title: TOLL-like receptor ligands stimulate aberrant class switch recombination in early B cell precursors.
abstract: TOLL-like receptor (TLR) ligands stimulate class switch recombination (CSR) in mature B cells. We showed earlier that developing B cells in the bone marrow (BM) express TLR9 and are responsive to CpG DNA. Since CSR is a critical process for synthesis of effector antibodies, we studied the competence of precursor B cells to undergo CSR in response to TLR ligands, and the regulation of these cells. We found that CSR is induced throughout B lymphopoiesis in response to CpG and to LPS. However, sequencing analysis revealed aberrant joining of the switch junctions. In addition, we found that this CSR is independent of IgM expression and/or VDJ assembly and is directed to a specific isotype by cytokines. Finally, we found that activation of the switched precursor B cells is regulated by Fas. Thus, BM B cells can be activated by TLR ligands to undergo CSR and to secrete non-IgM antibodies. However, the effector potential of these cells is regulated by the Fas pathway.
authors.affiliation: Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Edry
authors.forename: Hilla
authors.initials: H
authors.lastname: Azulay-Debby
authors.forename: Doron
authors.initials: D
authors.lastname: Melamed
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology*; D017404:In Situ Hybridization, Fluorescence; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; C491899:Fas protein, mouse; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; D051217:Toll-Like Receptor 9; D019014:fas Receptor