title: Spontaneous class switch recombination in B cell lymphopoiesis generates aberrant switch junctions and is increased after VDJ rearrangement.
abstract: Mature B cells replace the mu constant region of the H chain with a downstream isotype in a process of class switch recombination (CSR). Studies suggest that CSR induction is limited to activated mature B cells in the periphery. Recently, we have shown that CSR spontaneously occur in B lymphopoiesis. However, the mechanism and regulation of it have not been defined. In this study, we show that spontaneous CSR occurs at all stages of B cell development and generates aberrant joining of the switch junctions as revealed by: 1) increased load of somatic mutations around the CSR break points, 2) reduced sequence overlaps at the junctions, and 3) excessive switch region deletion. In addition, we found that incidence of spontaneous CSR is increased in cells carrying VDJ rearrangements. Our results reveal major differences between spontaneous CSR in developing B cells and CSR induced in mature B cells upon activation. These differences can be explained by deregulated expression or function of activation-induced cytidine deaminase early in B cell development.
authors.affiliation: Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Edry
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Doron
authors.initials: D
authors.lastname: Melamed
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007133:Immunoglobulin Joining Region / Q000235:genetics / Q000276:immunology*; D007134:Immunoglobulin Switch Region / Q000235:genetics / Q000276:immunology*; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology*; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011995:Recombination, Genetic / Q000235:genetics / Q000276:immunology
chemical_list: D007133:Immunoglobulin Joining Region; D007148:Immunoglobulin mu-Chains; D003564:Cytidine Deaminase