Genomes and Genes
b lymphocyte gene rearrangement
Summary: Ordered rearrangement of B-lymphocyte variable gene regions coding for the IMMUNOGLOBULIN CHAINS, thereby contributing to antibody diversity. It occurs during the differentiation of the IMMATURE B-LYMPHOCYTES.
- Silverman G. Adoptive transfer of a superantigen-induced hole in the repertoire of natural IgM-secreting cells. Cell Immunol. 2001;209:76-80 pubmed..These studies clarify the cellular mechanisms responsible for B-cell superantigen-induced modification of the repertoires of in vivo polyclonal B-cell populations. ..
- Cowell L, Davila M, Ramsden D, Kelsoe G. Computational tools for understanding sequence variability in recombination signals. Immunol Rev. 2004;200:57-69 pubmed..These models successfully predict RS activity and identify functional, cryptic RSs (cRSs). These models permit studies to identify RSs and cRSs for empiric study and constitute a tool useful for understanding RS structure and function. ..
- Koralov S, Novobrantseva T, Königsmann J, Ehlich A, Rajewsky K. Antibody repertoires generated by VH replacement and direct VH to JH joining. Immunity. 2006;25:43-53 pubmed..Thus, V(H) replacement is an efficient mechanism of antibody diversification, and its impact on the overall antibody repertoire could be greater than anticipated because it frequently leaves no molecular footprint. ..
- Brochet X, Lefranc M, Giudicelli V. IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 2008;36:W503-8 pubmed publisher..The 'Advanced parameters' allow to modify default parameters used by IMGT/V-QUEST and IMGT/JunctionAnalysis according to the users' interest. IMGT/V-QUEST is freely available for academic research at http://imgt.cines.fr. ..
- Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol. 2006;6:728-40 pubmed
- Souto Carneiro M, Fritsch R, Sepúlveda N, Lagareiro M, Morgado N, Longo N, et al. The NF-kappaB canonical pathway is involved in the control of the exonucleolytic processing of coding ends during V(D)J recombination. J Immunol. 2008;180:1040-9 pubmed..However, selection of the primary B cell repertoire appeared to be intact and was partially able to correct the defects generated by abnormal V(D)J recombination. ..
- Ikawa T, Kawamoto H, Wright L, Murre C. Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. Immunity. 2004;20:349-60 pubmed..These observations indicate that E2A-deficient hematopoietic progenitor cells remain pluripotent after long-term culture in vitro and that E2A proteins play a critical role in B cell commitment. ..
- Seo H, Masuoka M, Murofushi H, Takeda S, Shibata T, Ohta K. Rapid generation of specific antibodies by enhanced homologous recombination. Nat Biotechnol. 2005;23:731-5 pubmed
- Rooney S, Chaudhuri J, Alt F. The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev. 2004;200:115-31 pubmed..In this review, we discuss the factors that constitute this pathway as well as the evidence of their involvement in two lymphoid-specific DNA recombination events. ..
- Borghesi L, Aites J, Nelson S, Lefterov P, James P, Gerstein R. E47 is required for V(D)J recombinase activity in common lymphoid progenitors. J Exp Med. 2005;202:1669-77 pubmed..Taken together, this work defines a role for E47 in regulating lineage progression at the CLP stage in vivo and describes the first transcription factor required for lineage-specific recombinase activity. ..
- Johnson K, Angelin Duclos C, Park S, Calame K. Changes in histone acetylation are associated with differences in accessibility of V(H) gene segments to V-DJ recombination during B-cell ontogeny and development. Mol Cell Biol. 2003;23:2438-50 pubmed..Thus, changes in histone acetylation appear to be important for both promotion and inhibition of V-DJ rearrangement during B-cell ontogeny and development. ..
- Giudicelli V, Duroux P, Ginestoux C, Folch G, Jabado Michaloud J, Chaume D, et al. IMGT/LIGM-DB, the IMGT comprehensive database of immunoglobulin and T cell receptor nucleotide sequences. Nucleic Acids Res. 2006;34:D781-4 pubmed..They represent the main source of IG and TR gene and allele knowledge stored in IMGT/GENE-DB and in the IMGT reference directory. IMGT/LIGM-DB is freely available at http://imgt.cines.fr. ..
- Wang J, Alt F, Gostissa M, Datta A, Murphy M, Alimzhanov M, et al. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med. 2008;205:3079-90 pubmed publisher..Thus, Xrcc4/p53-deficient pro-B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy...
- Rumfelt L, Zhou Y, Rowley B, Shinton S, Hardy R. Lineage specification and plasticity in CD19- early B cell precursors. J Exp Med. 2006;203:675-87 pubmed..A) stage, and B/T lymphoid plasticity persists until the CD19+ pro-B stage. Thus, MLP, CLP, and Fr. A represent progressively B lineage-specified stages in development, before the CD19+ B lineage-committed pro-B stage. ..
- Igarashi H, Kuwata N, Kiyota K, Sumita K, Suda T, Ono S, et al. Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfp knockin mice. Blood. 2001;97:2680-7 pubmed
- Kouskoff V, Nemazee D. Role of receptor editing and revision in shaping the B and T lymphocyte repertoire. Life Sci. 2001;69:1105-13 pubmed..Recent studies have likewise suggested a role for receptor editing and revision in shaping the T cell repertoire during development and tolerance. ..
- Skok J, Brown K, Azuara V, Caparros M, Baxter J, Takacs K, et al. Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes. Nat Immunol. 2001;2:848-54 pubmed..However, this differential recruitment and expression of Ig alleles was not typically seen among transformed B cell lines. These data raise the possibility that epigenetic factors help maintain the monoallelic expression of Ig. ..
- Inlay M, Alt F, Baltimore D, Xu Y. Essential roles of the kappa light chain intronic enhancer and 3' enhancer in kappa rearrangement and demethylation. Nat Immunol. 2002;3:463-8 pubmed..Our findings also indicate that the two kappa enhancers play overlapping and distinct roles in the demethylation of kappa in B cells. ..
- Matthews A, Kuo A, Ramon Maiques S, Han S, Champagne K, Ivanov D, et al. RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature. 2007;450:1106-10 pubmed..Furthermore, our results provide the first evidence indicating that disrupting the read-out of histone modifications can cause an inherited human disease. ..
- Manis J, Tian M, Alt F. Mechanism and control of class-switch recombination. Trends Immunol. 2002;23:31-9 pubmed..In this review, we discuss the potential role of these factors in CSR, discuss potential relationships between CSR and somatic hypermutation, and speculate how CSR and related mechanisms might contribute to genomic instability. ..
- Sekiguchi J, Whitlow S, Alt F. Increased accumulation of hybrid V(D)J joins in cells expressing truncated versus full-length RAGs. Mol Cell. 2001;8:1383-90 pubmed..These results suggest a potential role for the non-core regions in repressing potentially harmful transposition events. ..
- Murre C. Helix-loop-helix proteins and lymphocyte development. Nat Immunol. 2005;6:1079-86 pubmed..This review discusses HLH proteins in lymphocyte development and homeostasis. ..
- Kurth J, Spieker T, Wustrow J, Strickler G, Hansmann L, Rajewsky K, et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity. 2000;13:485-95 pubmed
- Schatz D. V(D)J recombination. Immunol Rev. 2004;200:5-11 pubmed
- Schrader C, Linehan E, Mochegova S, Woodland R, Stavnezer J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J Exp Med. 2005;202:561-8 pubmed..Our results indicate that AID attacks cytosines on both DNA strands, and staggered breaks are processed to blunt DSBs at the initiating ss break sites. We propose a model to explain the types of end-processing events observed. ..
- Reynaud C, Dahan A, Anquez V, Weill J. Somatic hyperconversion diversifies the single Vh gene of the chicken with a high incidence in the D region. Cell. 1989;59:171-83 pubmed..Allelic exclusion appears to be performed by restriction of a complete VDJ rearrangement to a single allele. ..
- Ferradini L, Gu H, De Smet A, Rajewsky K, Reynaud C, Weill J. Rearrangement-enhancing element upstream of the mouse immunoglobulin kappa chain J cluster. Science. 1996;271:1416-20 pubmed..This cis-acting recombination-enhancing element affects the rearrangement process without being involved in regulating transcription. ..
- Fang W, Mueller D, Pennell C, Rivard J, Li Y, Hardy R, et al. Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a bcl-xL transgene. Immunity. 1996;4:291-9 pubmed..This analysis also demonstrated that immunoglobulin gene rearrangement is less precise than previously appreciated. ..
- Torres R, Flaswinkel H, Reth M, Rajewsky K. Aberrant B cell development and immune response in mice with a compromised BCR complex. Science. 1996;272:1804-8 pubmed..B cells that do develop demonstrate a differential dependence on Ig-alpha signaling in antibody responses such that a signaling-competent Ig-alpha appears to be critical for the response to T-independent, but not T-dependent, antigens. ..
- Nemazee D. Receptor selection in B and T lymphocytes. Annu Rev Immunol. 2000;18:19-51 pubmed..New information about receptor editing in T cells and B-1 B cells is also discussed. ..
- Bain G, Robanus Maandag E, te Riele H, Feeney A, Sheehy A, Schlissel M, et al. Both E12 and E47 allow commitment to the B cell lineage. Immunity. 1997;6:145-54 pubmed..Taken together, the data indicate that both E12 and E47 allow commitment to the B cell lineage and act synergistically to promote B lymphocyte maturation. ..
- Jacobs H, Fukita Y, van der Horst G, de Boer J, Weeda G, Essers J, et al. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice. J Exp Med. 1998;187:1735-43 pubmed..This appears also to be true for mismatch repair, RAD54-dependent double-strand-break repair, and AAG-mediated base excision repair. ..
- Spanopoulou E, Roman C, Corcoran L, Schlissel M, Silver D, Nemazee D, et al. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 1994;8:1030-42 pubmed..These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process. ..
- Chen C, Nagy Z, Prak E, Weigert M. Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity. 1995;3:747-55 pubmed..The sd-tg model thus provides direct evidence for secondary rearrangement at VH-D-JH. This process may play a role in tolerance by editing autoreactive receptors and may also serve to diversify the VH repertoire. ..
- Mendez M, Green L, Corvalan J, Jia X, Maynard Currie C, Yang X, et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet. 1997;15:146-56 pubmed..Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies. ..
- Phung Q, Winter D, Cranston A, Tarone R, Bohr V, Fishel R, et al. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein. J Exp Med. 1998;187:1745-51 pubmed..The results suggest that the hypermutation pathway frequently mutates G.C pairs, and a MSH2-dependent pathway preferentially corrects mismatches at G and C. ..
- Larijani M, Yu C, Golub R, Lam Q, Wu G. The role of components of recombination signal sequences in immunoglobulin gene segment usage: a V81x model. Nucleic Acids Res. 1999;27:2304-9 pubmed..Furthermore, the contribution of the heptamer and nonamer to differential VHusage in our assay is correlated inversely with their conservation throughout the VHlocus. ..
- Ramsden D, Gellert M. Formation and resolution of double-strand break intermediates in V(D)J rearrangement. Genes Dev. 1995;9:2409-20 pubmed..Efficient formation of signal junctions may require cell cycle progression, or down-regulation of the recombination machinery. ..
- Lin H, Grosschedl R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature. 1995;376:263-7 pubmed
- Yu W, Nagaoka H, Jankovic M, Misulovin Z, Suh H, Rolink A, et al. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature. 1999;400:682-7 pubmed..Our findings may help to reconcile a series of apparently contradictory observations, and suggest a new model for the mechanisms that regulate allelic exclusion, receptor editing and tolerance. ..
- Feeney A, Tang A, Ogwaro K. B-cell repertoire formation: role of the recombination signal sequence in non-random V segment utilization. Immunol Rev. 2000;175:59-69 pubmed..We also describe experiments showing that the sequence of the spacer of the RSS can play an important role in relative recombination frequencies. ..
- Hansen A, Dorner T, Lipsky P. Use of immunoglobulin variable-region genes by normal subjects and patients with systemic lupus erythematosus. Int Arch Allergy Immunol. 2000;123:36-45 pubmed
- Oettinger M, Schatz D, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248:1517-23 pubmed..RAG-1 and RAG-2 might activate the expression of the V(D)J recombinase but, more likely, they directly participate in the recombination reaction. ..
- Ji Y, Resch W, Corbett E, Yamane A, Casellas R, Schatz D. The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell. 2010;141:419-31 pubmed publisher..We propose that recombination centers coordinate V(D)J recombination by providing discrete sites within which gene segments are captured for recombination. ..
- Lutz J, Muller W, Jack H. VH replacement rescues progenitor B cells with two nonproductive VDJ alleles. J Immunol. 2006;177:7007-14 pubmed..In conclusion, VH replacement can occur in the absence of a muH chain signal and provides a potential rescue mechanism for pro-B cells with two nonproductive IgH alleles. ..
- Xu Z, Fulop Z, Zhong Y, Evinger A, Zan H, Casali P. DNA lesions and repair in immunoglobulin class switch recombination and somatic hypermutation. Ann N Y Acad Sci. 2005;1050:146-62 pubmed..Aberrant regulation of these events can result in chromosomal breaks and translocations, which are significant steps in B-cell neoplastic transformation. ..
- Zhang K, Wong H, Song B, Miller C, Scheuner D, Kaufman R. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest. 2005;115:268-81 pubmed..These results suggest specific requirements of the IRE1alpha-mediated UPR subpathway in the early and late stages of B lymphopoiesis. ..
- Atayar C, Poppema S, Blokzijl T, Harms G, Boot M, van den Berg A. Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas. Am J Pathol. 2005;166:127-34 pubmed..Overall, the T-cell TF and cytokine profiles of the HL cell lines showed a considerable degree of consistency. The expression of T-cell TFs may explain the production of various cytokines by HL cell lines and HRS cells. ..
- Fuentes Pananá E, Monroe J. Ligand-dependent and -independent processes in B-cell-receptor-mediated signaling. Springer Semin Immunopathol. 2001;23:333-50 pubmed..Here we discuss the evidence for ligand-independent functions for the BCR and postulate how it may be regulated and linked to biological processes associated with B cell development and survival. ..
- Rezk S, Spagnolo D, Brynes R, Weiss L. Indeterminate cell tumor: a rare dendritic neoplasm. Am J Surg Pathol. 2008;32:1868-76 pubmed publisher..Finally, Langerin immunostaining may be used as a surrogate marker for the ultrastructural demonstration of Birbeck granules, the absence of which represents a strong diagnostic criterion for ICT. ..
- Pike K, Iacampo S, Friedmann J, Ratcliffe M. The cytoplasmic domain of Ig alpha is necessary and sufficient to support efficient early B cell development. J Immunol. 2004;172:2210-8 pubmed