Update on the autoimmune pathology of multiple sclerosis: B-cells as disease-drivers and therapeutic targets

Abstract

Background: Collectively, research on the role of B-cells in the pathogenesis of multiple sclerosis (MS) illustrates how translational medicine has given rise to promising therapeutic approaches for one of the most debilitating chronic neurological diseases in young adults. First described in 1935, the experimental autoimmune/allergic encephalomyelitis model is a key animal model that has provided the foundation for important developments in targeted therapeutics.

Summary: While additional B-cell therapies for MS are presently being developed by the pharmaceutical industry, much remains to be understood about the role played by B-cells in MS. The goal of this review is to summarize how B-cells may contribute to MS pathogenesis and thereby provide a basis for understanding why B-cell depletion is so effective in the treatment of this disease. Key Messages: B-cells are key players in the pathogenesis of MS, and their depletion via B-cell-targeted therapy ameliorates disease activity.

Clinical implications: In 2008, data from the first CD20-targeting B-cell depleting therapeutic trials using rituximab in MS were published. Since then, there has been a large body of evidence demonstrating the effectiveness of B-cell depletion mediated via anti-CD20 antibodies. Intense research efforts focusing on the immunopathological relevance of B-cells has gained significant momentum and given rise to a constellation of promising therapeutic agents for this complex B-cell-driven disease, including novel anti-CD20 antibodies, as well as agents targeting CD19 and BAFF-R.

Figure 1. B cell functions

Depicted are basic immunological functions provided by B cells as relevant to MS immune pathology. Autoantigen presentation was shown to be the key B cell function for experimental CNS autoimmunity in myelin-oligodendrocyte induced EAE. Antibodies have long been hypothesized to play a role in MS; for example, clonal antibodies can be found as OCB in CSF. Ectopic lymphoid follicles are tertiary lymphoid tissues that become established at sites of inflammation. In MS, lymphoid follicle-like structures have been found associated with meningeal tissues. Cytokine production by B cells can support regulatory (IL-10) and pro-inflammatory T cell functions (IL-6, LT-α, TNF-α); cytokine production by B cells can occur following recognition of specific antigens or in an antigen-independent fashion. See text for detailed explanations.

Figure 2. B cells provide an immunologically active axis between the periphery and CNS

Naïve B cells emerge from the bone marrow (1) and undergo initial antigen-training and affinity maturation in peripheral germinal centers (GC). Memory B cells arising from GCs can be further stimulated in peripheral lymphoid tissues and/or migrate to the CNS compartment (2) where they participate in, and establish immunologically active sites in MS lesions (A) and pial meningeal tissues (B). An immunological continuum and “circulation” (3) of antigen-experienced B cells also involves the CSF compartment represented by schematic lateral ventricles in blue (C). Clonal and clonally related B cell receptors suggesting ongoing antigen-stimulation can be detected in all three CNS-sites (i.e. lesions, meninges, CSF) and in the periphery, suggesting MS disease-driving immunity to be active on both sides of the blood-brain barrier. The CSF (C) also contains OCB in the majority of MS patients, another sign of antigen-driven stimulation of B cells to differentiate into antibody producing plasmablasts or plasma cells. B cells are in blue shades, T cells in green shades. See text for details.

Figure 3. B cell development and expression of surface markers targeted by emerging MS therapeutics

CD19 is a pan-B cell marker expressed on nearly the entire B cell lineage starting from early Pro-B cells and disappearing on long-lived plasma cells; MEDI-551 (anti-CD19 antibody) currently in clinical development for MS therapy cuts deeply into the B cell compartment. CD20 is expressed on the majority of B cells; it appears on Pre B cells and becomes downregulated during terminal differentiation to plasmablasts/plasma cells. Interestingly, CD20 is also expressed by a small subset of T cells, which become depleted by rituximab. BAFF-R has a similar expression pattern as CD20; VAY736 is now also being studied as MS therapy.