A reappraisal of evidence for probabilistic models of allelic exclusion

Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):516-21. doi: 10.1073/pnas.0808764105. Epub 2008 Dec 30.

Abstract

B cell development requires the coordinated rearrangement of Ig heavy (IgH) and light chain loci (IgL). Most mature B cells express a single B cell receptor of unique specificity, and a central question in immunology concerns the mechanisms that prevent the productive rearrangement of >1 IgH and IgL allele per cell. Probabilistic models of allelic exclusion maintain that simultaneous rearrangement of both alleles is rare, because the likelihood of undergoing rearrangement is low for a given Ig allele. Strong support for this idea came from studies in which a GFP marker was inserted into the Igk locus. In this system, the probability of high-level germ-line transcription and subsequent locus rearrangement appeared to be low in pre-B cells. Readdressing the validity of GFP expression as a reporter for the level of germ-line transcription, we found a striking discordance between GFP transcript and protein levels at the pre-B cell stage, which is explained at least in part by the developmentally regulated usage of 2 alternative Igk-J germ-line promoters. These results question the validity of the kappa-GFP system as evidence for probabilistic models of allelic exclusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Bone Marrow Cells
  • Cells, Cultured
  • Gene Rearrangement*
  • Green Fluorescent Proteins
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Light Chains / genetics
  • Immunoglobulins / genetics
  • Mice
  • Models, Statistical*
  • Receptors, Antigen, B-Cell / genetics*
  • Transcription, Genetic

Substances

  • IgK
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Immunoglobulins
  • Receptors, Antigen, B-Cell
  • Green Fluorescent Proteins