Receptor editing occurs frequently during normal B cell development.
Allelic exclusion is established in development through a feedback mechanism in which the assembled immunoglobulin (Ig) suppresses further V(D)J rearrangement. But Ig expression sometimes fails to prevent further rearrangement. In autoantibody transgenic mice, reactivity of immature B cells with autoantigen can induce receptor editing, in which allelic exclusion is transiently prevented or reversed through nested light chain gene rearrangement, often resulting in altered B cell receptor specificity. To determine the extent of receptor editing in a normal, non-Ig transgenic immune system, we took advantage of the fact that lambda light chain genes usually rearrange after kappa genes. This allowed us to analyze kappa loci in IgMlambda+ cells to determine how frequently in-frame kappa genes fail to suppress lambda gene rearrangements. To do this, we analyzed recombined VkappaJkappa genes inactivated by subsequent recombining sequence (RS) rearrangement. RS rearrangements delete portions of the kappa locus by a V(D)J recombinase-dependent mechanism, suggesting that they play a role in receptor editing. We show that RS recombination is frequently induced by, and inactivates, functionally rearranged kappa loci, as nearly half (47%) of the RS-inactivated VkappaJkappa joins were in-frame. These findings suggest that receptor editing occurs at a surprisingly high frequency in normal B cells.
National Jewish Medical and Research Center, Division of Basic Sciences, Department of Pediatrics, Denver, Colorado 80206, USA.
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D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D007075:Immunoglobulin M / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology; D007438:Introns; D019891:Leukopoiesis; D051379:Mice; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*
D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D011947:Receptors, Antigen, B-Cell