title: Normal human IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts.
abstract: Somatic hypermutation in immunoglobulin variable region genes occurs within germinal centers. Here, we describe a subset of germinal center dark zone centroblasts that express only sIgD and have accumulated up to 80 mutations per heavy chain variable region (IgVH delta gene). Over half of the hypermutated IgVH delta sequences were found to be clonally related. This level of mutation is not observed in either IgVH gamma transcripts from the same sample or IgVH delta transcripts from peripheral blood, suggesting that these cells neither undergo isotype switch nor mature into circulating memory B cells. Optimal growth of these cells in vitro depends on CD40 ligand, T cell cytokines, and a fibroblast stroma, a combination possibly mimicking the dark zone microenvironment. Our hypothesis is that these cells may be sequestered within germinal centers, where their somatic mutation machinery is triggered. The isolation of these hypermutated B cells may represent a critical step for studying both the biology and biochemistry of somatic hypermutation.
authors.affiliation: Schering-Plough Laboratory for Immunological Research, Dardilly, France.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Liu
authors.forename: O
authors.initials: O
authors.lastname: de Bouteiller
authors.forename: C
authors.initials: C
authors.lastname: Arpin
authors.forename: F
authors.initials: F
authors.lastname: Brière
authors.forename: L
authors.initials: L
authors.lastname: Galibert
authors.forename: S
authors.initials: S
authors.lastname: Ho
authors.forename: H
authors.initials: H
authors.lastname: Martinez-Valdez
authors.forename: J
authors.initials: J
authors.lastname: Banchereau
authors.forename: S
authors.initials: S
authors.lastname: Lebecque
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D015415:Biomarkers; D002453:Cell Cycle / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002999:Clone Cells; D018858:Germinal Center / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007156:Immunologic Memory; D008562:Membrane Glycoproteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D009699:N-Glycosyl Hydrolases / Q000235:genetics; D014066:Palatine Tonsil / Q000166:cytology; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D015415:Biomarkers; D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1