Abstract
V, D, and J gene segments rearrange at different frequencies in vivo. In my laboratory, we are interested in determining the reasons for this unequal rearrangement of V genes during B cell development, and also in gaining insights into the mechanisms that control recombination. Every V, D, and J gene segment is flanked on its recombining side(s) by a recombination signal sequence (RSS), which is composed of a conserved heptamer and nonamer, separated by a spacer of conserved length. In this article, we summarize data showing that in many cases the RSS can account for differences in recombination frequencies observed in vivo. The approach that we use is to determine the frequency of initial rearrangement of the V genes in vivo. The RSSs of two V genes are then placed into a competition recombination substrate to determine the relative frequency with which the two RSSs recombine. In one example, we have shown that a single base pair polymorphism in the RSS of a Vκ gene may play a major role in susceptibility ot Haemophilus influenzae type b infection.
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References
Tonegawa S: Somatic generation of antibody diversity. Nature 1983;14:575–581.
Schäble KF, Zachau HG: The variable genes of the human immunoglo bulin κ locus. Biol Chem Hoppe-Seyler 1993;374: 1001–1022.
Weichhold GM, Ohnheiser R, Zachau HG: The human immunoglobulin κ locus consists of two copies that are organized in opposite polarity. Genomics 1993;16: 503–511.
Feeney AJ, Lugo G, Escuro G: Human cord blood κ repertoire. J Immunol 1997:158:3761–3768.
Klein R, Jaenichen R, Zachau HG: Expressed human immunoglobulin κ genes and their hypermutation. Eur J Immunol 1993:23: 3248–3271.
Cox JPL, Tomtlinson IM, Winter G: A directory of human germ-line Sκ segments reveals a strong bias in their usage. Eur J Immunol 1994; 24:827–836.
Foster SF, Brezinschek H-P, Brezinschek RI, Lipsky PE: Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ cells. J Clin Invest 1997;99:1614–1627.
Akira S, Okazaki K, Sakano H: Two pairs of recombination signals are sufficient to cause immunoglobulin V-(D)-J joining. Science 1987;238:1134–1138.
Hesse JE, Lieber MR, Mizuuchi K, Gellert M: V (D) J recombination: a functional de finition of the joining signals. Genes Dev 1989;3: 1053–1061.
Schroeder HW Jr, Hillson JL, Perlmutter RM: Structure and evolution of mammalian Vh families. Int Immunol 1990;2:41–50.
Ramsden DA, Paige CJ, Wu GE: κ light chain rearrangement in mouse fetal liver. J Immunol 1994;153:1150–1160.
Connor AM, Fanning LJ, Celler JW, Hicks LK, Ramsden DA, Wu GE: Mouse VH7183 recombination signal sequences mediate recombination more frequently than those of VH3558. J Immunol 1995;155:5268–5272.
Nadel B, Tang A, Lugo G, Love V, Escuro G, Feeney AJ: Decreased frequency of rearrangement due to synergistic effect of nucleotide changes in the heptamer and nonamer of the recombination signal sequence of the Vκ gene A2b, which is associated with increased susceptibility of Navajosto Haemophilus influenzae type b disease. J Immunol 1998;161:6068–6073.
Yu CCK, Larijani M, Miljanic IN, Wu GE: Differential usage of VH gene segments is mediated by cis elements. J Immunol 1998;161: 3444–3454.
Nadel B, Tang A, Escuro G, Lugo G, Feeney AJ: Sequence of the spacer in the RSS affects V(D)J rearrangement frequency and correlates with non-random Vκ usage in vivo. J Exp Med 1998;187: 1495–1503.
Hesse JE, Lieber MR, Gellert M, Mizuuchi K: Extrachromosomal DNA substrates in pre-B cells undergo inversion or deletion at immunoglobulin V-(D)-J joining signals. Cell 1987;49:775–783.
Atkinson MJ, Cowan MJ, Feeney AJ: New alleles of 1GKV genes A2 and A18 suggest significant polymorphism of the human IGKV locus. Immunogenetics 1996;44: 115–120.
Insel RA, Kittelberger A, Anderson P: Isoelectic focusing of human antibody to the Haemophilus influenzae type b capsular polysaccharide: restricted and identical spectrotypes in adults. J Immunol 1985;135:2810–2816.
Lucas AH, Langley RJ, Granoff DM, Nahm MH, Kitamura MY, Scott MG: An idiotypic marker associated with a germ-line encoded κ light chain variable region that predominates the vaccine-induced human antibody response to the Haemophilus influenzae b poly saccharide. J Clin Invest 1991;88:1811–1818.
Adderson EE, Shackelford PG, Quinn A, Wilson PM, Carroll WL: Diversity of immunoglobulin light chain usage in the human immune response to Haemophilus influenzae type b capsular polysaccharide. Pediatr Res 1993;33: 307–311.
Adderson EE, Shackelford PG, Quinn A, Wilson PM, Cunningham MW, Insel RA, Carroll WL: Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide. J Clin Invest 1993;91: 2734–2743.
Scott MG, Crimmins DL, McCourt DW, Chung G, Schable KF, Thiebe R, Quenzel EM, Zachau HG, Nahm MH: Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogenous. J Immunol 1991;147: 4007–4013.
Petersen GM, Silimperi DR, Rotter JI, Terasaki PI, Schanfield MS, Park MS, Ward JI. Genetic factors in Haemophilus influenzae type b diseasesusceptibility andantibody acquisition. J Pediatr 1987;110: 228–233.
Losonsky GA, Santosham M, Sehgal VM, Zwahlen A, Moxon ER: Haemophilus influenzae disease in the While Mountain Apaches: molecularepidemiology of a high risk population. Pediatr Infect Dis 1985;3:539–547.
Feeney AJ, Atkinson MJ, Cowan MJ, Escuno G, Lugo G: A defective VκA 2allele in Navajos which may play a role in increased susceptibility to Haemophilus influenzae type b disease. J Clin Invest 1996;97:2277–2282.
Scott MG, Crimmins DL, McCourt DW, Zocher I, Thiebe R, Zachau HG, Nahm MH: Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide III. A single VκII gene and one of several Jκ genes are joined by an invariant arginine to form the most common L chain V region. J Immunol 1989;143:4110–4116.
Feeney AJ: Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. J Exp Med 1990;172: 1377–1390.
Feeney AJ: Predominance of the prototypic T15 anti-phosphory l-choline junctional sequence in neonatal pre-B cells. J Immunol 1991;147:4343–4350.
Kitamura D, Roes J, Kühn R, Rajewsky K: A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature 1991;350:423–426.
Love VA, Lugo G, Merz D, Feeney AJ: Individual VH promoters vary in strength, but the frequency of rearrangement of those VH genes does not correlate with promoter strengthnorenhancer-independence. Mol Immunol, in press 2000.
Gerstein RM, Lieber MR: Coding end sequence can markedly affect the initiation of V(D)J recombination. Genes Dev 1993;7: 1459–1469.
Ezekiel UR, Engler P, Stern D, Storb U: Asymmetric processing of coding ends and the effect of coding end nucleotide composition on V(D)J recombination. Immunity 1995;2:381–389.
Ezekiel UR, Sun T, Bozek G, Storb U: The composition of coding joints formed in V(D)J recombination is strongly affected by the nucleotide sequence of the coding ends and their relationship to the recombination signal sequences. Mol Cell Biol 1997;17:4191–4197.
Gauss GH, Lieber MR: The basis for the mechanistic bias for deletional over inversional V(D)J recombination. Genes Dev 1992;6: 1553–1561.
Pan PY, Lieber MR, Teale JM: The role of recombination signal sequences in the preferential joining by delection in DH-JH recombination and in the ordered rearrangement of the IgH locus. Int Immunol 1997;9:515–522.
VanDy k LF, Wise TW, Moore BB, Meek K: Immunoglobulin DH recombination signal sequence targeting. J Immunol 1996:157
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Feeney, A.J. Factors that influence formation of B cell repertoire. Immunol Res 21, 195–202 (2000). https://doi.org/10.1385/IR:21:2-3:195
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DOI: https://doi.org/10.1385/IR:21:2-3:195