B Cells and Antibodies as Targets of Therapeutic Intervention in Neuromyelitis Optica Spectrum Disorders

Abstract

The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.

Keywords: B cells; antibodies; eculizumab; inebilizumab; neuromyelitis optica spectrum disorders; ravulizumab; satralizumab; tocilizumab; ublituximab.

Figure 1

Approved (*) and experimental B cell- and antibody-targeting treatment options in neuromyelitis optica spectrum disorders. B cell development begins in the bone marrow, where hematopoietic stem cells proliferate into pro- and pre-B cells. Immature B cells, the earliest B cell subset in the peripheral blood undergo maturation into transitional, mature and memory B cells upon stimuli like interlukin-6 (IL-6), B cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL). Plasmablasts and plasma cells are capable of producing immunoglobulins, including pathological anti-aquaporin-4 (AQP4) immunoglobulin G (IgG). After binding AQP4 on astrocytic foot processes at the blood-brain barrier, complement activation (including complement factor 5(C5)) causes cytotoxicity by forming membrane attack complexes with subsequent neuronal injury. BAFFR = BAFF receptor; BCMA = B cell maturation antigen; BTK = Bruton’s tyrosine kinase; CAR = chimeric antigen receptors; CD = cluster of differentiation; IL-6R = interleukin-6 receptor; TACI = transmembrane activator and calcium-modulator and cyclophilin-ligand activator.