Abstract
BackgroundClinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naïve B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders.MethodsMyelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b+ antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM).ResultsWe observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b+ APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM.ConclusionsThese data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.
Highlights
Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results
While one study suggested that clinical benefit may relate to a decline in anti-AQP-4 antibody titers [4], it is unclear whether depletion of CD20+ AQP4-specific plasma cell precursors provides the sole and entire basis for therapeutic benefit of antiCD20 in NMO [6]
Paralleling our findings in EAE, we report that anti-CD20 treatment of MS and NMO is associated with an accentuation of pro-inflammatory monocyte function, providing the first evidence that besides abrogation of pathogenic B-cell function, anti-CD20 diminishes B-cell regulation of myeloid antigen presenting cells (APC)
Summary
Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. While target and plasma cells, the interaction of auto-reactive B- and Tcells may foster each other’s development in progression of CNS autoimmune disease Based on these pathogenic B-cell properties, substantial interest has developed for testing anti-CD20 antibodies (rituximab, ocrelizumab, ofatumumab) in MS and NMO. Immunological analyses revealed that anti-CD20 B-cell depletion diminished proliferation and pro-inflammatory differentiation of peripheral T-cells [10]; further, rituximab-treatment was associated with a reduced number of B-cells, and of T-cells within the CSF of patients with relapsing-remitting (RR)-MS [11] Together, these findings highlight abrogation of B-cell-mediated T-cell activation as an important mechanism for the prompt effect of anti-CD20 treatment in CNS demyelinating disorders
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