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Receptor editing occurs frequently during normal B cell development.

ABSTRACT: 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.

SUBMITTER: Retter MW

PROVIDER: S-EPMC2212498 | biostudies-literature | 1998 Oct

REPOSITORIES: biostudies-literature

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Receptor editing occurs frequently during normal B cell development.

Retter M W MW Nemazee D D

The Journal of experimental medicine 19981001 7

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 specific ...[more]

PMID: 9763602

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Project description:Thoracic aortic aneurysms result from dysregulated remodeling of the vascular extracellular matrix, which may occur as a result of altered resident cellular function. The present study tested the hypothesis that aortic fibroblasts undergo a stable change in cellular phenotype during thoracic aortic aneurysm formation.Primary murine aortic fibroblasts were isolated from normal and thoracic aortic aneurysm-induced aortas (4 weeks post induction with 0.5 mol/L CaCl(2) 15 minutes) by the outgrowth method. Normal and thoracic aortic aneurysm cultures were examined using a focused polymerase chain reaction array to determine fibroblast-specific changes in gene expression in the absence and presence of biological stimulation (endothelin-1, phorbol-12-myristate-13-acetate, angiotensin-II). The relative expression of 38 genes, normalized to 4 housekeeping genes, was determined, and genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized cycle threshold values were considered to have altered expression.At steady state, thoracic aortic aneurysm fibroblasts revealed elevated expression of several matrix metalloproteinases (Mmp2, Mmp11, Mmp14), collagen genes/elastin (Col1a1, Col1a2, Col3a1, Eln), and other matrix proteins, as well as decreased expression of Mmp3, Timp3, and Ltbp1. Moreover, gene expression profiles in thoracic aortic aneurysm fibroblasts were different than normal fibroblasts after equivalent biological stimuli.This study demonstrated for the first time that isolated primary aortic fibroblasts from thoracic aortic aneurysm-induced mice possess a unique and stable gene expression profile, and when challenged with biological stimuli, induce a transcriptional response that is different from normal aortic fibroblasts. Together, these data suggest that aortic fibroblasts undergo a stable phenotypic change during thoracic aortic aneurysm development, which may drive the enhancement of extracellular matrix proteolysis in thoracic aortic aneurysm progression.

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Receptor editing occurs frequently during normal B cell development.

Publications

Receptor editing occurs frequently during normal B cell development.

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