Antibodies in a heavy chain knock-in mouse exhibit characteristics of early heavy chain rearrangement

J Immunol. 2009 Jul 1;183(1):452-61. doi: 10.4049/jimmunol.0804060.

Abstract

Studies in autoantibody transgenic mice have demonstrated receptor editing rearrangements at Ab H and L chain loci. However, the physiologic role of H chain editing (V(H) replacement and rearrangement on the second allele) has been called into question. It is unclear if additional rounds of H chain rearrangement are driven by BCR specificity. In this study, we analyze the manner in which B cells undergo additional H chain rearrangements in an anti-DNA H chain knock-in mouse, B6.56R. We find that rearrangements in 56R(+) B cells tend to involve the D gene locus on both alleles and the most J(H)-proximal V(H) gene segments on the endogenous allele. As a result, some B cells exhibit V(D)J rearrangements on both H chain alleles, yet allelic exclusion is tightly maintained in mature 56R B cells. As B cells mature, a higher proportion expresses the nontransgenic H chain allele. Rearrangements on both H chain alleles exhibit junctional diversity consistent with TdT-mediated N-addition, and TdT RNA is expressed exclusively at the pro-B cell stage in B6.56R. Collectively, these findings favor a single, early window of H chain rearrangement in B6.56R that precedes the expression of a functional BCR. B cells that happen to successfully rearrange another H chain may be favored in the periphery.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Antibodies, Antinuclear / chemistry
  • Antibodies, Antinuclear / genetics
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Gene Knock-In Techniques / methods
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain / genetics*
  • Immunoglobulin D / biosynthesis
  • Immunoglobulin D / chemistry
  • Immunoglobulin D / genetics
  • Immunoglobulin Heavy Chains / biosynthesis
  • Immunoglobulin Heavy Chains / chemistry*
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin M / biosynthesis
  • Immunoglobulin M / chemistry*
  • Immunoglobulin M / genetics*
  • Immunoglobulin Variable Region / biosynthesis
  • Immunoglobulin Variable Region / chemistry
  • Immunoglobulin Variable Region / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, B-Cell / biosynthesis
  • Receptors, Antigen, B-Cell / genetics
  • Stem Cells / cytology
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Time Factors

Substances

  • Antibodies, Antinuclear
  • Immunoglobulin D
  • Immunoglobulin Heavy Chains
  • Immunoglobulin M
  • Immunoglobulin Variable Region
  • Receptors, Antigen, B-Cell