I and OPERA II studies therefore provide strong support of for the theory that targeting CD20+ B cells as a potential therapeutic approach in relapsing MS.
Much progress has been achieved in the treatment of multiple sclerosis (MS), however, many important unmet needs remain. A large proportion of patients with MS experience disease activity despite treatment with disease-modifying therapies (DMTs), whereas the desired treatments would have the potential to impact neurodegeneration and promote re-myelination. For some treatments there may be a compromise between efficacy and safety, however, ideally treatments would be well tolerated, highly efficacious and have favourable benefit–risk profiles. The attributes of currently available treatments can present adherence challenges. Treatments with mechanisms of action that promote persistence and adherence are therefore needed. There are a number of treatments currently in development that may meet at least some of these needs and have interesting potential to improve outcomes in MS (Table 1).
The role of B cells in multiple sclerosis
Derived from haematopoietic stem cells residing in the bone marrow or liver, pre-B cells can evolve into mature naïve cells that can migrate throughout the body into secondary lymphoid tissue (Figure 1). If they encounter an antigen that can activate or cross-link their B-cell receptors, they are activated and can move into germinal centres, where they receive help from dendritic cells and T-cells to proliferate, clonally expand and undergo further antigen-driven maturation of the B-cell receptor. This then ultimately yields plasmablasts and memory B cells. The plasmablasts can move into other tissues, in particular, the bone marrow, and continue to produce antibodies for years, potentially decades. The memory B cells also circulate and can mediate surveillance of the entire body, in this case, they can enter the brain and, again, if their B-cell receptors encounter appropriate antigens, they can become activated and receive T-cell help to undergo further clonal expansion. The cells that are clonally expanded can become long-lived in the central nervous system (CNS), ultimately developing the follicle-like aggregates that characterise the brain of MS patients with chronic disease. The result is development of plasmablasts and plasma cells, which are believed to be the source of oligoclonal bands seen in the cerebrospinal fluid of patients with MS. In addition, the CNS-educated B cells can recirculate. Research carried out at the University of San Francisco using a deep sequencing technique to identify the lineage of individual B cells indicates that it is possible to identify B cells in the periphery that are derived from the same clonal lineage as those residing chronically in the brain. The findings suggest that the B-cell population is moving rapidly back and forth across the blood–brain barrier and, further, it appears that B cells are undergoing more clonal expansion in the periphery.
There is another evolving concept in the cellular aetiology of MS. The brain is not an ‘immune desert’ and, in fact, 40–60% of cells in the brain are members of the innate immune system, i.e., astrocytes, which express class I and II major histocompatibility complex; and can internalise and process antigens and present them to T-cells (Figure 2).1–7 There is an emerging model suggests that this T-cell–Bcell interaction may be more complicated than formerly believed. This is based on two key processes. Firstly, B cells that internalize antigen that bind to their B-cell receptor are highly efficient antigenpresenting cells, being up to 10,000 times more efficient than dendritic cells. B cells may consequently be the primary antigen-presenting cell in an MS plaque that activate T cells, resulting in the inflammatory cascade. Secondly, there appears to be involvement of astrocytes, the innate immune cells Interleukin-1β and interferon-γ activate astrocytes to become type II astrocytes that upregulate inducible nitric oxide synthase (iNOS) and produce tumour necrosis factor, leading to axonal injury and oligodendrocyte and neuronal death. This means that there may be two steps with two different targets in the immune cascade, i.e., in both the innate and adaptive immune system. Whether purified B cells from MS patients could themselves damage the brain has been the subject of much exploration. CD19+ B lymphocytes from treatment-naive patients with MS-induced demyelination of cerebellar slices derived from mice, suggesting that B-cells have a direct effect on the brain.8 Although we currently consider the approved therapies as working via T cells, all therapies have now been reported to have B cell effects.