The Journal of Immunology, Vol 149, Issue 1 222-229, Copyright © 1992 by American Association of Immunologists

ARTICLES

Predominance of VH-D-JH junctions occurring at sites of short sequence homology results in limited junctional diversity in neonatal antibodies

AJ Feeney
Division of Immunology, Medical Biology Institute, La Jolla, CA 92037.

Sequence diversity at the junctions of Ig genes differs between newborn and adult mice in two respects: 1) fetal/newborn Ig lack N regions; and 2) these N- junctional sequences very often contain 1 to 6 nucleotides that could have been encoded by either of the two joined gene segments. We address the hypothesis that such short homologies preferentially direct recombination to that site, and we analyze the effect of such homology-directed recombination upon the neonatal Ig repertoire. We examined 546 CDR3 sequences that were generated from polymerase chain reaction-amplified DNA from fetal and newborn liver using primers from three different VH families: S107, 7183, and J558. All junctional sequences using 14 frequently occurring IgH V-D and D-J gene combinations were analyzed. In 12 of the 14 combinations analyzed, there were 1 to 3 short sequence homologies, and the junctional sequences that would be created by those homologies were observed with high frequency. The D-J junctions often had two to three predominant junctional sequences, whereas the V-D junctions had one dominant junctional sequence. The only exceptions were the VHJ558-D junctions, where homology-directed recombination using the sequence homology between VHJ558 genes and most D genes would result in an out-of-frame join, and most of our sequences were productive. This latter result further suggests that homology-directed recombination may play a role in the nonrandom VH gene usage observed in fetal and newborn mice. Thus, most neonatal IgH junctions show limited diversity, not only due to the lack of N regions, but also because of nonrandom junctional sequences. Inasmuch as the few adult N- junctions also show a high frequency of homology-directed junctional sequences, V-D-J recombination throughout life may involve pairing via short homologies, with addition of N regions obscuring its role in the formation of adult IgH junctions.

This article has been cited by other articles:

				B. Gozalbo-Lopez, P. Andrade, G. Terrados, B. de Andres, N. Serrano, I. Cortegano, B. Palacios, A. Bernad, L. Blanco, M. A. R. Marcos, et al. A Role for DNA Polymerase {micro} in the Emerging DJH Rearrangements of the Postgastrulation Mouse Embryo Mol. Cell. Biol., March 1, 2009; 29(5): 1266 - 1275. [Abstract] [Full Text] [PDF]

				S. Yoshikawa, Y. Kawano, Y. Minegishi, and H. Karasuyama The skewed heavy-chain repertoire in peritoneal B-1 cells is predetermined by the selection via pre-B cell receptor during B cell ontogeny in the fetal liver Int. Immunol., January 1, 2009; 21(1): 43 - 52. [Abstract] [Full Text] [PDF]

				Z. E. Parra, M. L. Baker, A. M. Lopez, J. Trujillo, J. M. Volpe, and R. D. Miller TCR{micro} Recombination and Transcription Relative to the Conventional TCR during Postnatal Development in Opossums J. Immunol., January 1, 2009; 182(1): 154 - 163. [Abstract] [Full Text] [PDF]

				M. Zemlin, R. L. Schelonka, G. C. Ippolito, C. Zemlin, Y. Zhuang, G. L. Gartland, L. Nitschke, J. Pelkonen, K. Rajewsky, and H. W. Schroeder Jr. Regulation of Repertoire Development through Genetic Control of DH Reading Frame Preference J. Immunol., December 15, 2008; 181(12): 8416 - 8424. [Abstract] [Full Text] [PDF]

				J. B. Carey, C. S. Moffatt-Blue, L. C. Watson, A. L. Gavin, and A. J. Feeney Repertoire-based selection into the marginal zone compartment during B cell development J. Exp. Med., September 1, 2008; 205(9): 2043 - 2052. [Abstract] [Full Text] [PDF]

				H. Lu, K. Schwarz, and M. R. Lieber Extent to which hairpin opening by the Artemis:DNA-PKcs complex can contribute to junctional diversity in V(D)J recombination Nucleic Acids Res., November 29, 2007; 35(20): 6917 - 6923. [Abstract] [Full Text] [PDF]

				R. R. Hardy B-1 B cell development. J. Immunol., September 1, 2006; 177(5): 2749 - 2754. [Abstract] [Full Text] [PDF]

				L. C. Watson, C. S. Moffatt-Blue, R. Z. McDonald, E. Kompfner, D. Ait-Azzouzene, D. Nemazee, A. N. Theofilopoulos, D. H. Kono, and A. J. Feeney Paucity of V-D-D-J Rearrangements and VH Replacement Events in Lupus Prone and Nonautoimmune TdT-/- and TdT+/+ Mice J. Immunol., July 15, 2006; 177(2): 1120 - 1128. [Abstract] [Full Text] [PDF]

				M. M. Souto-Carneiro, G. P. Sims, H. Girschik, J. Lee, and P. E. Lipsky Developmental Changes in the Human Heavy Chain CDR3 J. Immunol., December 1, 2005; 175(11): 7425 - 7436. [Abstract] [Full Text] [PDF]

				R. J. Romeijn, M. M. Gorski, M. A. van Schie, J. N. Noordermeer, L. H. Mullenders, W. Ferro, and A. Pastink Lig4 and Rad54 Are Required for Repair of DNA Double-Strand Breaks Induced by P-Element Excision in Drosophila Genetics, February 1, 2005; 169(2): 795 - 806. [Abstract] [Full Text] [PDF]

				I. F. Robey, M. Peterson, M. S. Horwitz, D. H. Kono, T. Stratmann, A. N. Theofilopoulos, N. Sarvetnick, L. Teyton, and A. J. Feeney Terminal Deoxynucleotidyltransferase Deficiency Decreases Autoimmune Disease in Diabetes-Prone Nonobese Diabetic Mice and Lupus-Prone MRL-Faslpr Mice J. Immunol., April 1, 2004; 172(7): 4624 - 4629. [Abstract] [Full Text] [PDF]

				M. M. Gorski, J. C. J. Eeken, A. W. M. de Jong, I. Klink, M. Loos, R. J. Romeijn, B. L. van Veen, L. H. Mullenders, W. Ferro, and A. Pastink The Drosophila melanogaster DNA Ligase IV Gene Plays a Crucial Role in the Repair of Radiation-Induced DNA Double-Strand Breaks and Acts Synergistically With Rad54 Genetics, December 1, 2003; 165(4): 1929 - 1941. [Abstract] [Full Text] [PDF]

				K. Grigoriadou, L. Boucontet, and P. Pereira Most IL-4-Producing {gamma}{delta} Thymocytes of Adult Mice Originate from Fetal Precursors J. Immunol., September 1, 2003; 171(5): 2413 - 2420. [Abstract] [Full Text] [PDF]

				C. S. Goodyear and G. J. Silverman Death by a B Cell Superantigen: In Vivo VH-targeted Apoptotic Supraclonal B Cell Deletion by a Staphylococcal Toxin J. Exp. Med., May 5, 2003; 197(9): 1125 - 1139. [Abstract] [Full Text] [PDF]

				C. N. Jenne, L. J. Kennedy, P. McCullagh, and J. D. Reynolds A New Model of Sheep Ig Diversification: Shifting the Emphasis Toward Combinatorial Mechanisms and Away from Hypermutation J. Immunol., April 1, 2003; 170(7): 3739 - 3750. [Abstract] [Full Text] [PDF]

				K. Bauer, M. Zemlin, M. Hummel, S. Pfeiffer, J. Karstaedt, G. Steinhauser, X. Xiao, H. Versmold, and C. Berek Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens J. Immunol., August 1, 2002; 169(3): 1349 - 1356. [Abstract] [Full Text] [PDF]

				A. J. Feeney, B. R. Lawson, D. H. Kono, and A. N. Theofilopoulos Terminal Deoxynucleotidyl Transferase Deficiency Decreases Autoimmune Disease in MRL-Faslpr Mice J. Immunol., September 15, 2001; 167(6): 3486 - 3493. [Abstract] [Full Text] [PDF]

				A. L. Miracle, M. K. Anderson, R. T. Litman, C. J. Walsh, C. A. Luer, E. V. Rothenberg, and G. W. Litman Complex expression patterns of lymphocyte-specific genes during the development of cartilaginous fish implicate unique lymphoid tissues in generating an immune repertoire Int. Immunol., April 1, 2001; 13(4): 567 - 580. [Abstract] [Full Text] [PDF]

				C. L. Benedict, S. Gilfillan, and J. F. Kearney The Long Isoform of Terminal Deoxynucleotidyl Transferase Enters the Nucleus And, Rather than Catalyzing Nontemplated Nucleotide Addition, Modulates the Catalytic Activity of the Short Isoform J. Exp. Med., January 1, 2001; 193(1): 89 - 100. [Abstract] [Full Text] [PDF]

				J. E. Butler, P. Weber, M. Sinkora, J. Sun, S. J. Ford, and R. K. Christenson Antibody Repertoire Development in Fetal and Neonatal Piglets. II. Characterization of Heavy Chain Complementarity-Determining Region 3 Diversity in the Developing Fetus J. Immunol., December 15, 2000; 165(12): 6999 - 7010. [Abstract] [Full Text] [PDF]

				J. Lee, N. L. Monson, and P. E. Lipsky The V{lambda}J{lambda} Repertoire in Human Fetal Spleen: Evidence for Positive Selection and Extensive Receptor Editing J. Immunol., December 1, 2000; 165(11): 6322 - 6333. [Abstract] [Full Text] [PDF]

				K. D. Klonowski and M. Monestier Heavy Chain Revision in MRL Mice: A Potential Mechanism for the Development of Autoreactive B Cell Precursors J. Immunol., October 15, 2000; 165(8): 4487 - 4493. [Abstract] [Full Text] [PDF]

				N. Tuaillon and J. D. Capra Evidence That Terminal Deoxynucleotidyltransferase Expression Plays a Role in Ig Heavy Chain Gene Segment Utilization J. Immunol., June 15, 2000; 164(12): 6387 - 6397. [Abstract] [Full Text] [PDF]

				M. J. Chumley, J. M. Dal Porto, S. Kawaguchi, J. C. Cambier, D. Nemazee, and R. R. Hardy2 A VH11V{kappa}9 B Cell Antigen Receptor Drives Generation of CD5+ B Cells Both In Vivo and In Vitro J. Immunol., May 1, 2000; 164(9): 4586 - 4593. [Abstract] [Full Text] [PDF]

				S. Shiokawa, F. Mortari, J. O. Lima, C. Nunez, F. E. Bertrand III, P. M. Kirkham, S. Zhu, A. P. Dasanayake, and H. W. Schroeder Jr. IgM Heavy Chain Complementarity-Determining Region 3 Diversity Is Constrained by Genetic and Somatic Mechanisms Until Two Months After Birth J. Immunol., May 15, 1999; 162(10): 6060 - 6070. [Abstract] [Full Text] [PDF]

				K. D. Klonowski, L. L. Primiano, and M. Monestier Atypical VH-D-JH Rearrangements in Newborn Autoimmune MRL Mice J. Immunol., February 1, 1999; 162(3): 1566 - 1572. [Abstract] [Full Text] [PDF]

				A. J. Marshall, N. Doyen, L. A. Bentolila, C. J. Paige, and G. E. Wu Terminal Deoxynucleotidyl Transferase Expression During Neonatal Life Alters DH Reading Frame Usage and Ig-Receptor-Dependent Selection of V Regions J. Immunol., December 15, 1998; 161(12): 6657 - 6663. [Abstract] [Full Text] [PDF]

				C. A. Giorgetti and J. L. Press Somatic Mutation in the Neonatal Mouse J. Immunol., December 1, 1998; 161(11): 6093 - 6104. [Abstract] [Full Text] [PDF]

				J. Sun, C. Hayward, R. Shinde, R. Christenson, S. P. Ford, and J. E. Butler Antibody Repertoire Development in Fetal and Neonatal Piglets. I. Four VH Genes Account for 80 Percent of VH Usage During 84 Days of Fetal Life J. Immunol., November 1, 1998; 161(9): 5070 - 5078. [Abstract] [Full Text] [PDF]

				C. C. K. Yu, M. Larijani, I. N. Miljanic, and G. E. Wu Differential Usage of VH Gene Segments Is Mediated by cis Elements J. Immunol., October 1, 1998; 161(7): 3444 - 3454. [Abstract] [Full Text] [PDF]

				T Komori, A Okada, V Stewart, and F. Alt Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes Science, August 27, 1993; 261(5125): 1171 - 1175. [Abstract] [PDF]

				S Gilfillan, A Dierich, M Lemeur, C Benoist, and D Mathis Mice lacking TdT: mature animals with an immature lymphocyte repertoire Science, August 27, 1993; 261(5125): 1175 - 1178. [Abstract] [PDF]

				T. T. Paull and M. Gellert A mechanistic basis for Mre11-directed DNA joining at microhomologies PNAS, June 6, 2000; 97(12): 6409 - 6414. [Abstract] [Full Text] [PDF]