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Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells.

Publication ,  Journal Article
Lieberman, AE; Kuraoka, M; Davila, M; Kelsoe, G; Cowell, LG
Published in: BMC Immunol
June 25, 2009

BACKGROUND: The cleavage of recombination signals (RS) at the boundaries of immunoglobulin V, D, and J gene segments initiates the somatic generation of the antigen receptor genes expressed by B lymphocytes. RS contain a conserved heptamer and nonamer motif separated by non-conserved spacers of 12 or 23 nucleotides. Under physiologic conditions, V(D)J recombination follows the "12/23 rule" to assemble functional antigen-receptor genes, i.e., cleavage and recombination occur only between RS with dissimilar spacer types. Functional, cryptic RS (cRS) have been identified in VH gene segments; these VH cRS were hypothesized to facilitate self-tolerance by mediating VH --> VHDJH replacements. At the Igkappa locus, however, secondary, de novo rearrangements can delete autoreactive VkappaJkappa joins. Thus, under the hypothesis that V-embedded cRS are conserved to facilitate self-tolerance by mediating V-replacement rearrangements, there would be little selection for Vkappa cRS. Recent studies have demonstrated that VH cRS cleavage is only modestly more efficient than V(D)J recombination in violation of the 12/23 rule and first occurs in pro-B cells unable to interact with exogenous antigens. These results are inconsistent with a model of cRS cleavage during autoreactivity-induced VH gene replacement. RESULTS: To test the hypothesis that cRS are absent from Vkappa gene segments, a corollary of the hypothesis that the need for tolerizing VH replacements is responsible for the selection pressure to maintain VH cRS, we searched for cRS in mouse Vkappa gene segments using a statistical model of RS. Scans of 135 mouse Vkappa gene segments revealed highly conserved cRS that were shown to be cleaved in the 103/BCL2 cell line and mouse bone marrow B cells. Analogous to results for VH cRS, we find that Vkappa cRS are conserved at multiple locations in Vkappa gene segments and are cleaved in pre-B cells. CONCLUSION: Our results, together with those for VH cRS, support a model of cRS cleavage in which cleavage is independent of BCR-specificity. Our results are inconsistent with the hypothesis that cRS are conserved solely to support receptor editing. The extent to which these sequences are conserved, and their pattern of conservation, suggest that they may serve an as yet unidentified purpose.

Duke Scholars

Published In

BMC Immunol

DOI

EISSN

1471-2172

Publication Date

June 25, 2009

Volume

10

Start / End Page

37

Location

England

Related Subject Headings

  • Sequence Alignment
  • Self Tolerance
  • RNA Splice Sites
  • Precursor Cells, B-Lymphoid
  • Pre-B Cell Receptors
  • Molecular Sequence Data
  • Mice, Inbred C57BL
  • Mice
  • Immunology
  • Immunoglobulin kappa-Chains
 

Citation

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Lieberman, A. E., Kuraoka, M., Davila, M., Kelsoe, G., & Cowell, L. G. (2009). Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells. BMC Immunol, 10, 37. https://doi.org/10.1186/1471-2172-10-37
Lieberman, Anne E., Masayuki Kuraoka, Marco Davila, Garnett Kelsoe, and Lindsay G. Cowell. “Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells.BMC Immunol 10 (June 25, 2009): 37. https://doi.org/10.1186/1471-2172-10-37.
Lieberman AE, Kuraoka M, Davila M, Kelsoe G, Cowell LG. Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells. BMC Immunol. 2009 Jun 25;10:37.
Lieberman, Anne E., et al. “Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells.BMC Immunol, vol. 10, June 2009, p. 37. Pubmed, doi:10.1186/1471-2172-10-37.
Lieberman AE, Kuraoka M, Davila M, Kelsoe G, Cowell LG. Conserved cryptic recombination signals in Vkappa gene segments are cleaved in small pre-B cells. BMC Immunol. 2009 Jun 25;10:37.
Journal cover image

Published In

BMC Immunol

DOI

EISSN

1471-2172

Publication Date

June 25, 2009

Volume

10

Start / End Page

37

Location

England

Related Subject Headings

  • Sequence Alignment
  • Self Tolerance
  • RNA Splice Sites
  • Precursor Cells, B-Lymphoid
  • Pre-B Cell Receptors
  • Molecular Sequence Data
  • Mice, Inbred C57BL
  • Mice
  • Immunology
  • Immunoglobulin kappa-Chains