title: B-cell receptor for antigen modulates B-cell responses to complex TLR9 agonists and antagonists: implications for systemic lupus erythematosus.
abstract: The capacity to make secondary structures significantly affects the ability of Toll-like receptor 9 (TLR9) agonists and antagonists to either induce or block TLR9-dependent activation in B cells. However, it has a minor impact on TLR9-induced activation in interferon alpha (IFNα)-producing dendritic cells. Based on the ability of inhibitory oligodeoxynucleotides to form predictable secondary structures, we have classified TLR9-antagonists into Class R ('restricted', palindromic) and Class B ('broadly reactive', linear) oligodeoxynucleotides. In non-autoreactive B cells, Class R oligodeoxynucleotides are at least 10-fold less potent TLR9-inhibitors. We wanted to determine whether engagement of the B-cell receptor for antigen could overcome this restriction. Here we show that in non-autoreactive mouse B cells, B-cell receptor for antigen engagement increased the potency of Class R oligodeoxynucleotides for TLR9 activation at least 10-fold, making it equal in potency to linear oligodeoxynucleotides. However, this enhanced potency was selective for TLR9-induced B-cell cycling and apoptosis protection while TLR9-induced IL-6, an event that strongly depends on signaling via late endosomes, still required 10 times more Class R oligodeoxynucleotides. Thus, pathway-specific effects of Class R oligodeoxynucleotides for TLR9/B-cell receptor for antigen co-stimulated B cells may have therapeutic advantages over non-selective targeting of B cells, a strategy that may be seen as a potential therapy for human systemic lupus erythematosus.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Goeken
authors.forename: T
authors.initials: T
authors.lastname: Layer
authors.forename: S
authors.initials: S
authors.lastname: Fleenor
authors.forename: M
authors.initials: M
authors.lastname: Laccheo
authors.forename: P
authors.initials: P
authors.lastname: Lenert
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007075:Immunoglobulin M; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; D051217:Toll-Like Receptor 9