title: NMDA-receptor antagonists block B-cell function but foster IL-10 production in BCR/CD40-activated B cells.
abstract: BACKGROUND
  B cells are important effectors and regulators of adaptive and innate immune responses, inflammation and autoimmunity, for instance in anti-NMDA-receptor (NMDAR) encephalitis. Thus, pharmacological modulation of B-cell function could be an effective regimen in therapeutic strategies. Since the non-competitive NMDAR antagonist memantine is clinically applied to treat advanced Alzheimer`s disease and ketamine is supposed to improve the course of resistant depression, it is important to know how these drugs affect B-cell function.
  
  
  RESULTS
  Non-competitive NMDAR antagonists impaired B-cell receptor (BCR)- and lipopolysaccharide (LPS)-induced B-cell proliferation, reduced B-cell migration towards the chemokines SDF-1α and CCL21 and downregulated IgM and IgG secretion. Mechanistically, these effects were mediated through a blockade of Kv1.3 and KCa3.1 potassium channels and resulted in an attenuated Ca(2+)-flux and activation of Erk1/2, Akt and NFATc1. Interestingly, NMDAR antagonist treatment increased the frequency of IL-10 producing B cells after BCR/CD40 stimulation.
  
  
  CONCLUSIONS
  Non-competitive NMDAR antagonists attenuate BCR and Toll-like receptor 4 (TLR4) B-cell signaling and effector function and can foster IL-10 production. Consequently, NMDAR antagonists may be useful to target B cells in autoimmune diseases or pathological systemic inflammation. The drugs' additional side effects on B cells should be considered in treatments of neuronal disorders with NMDAR antagonists.
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Narasimhulu.Simma@st.ovgu.de.
authors.forename: Narasimhulu
authors.initials: N
authors.lastname: Simma
authors.affiliation: RG Molecular Physiology, Leibniz Institute of Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany. tbose@lin-magdeburg.de.
authors.forename: Tanima
authors.initials: T
authors.lastname: Bose
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. sabiotic@st.ovgu.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: Kahlfuss
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Judith.Mankiewicz@st.ovgu.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Mankiewicz
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Theresa.Lowinus@st.ovgu.de.
authors.forename: Theresa
authors.initials: T
authors.lastname: Lowinus
authors.affiliation: Department of Neuroimmunology, Institute for Multiple Sclerosis Research and The Hertie Foundation, Waldweg 33, 37073, Göttingen, Germany. fred.luehder@med.uni-goettingen.de.
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Thomas.Schueler@med.ovgu.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schüler
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Burkhart.Schraven@med.ovgu.de.|Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124, Braunschweig, Germany. Burkhart.Schraven@med.ovgu.de.
authors.forename: Burkhart
authors.initials: B
authors.lastname: Schraven
authors.affiliation: RG Molecular Physiology, Leibniz Institute of Neurobiology, Brenneckestr. 6, 39118, Magdeburg, Germany. Martin.Heine@lin-magdeburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Heine
authors.affiliation: Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany. Ursula.Bommhardt@med.ovgu.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Bommhardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D051664:Kv1.3 Potassium Channel; D008070:Lipopolysaccharides; D010880:Piperidines; D011947:Receptors, Antigen, B-Cell; D016194:Receptors, N-Methyl-D-Aspartate; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D007371:Interferon-gamma; C010739:ifenprodil