Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders
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RESEARCH
JOURNAL OF NEUROINFLAMMATION
Open Access
Anti-CD20 B-cell depletion enhances monocyte reactivity in neuroimmunological disorders Klaus Lehmann-Horn1, Eva Schleich1, Deetje Hertzenberg1, Alexander Hapfelmeier2, Tania Kümpfel3, Nikolas von Bubnoff4, Reinhard Hohlfeld3, Achim Berthele1, Bernhard Hemmer1 and Martin S Weber1*
Abstract Background: Clinical 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. Methods: Myelin 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). Results: We 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. Conclusions: These 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. Keywords: multiple sclerosis, neuromyelitis optica, anti-CD20, B-cell regulation, monocytes, experimental autoimmune encephalomyelitis
Background Accumulating evidence suggests that in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO), B-cells, plasma cells and self-reactive antibodies play an essential pathogenic role. In MS, an oligoclonal antibody response generated by a limited repertoire of activated B-cells remains a hallmark diagnostic finding in the cerebrospinal fluid (CSF)[1]. While target and * Correspondence: [email protected] 1 Department of Neurology, Technische Universität München, Munich, Germany Full list of a
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