Roles of the Ig kappa light chain intronic and 3' enhancers in Igk somatic hypermutation

J Immunol. 2006 Jul 15;177(2):1146-51. doi: 10.4049/jimmunol.177.2.1146.

Abstract

Somatic hypermutation (SHM) of the rearranged Ig genes is required for the affinity maturation of Abs. SHM is almost exclusively targeted to the rearranged Ig loci, but the mechanism of this gene-specific targeting remains unclear. The Ig kappa L chain locus contains multiple enhancers, including the MAR/intronic (iE(kappa)) and 3' enhancers (3'E(kappa)). Previous transgenic studies indicate that both kappa enhancers are individually necessary for SHM of Igk. In contrast, later studies of Ag-selected V(kappa) genes in 3'E(kappa)(-/-) mice found no absolute requirement for 3'E(kappa) in kappa SHM. To address the roles of the two kappa enhancers in SHM in a physiological context, we analyzed SHM of the endogenous Igk in mice with a targeted deletion of either iE(kappa) or 3'E(kappa) in Peyer's patch germinal center B cells. Our findings indicate that, although 3'E(kappa) is quantitatively important for SHM of Igk, iE(kappa) is not required for kappa SHM. In addition, a reduction of kappa mRNA levels is also detected in activated 3'E(kappa)(-/-) B cells. These findings suggest that iE(kappa) and 3'E(kappa) play distinct roles in regulating Igk transcription and SHM.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions / physiology*
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Enhancer Elements, Genetic / physiology*
  • Gene Deletion
  • Gene Expression Regulation / immunology
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Immunoglobulin kappa-Chains / biosynthesis
  • Immunoglobulin kappa-Chains / genetics*
  • Immunoglobulin kappa-Chains / metabolism*
  • Introns / physiology*
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Somatic Hypermutation, Immunoglobulin*
  • Spleen / cytology
  • Spleen / immunology

Substances

  • 3' Untranslated Regions
  • Immunoglobulin kappa-Chains
  • RNA, Messenger