Genomes and Genes
Summary: The phenomenon of immense variability characteristic of ANTIBODIES. It enables the IMMUNE SYSTEM to react specifically against the essentially unlimited kinds of ANTIGENS it encounters. Antibody diversity is accounted for by three main theories: (1) the Germ Line Theory, which holds that each antibody-producing cell has genes coding for all possible antibody specificities, but expresses only the one stimulated by antigen; (2) the Somatic Mutation Theory, which holds that antibody-producing cells contain only a few genes, which produce antibody diversity by mutation; and (3) the Gene Rearrangement Theory, which holds that antibody diversity is generated by the rearrangement of IMMUNOGLOBULIN VARIABLE REGION gene segments during the differentiation of the ANTIBODY-PRODUCING CELLS.
- Rada C, Williams G, Nilsen H, Barnes D, Lindahl T, Neuberger M. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol. 2002;12:1748-55 pubmed
- Enshell Seijffers D, Smelyanski L, Vardinon N, Yust I, Gershoni J. Dissection of the humoral immune response toward an immunodominant epitope of HIV: a model for the analysis of antibody diversity in HIV+ individuals. FASEB J. 2001;15:2112-20 pubmed..We used a combinatorial phage display peptide library to elucidate antibody diversity in HIV-infected individuals to a single immunodominant epitope in gp41...
- Verma N, Dimitrova M, Carter D, Crevar C, Ross T, Golding H, et al. Influenza virus H1N1pdm09 infections in the young and old: evidence of greater antibody diversity and affinity for the hemagglutinin globular head domain (HA1 Domain) in the elderly than in young adults and children. J Virol. 2012;86:5515-22 pubmed publisher..These findings may help explain the age-related morbidity and mortality pattern observed during the H1N1pdm09 pandemic. ..
- Kim S, Davis M, Sinn E, Patten P, Hood L. Antibody diversity: somatic hypermutation of rearranged VH genes. Cell. 1981;27:573-81 pubmed..We conclude that this somatic variation is generated by a special hypermutational mechanism highly localized in its site of execution and highly restricted in its time of operation during B-cell development. ..
- MacDuff D, Harris R. Directed DNA deamination by AID/APOBEC3 in immunity. Curr Biol. 2006;16:R186-9 pubmed
- Honjo T, Muramatsu M, Fagarasan S. AID: how does it aid antibody diversity?. Immunity. 2004;20:659-68 pubmed..Recent findings, namely requirement of protein synthesis for DNA breakage and dispensability of U removal activity of uracil DNA glycosylase, force us to reconsider DNA deamination hypothesis. ..
- Knappik A, Ge L, Honegger A, Pack P, Fischer M, Wellnhofer G, et al. Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J Mol Biol. 2000;296:57-86 pubmed..V(H) and seven V(L) (four Vkappa and three Vlambda) germline families cover more than 95 % of the human antibody diversity used. A consensus sequence was derived for each family and optimized for expression in Escherichia coli...
- Gearhart P. Immunology: the roots of antibody diversity. Nature. 2002;419:29-31 pubmed
- Mora T, Walczak A, Bialek W, Callan C. Maximum entropy models for antibody diversity. Proc Natl Acad Sci U S A. 2010;107:5405-10 pubmed publisher..Our results suggest that antibody diversity is not limited by the sequences encoded in the genome and may reflect rapid adaptation to antigenic ..
- Jenne C, Kennedy L, McCullagh P, Reynolds J. A new model of sheep Ig diversification: shifting the emphasis toward combinatorial mechanisms and away from hypermutation. J Immunol. 2003;170:3739-50 pubmed..We suggest that combinatorial rearrangement makes a much larger contribution, and somatic hypermutation makes a much smaller contribution to the generation of diversity within the sheep Ig repertoire than is currently acknowledged. ..
- MacDuff D, Demorest Z, Harris R. AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity. Nucleic Acids Res. 2009;37:1854-67 pubmed publisher..Together with evidence for AID expression in the ovary, our data combined to suggest that AID has innate immune functions in addition to its integral roles in creating antibody diversity.
- Butler J, Weber P, Sinkora M, Sun J, Ford S, Christenson R. Antibody repertoire development in fetal and neonatal piglets. II. Characterization of heavy chain complementarity-determining region 3 diversity in the developing fetus. J Immunol. 2000;165:6999-7010 pubmed
- Di Noia J, Neuberger M. Immunoglobulin gene conversion in chicken DT40 cells largely proceeds through an abasic site intermediate generated by excision of the uracil produced by AID-mediated deoxycytidine deamination. Eur J Immunol. 2004;34:504-8 pubmed
- Desiderio A, Franconi R, Lopez M, Villani M, Viti F, Chiaraluce R, et al. A semi-synthetic repertoire of intrinsically stable antibody fragments derived from a single-framework scaffold. J Mol Biol. 2001;310:603-15 pubmed..The antibody library described here allows the isolation of new stable binding specificities, potentially exploitable as immunochemical reagents for intracellular applications. ..
- de Yebenes V, Ramiro A. Activation-induced deaminase: light and dark sides. Trends Mol Med. 2006;12:432-9 pubmed..Here, we review the most recent findings on the regulation of AID targeting and discuss how AID activity on non-Ig genes is relevant to the generation of chromosome translocations and to lymphomagenesis. ..
- Cook G, Tomlinson I, Walter G, Riethman H, Carter N, Buluwela L, et al. A map of the human immunoglobulin VH locus completed by analysis of the telomeric region of chromosome 14q. Nat Genet. 1994;7:162-8 pubmed
- Zhang Z. VH replacement in mice and humans. Trends Immunol. 2007;28:132-7 pubmed..Here, I review the evidence for whether V(H) replacement genuinely offers an in vivo RAG-mediated recombinatorial mechanism to alter preformed IgH genes in mice and humans. ..
- Benedict C, Kearney J. Increased junctional diversity in fetal B cells results in a loss of protective anti-phosphorylcholine antibodies in adult mice. Immunity. 1999;10:607-17 pubmed..These results show that maintenance of lower Ig diversity in early life is essential for the acquisition of a complete functional adult repertoire. ..
- James L, Roversi P, Tawfik D. Antibody multispecificity mediated by conformational diversity. Science. 2003;299:1362-7 pubmed..Conformational diversity, whereby one sequence adopts multiple structures and multiple functions, can increase the effective size of the antibody repertoire but may also lead to autoimmunity and allergy. ..
- Silverstein A. Splitting the difference: the germline-somatic mutation debate on generating antibody diversity. Nat Immunol. 2003;4:829-33 pubmed..Then, as data developed favoring first one and then the other side, concessions were made, until the final solution showed that each had been at least partially correct. ..
- Pavri R, Nussenzweig M. AID targeting in antibody diversity. Adv Immunol. 2011;110:1-26 pubmed publisher..We propose a model for AID recruitment based on transcriptional stalling, which reconciles several of the key features of SHM, CSR, and lymphoma-associated translocation. ..
- Liu M, Duke J, Richter D, Vinuesa C, Goodnow C, Kleinstein S, et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature. 2008;451:841-5 pubmed publisher..Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair. ..
- Eyerman M, Zhang X, Wysocki L. T cell recognition and tolerance of antibody diversity. J Immunol. 1996;157:1037-46 pubmed..In agreement with these findings, we found that germ-line-encoded Ab V regions are presented by endogenous splenic APC at a level that is physiologically significant. ..
- Davis M. The evolutionary and structural 'logic' of antigen receptor diversity. Semin Immunol. 2004;16:239-43 pubmed..Thus, the wide variations seen in V region repertoires amongst vertebrates is likely to be of lesser importance than the preservation of one or more diverse CDR3 regions. ..
- Sernández I, de Yebenes V, Dorsett Y, Ramiro A. Haploinsufficiency of activation-induced deaminase for antibody diversification and chromosome translocations both in vitro and in vivo. PLoS ONE. 2008;3:e3927 pubmed publisher..These findings suggest that limiting the physiologic levels of AID expression can be a regulatory mechanism that ensures an optimal balance between immune proficiency and genome integrity. ..
- MacDuff D, Neuberger M, Harris R. MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells. Mol Immunol. 2006;43:1099-108 pubmed..Intriguingly, the same carboxy-terminal residues of AID were recently shown to be inessential for somatic hypermutation and immunoglobulin gene conversion but they were strictly required for class switch recombination. ..
- Nagaoka H, Tran T, Kobayashi M, Aida M, Honjo T. Preventing AID, a physiological mutator, from deleterious activation: regulation of the genomic instability that is associated with antibody diversity. Int Immunol. 2010;22:227-35 pubmed publisher..This is probably because immediate protection against pathogens is more critical for species survival than complete protection from the slower acting consequences of genomic instability, such as tumor formation. ..
- Butler J, Sun J, Weber P, Ford S, Rehakova Z, Sinkora J, et al. Antibody repertoire development in fetal and neonatal piglets. IV. Switch recombination, primarily in fetal thymus, occurs independent of environmental antigen and is only weakly associated with repertoire diversification. J Immunol. 2001;167:3239-49 pubmed
- Wang F, Ekiert D, Ahmad I, Yu W, Zhang Y, Bazirgan O, et al. Reshaping antibody diversity. Cell. 2013;153:1379-93 pubmed publisher..Thus, the bovine immune system produces an antibody repertoire composed of ultralong CDR H3s that fold into a diversity of minidomains generated through combinations of somatically generated disulfides. ..
- Wang X, Miller R. Recombination, transcription, and diversity of a partially germline-joined VH in a mammal. Immunogenetics. 2012;64:713-7 pubmed publisher..Compared to opossum IgH transcripts using the conventional VH genes, those with VH3.1 have unusually long CDR3 due to the length of the germline-joined DH...
- Nussenzweig M, Alt F. Antibody diversity: one enzyme to rule them all. Nat Med. 2004;10:1304-5 pubmed
- Knight K, Winstead C. Generation of antibody diversity in rabbits. Curr Opin Immunol. 1997;9:228-32 pubmed..Still to be determined is whether this diversification is developmentally programmed or is driven by exogenous microbial antigens. ..
- Li Z, Woo C, Iglesias Ussel M, Ronai D, Scharff M. The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev. 2004;18:1-11 pubmed
- Specht C, Schlüter B, Rolfing M, Brüning K, Pauels H, Kölsch E. Idiotype-specific CD4+CD25+ T suppressor cells prevent, by limiting antibody diversity, the occurrence of anti-dextran antibodies crossreacting with histone H3. Eur J Immunol. 2003;33:1242-9 pubmed..This increase of antibody diversity caused by a lack of CD25(+) Ts cells, e.g...
- Di Noia J, Neuberger M. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature. 2002;419:43-8 pubmed..This is good evidence that antibody diversification involves dC --> dU deamination within the immunoglobulin locus itself. ..
- Jung D, Giallourakis C, Mostoslavsky R, Alt F. Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol. 2006;24:541-70 pubmed..In this review, we summarize advances that have been made in understanding how V(D)J recombination at the IgH locus is controlled and discuss important areas for future investigation. ..
- Cannon J, Haire R, Rast J, Litman G. The phylogenetic origins of the antigen-binding receptors and somatic diversification mechanisms. Immunol Rev. 2004;200:12-22 pubmed..Such studies have the potential for uncovering previously unknown mechanisms of generating receptor diversity. ..
- Ohlin M, Zouali M. The human antibody repertoire to infectious agents: implications for disease pathogenesis. Mol Immunol. 2003;40:1-11 pubmed
- Schwager J, Bürckert N, Courtet M, Du Pasquier L. The ontogeny of diversification at the immunoglobulin heavy chain locus in Xenopus. EMBO J. 1991;10:2461-70 pubmed..These observations can account for the fact that larval antibody responses are less heterogeneous than those of adults. ..
- Peggs K, Verfuerth S, Pizzey A, Ainsworth J, Moss P, Mackinnon S. Characterization of human cytomegalovirus peptide-specific CD8(+) T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells. Blood. 2002;99:213-23 pubmed..These data provide further insight into the range of anti-HCMV responses and will aid the design and monitoring of adoptive immunotherapy protocols. ..
- Fu S, Deshmukh U, Gaskin F. Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J Autoimmun. 2011;37:104-12 pubmed publisher..This hypothesis accounts for most of the features unique to SLE and has clinical implications as to how patients should be treated. ..
- Sinkora M, Sun J, Sinkorova J, Christenson R, Ford S, Butler J. Antibody repertoire development in fetal and neonatal piglets. VI. B cell lymphogenesis occurs at multiple sites with differences in the frequency of in-frame rearrangements. J Immunol. 2003;170:1781-8 pubmed..We propose the latter to result from differential selection or a developmentally dependent change in the intrinsic mechanism of VDJ rearrangement. ..
- Ekman A, Niku M, Liljavirta J, Iivanainen A. Bos taurus genome sequence reveals the assortment of immunoglobulin and surrogate light chain genes in domestic cattle. BMC Immunol. 2009;10:22 pubmed publisher..The heavy chains probably contribute more to recombinational immunoglobulin repertoire diversity than the light chains but the heavy chain locus could not be annotated from the version 3.1 of Bos taurus genome. ..
- Shahaf G, Barak M, Zuckerman N, Swerdlin N, Gorfine M, Mehr R. Antigen-driven selection in germinal centers as reflected by the shape characteristics of immunoglobulin gene lineage trees: a large-scale simulation study. J Theor Biol. 2008;255:210-22 pubmed publisher..These two parameters were found to be the main factors affecting lineage tree shapes in both primary and secondary response trees. The results also confirm that recycling from centrocytes back to centroblasts is highly likely. ..
- Franklin A, Blanden R. The strand bias paradox of somatic hypermutation at immunoglobulin loci. Trends Immunol. 2008;29:167-72 pubmed publisher..To explain the strand bias paradox, we propose that phase 1 and phase 2 hypermutations are generated at different stages of the cell cycle. ..
- Ogle B, Cascalho M, Joao C, Taylor W, West L, Platt J. Direct measurement of lymphocyte receptor diversity. Nucleic Acids Res. 2003;31:e139 pubmed..In addition, this approach could be more broadly applied, for example to measure diversity of viral quasi-species. ..
- De Re V, De Vita S, Carbone A, Ferraccioli G, Gloghini A, Marzotto A, et al. The relevance of VDJ PCR protocols in detecting B-cell clonal expansion in lymphomas and other lymphoproliferative disorders. Tumori. 1995;81:405-9 pubmed
- Vora K, Manser T. Altering the antibody repertoire via transgene homologous recombination: evidence for global and clone-autonomous regulation of antigen-driven B cell differentiation. J Exp Med. 1995;181:271-81 pubmed..Thus, the development of B cell memory is regulated in a "clone-autonomous" fashion...
- Jaszczur M, Bertram J, Pham P, Scharff M, Goodman M. AID and Apobec3G haphazard deamination and mutational diversity. Cell Mol Life Sci. 2013;70:3089-108 pubmed publisher..to initiate the somatic hypermutation (SHM) and class switch recombination (CSR) that are essential for antibody diversity. Apo3G expressed in T cells catalyzes C deaminations on reverse transcribed cDNA causing HIV-1 retroviral ..
- Sakaguchi N. [Origin of antibody diversity]. Nihon Rinsho. 2005;63 Suppl 4:254-9 pubmed