Genomes and Genes
immunoglobulin heavy chains
Summary: The largest of polypeptide chains comprising immunoglobulins. They contain 450 to 600 amino acid residues per chain, and have molecular weights of 51-72 kDa.
- Buck D, Albrecht E, Aslam M, Goris A, Hauenstein N, Jochim A, et al. Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis. Ann Neurol. 2013;73:86-94 pubmed publisher..The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease. ..
- Rouaud P, Vincent Fabert C, Saintamand A, Fiancette R, Marquet M, Robert I, et al. The IgH 3' regulatory region controls somatic hypermutation in germinal center B cells. J Exp Med. 2013;210:1501-7 pubmed publisher..Beyond class switch recombination, the IgH 3'RR is a central element that controls heavy chain accessibility to activation-induced deaminase modifications including SHM. ..
- Bebin A, Carrion C, Marquet M, Cogne N, Lecardeur S, Cogne M, et al. In vivo redundant function of the 3' IgH regulatory element HS3b in the mouse. J Immunol. 2010;184:3710-7 pubmed publisher..In conclusion, our study highlights a major effect of the global ambiance of the IgH locus; enhancers demonstrated as being strongly synergistic in transgenes turn out to be redundant in their endogenous context. ..
- Klein I, Resch W, Jankovic M, Oliveira T, Yamane A, Nakahashi H, et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011;147:95-106 pubmed publisher..Finally, we find that activation-induced cytidine deaminase (AID) induces the rearrangement of many genes found as translocation partners in mature B cell lymphoma. ..
- Subrahmanyam R, Sen R. Epigenetic features that regulate IgH locus recombination and expression. Curr Top Microbiol Immunol. 2012;356:39-63 pubmed publisher..In this review we discuss the regulatory features of each step of IgH gene assembly and the role of epigenetic mechanisms in achieving regulatory precision. ..
- Schroeder H, Zemlin M, Khass M, Nguyen H, Schelonka R. Genetic control of DH reading frame and its effect on B-cell development and antigen-specifc antibody production. Crit Rev Immunol. 2010;30:327-44 pubmed..This change in the repertoire variably affects antibody production and the development of specific B-cell subsets. ..
- Tromp J, Tonino S, Elias J, Jaspers A, Luijks D, Kater A, et al. Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene. 2010;29:5071-82 pubmed publisher..Thus, a distinction in NF-kappaB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X(L) levels. ..
- Kastelic D, Frkovic Grazio S, Baty D, Truan G, Komel R, Pompon D. A single-step procedure of recombinant library construction for the selection of efficiently produced llama VH binders directed against cancer markers. J Immunol Methods. 2009;350:54-62 pubmed publisher..1997), they constitute very interesting agents in therapeutic applications, especially in human immunotherapy and cancer treatment. ..
- Chiarle R, Zhang Y, Frock R, Lewis S, Molinie B, Ho Y, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147:107-19 pubmed publisher..The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics. ..
- Vincent Fabert C, Fiancette R, Pinaud E, Truffinet V, Cogne N, Cogne M, et al. Genomic deletion of the whole IgH 3' regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes. Blood. 2010;116:1895-8 pubmed publisher..Our study shows that transcriptional changes and recombinations occurring after antigen-encounter appear mainly controlled by the 3'RR working as a single functional unit. ..
- Vernersson M, Belov K, Aveskogh M, Hellman L. Cloning and structural analysis of two highly divergent IgA isotypes, IgA1 and IgA2 from the duck billed platypus, Ornithorhynchus anatinus. Mol Immunol. 2010;47:785-91 pubmed publisher..The platypus may require a more effective mucosal immunity, with two highly divergent IgA forms, than the terrestrial echidna, due to its lifestyle, where it is exposed to pathogens both on land and in the water. ..
- Thullier P, Huish O, Pelat T, Martin A. The humanness of macaque antibody sequences. J Mol Biol. 2010;396:1439-50 pubmed publisher..In addition, the humanness of macaque sequences presented in patents has been analyzed. The H-score and G-score define objectively the humanness of antibody V-regions, and their use is exemplified here. ..
- Jackman J, Chen Y, Huang A, Moffat B, Scheer J, Leong S, et al. Development of a two-part strategy to identify a therapeutic human bispecific antibody that inhibits IgE receptor signaling. J Biol Chem. 2010;285:20850-9 pubmed publisher..Our approach for producing human bispecific full-length antibodies enables the clinical application of bispecific antibodies to a validated therapeutic pathway in asthma. ..
- Mouquet H, Scheid J, Zoller M, Krogsgaard M, Ott R, Shukair S, et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature. 2010;467:591-5 pubmed publisher..Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV. ..
- Arnaout R, Lee W, Cahill P, Honan T, Sparrow T, Weiand M, et al. High-resolution description of antibody heavy-chain repertoires in humans. PLoS ONE. 2011;6:e22365 pubmed publisher..Finally, we find that while there are a near-infinite number of heavy-chain CDR3s in principle, there are about 3-9 million in the blood of an adult human being. ..
- Ebert A, McManus S, Tagoh H, Medvedovic J, Salvagiotto G, Novatchkova M, et al. The distal V(H) gene cluster of the Igh locus contains distinct regulatory elements with Pax5 transcription factor-dependent activity in pro-B cells. Immunity. 2011;34:175-87 pubmed publisher..The pro-B cell-specific and Pax5-dependent activity of the PAIR elements suggests that they are involved in the regulation of distal V(H)-DJ(H) recombination at the Igh locus. ..
- Hinz A, Lutje Hulsik D, Forsman A, Koh W, Belrhali H, Gorlani A, et al. Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction. PLoS ONE. 2010;5:e10482 pubmed publisher..Furthermore, our data confirm that the structural plasticity of gp120 can accommodate multiple modes of antibody binding within the CD4 binding site. ..
- Giambra V, Cianci R, Lolli S, Mattioli C, Tampella G, Cattalini M, et al. Allele *1 of HS1.2 enhancer associates with selective IgA deficiency and IgM concentration. J Immunol. 2009;183:8280-5 pubmed publisher..2 allelic frequence variation. Overall our candidate gene approach confirms that the study of polymorphisms in human diseases is a valid tool to investigate the function of these Regulatory Regions that confers multiple immune features. ..
- Steininger C, Widhopf G, Ghia E, Morello C, Vanura K, Sanders R, et al. Recombinant antibodies encoded by IGHV1-69 react with pUL32, a phosphoprotein of cytomegalovirus and B-cell superantigen. Blood. 2012;119:2293-301 pubmed publisher..The observed reactivity of multiple different CLL rAbs and natural antibodies from CMV-seronegative adults with pUL32 is consistent with the properties of a superantigen. ..
- Wu L, Oficjalska K, Lambert M, Fennell B, Darmanin Sheehan A, Ní Shúilleabháin D, et al. Fundamental characteristics of the immunoglobulin VH repertoire of chickens in comparison with those of humans, mice, and camelids. J Immunol. 2012;188:322-33 pubmed publisher..This study supports the hypothesis that disulfide bond-constrained CDR3s are a structural diversification strategy in the restricted germline v-gene repertoire of chickens. ..
- Guo Y, Bao Y, Wang H, Hu X, Zhao Z, Li N, et al. A preliminary analysis of the immunoglobulin genes in the African elephant (Loxodonta africana). PLoS ONE. 2011;6:e16889 pubmed publisher..Our results provide insights into the immunoglobulin genes in a placental mammal that is evolutionarily distant from humans, mice, and domestic animals. ..
- Abhinandan K, Martin A. Analysis and prediction of VH/VL packing in antibodies. Protein Eng Des Sel. 2010;23:689-97 pubmed publisher..Thus, not only do we provide a rapid method for predicting the packing angle, but also we define a set of residues that may be important in antibody humanization in order to obtain the correct binding site topography. ..
- Hultberg A, Temperton N, Rosseels V, Koenders M, Gonzalez Pajuelo M, Schepens B, et al. Llama-derived single domain antibodies to build multivalent, superpotent and broadened neutralizing anti-viral molecules. PLoS ONE. 2011;6:e17665 pubmed publisher..The results show that multimerization of VHH fragments targeting multiple epitopes on a viral trimeric spike protein is a powerful tool for anti-viral therapy to achieve "best-in-class" and broader neutralization capacity. ..
- Ryckaert S, Pardon E, Steyaert J, Callewaert N. Isolation of antigen-binding camelid heavy chain antibody fragments (nanobodies) from an immune library displayed on the surface of Pichia pastoris. J Biotechnol. 2010;145:93-8 pubmed publisher..This technology for displaying protein libraries on P. pastoris enables the isolation and engineering of antibody-derived molecules in a robust eukaryotic expression host. ..
- Bao Y, Guo Y, Xiao S, Zhao Z. Molecular characterization of the VH repertoire in Canis familiaris. Vet Immunol Immunopathol. 2010;137:64-75 pubmed publisher..Our results suggest that the dog VH repertoire appears to be derived from limited germline gene families, and its diversity may rely on junctional diversity and somatic hypermutation. ..
- Krause J, Ekiert D, Tumpey T, Smith P, Wilson I, Crowe J. An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody. MBio. 2011;2:e00345-10 pubmed publisher..Removal of the insertion restores the canonical structure of CDR H1 and CDR H2, but binding, neutralization activity, and in vivo activity were reduced markedly because of steric conflict of CDR H1 with the hemagglutinin antigen. ..
- Giallourakis C, Franklin A, Guo C, Cheng H, Yoon H, Gallagher M, et al. Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination. Proc Natl Acad Sci U S A. 2010;107:22207-12 pubmed publisher..Thus, the V(H)-D intergenic region, and likely elements within it, can influence silencing of sense and antisense germ-line transcription from the IgH D cluster and thereby influence targeting of V(D)J recombination. ..
- Govaert J, Pellis M, Deschacht N, Vincke C, Conrath K, Muyldermans S, et al. Dual beneficial effect of interloop disulfide bond for single domain antibody fragments. J Biol Chem. 2012;287:1970-9 pubmed publisher..This dual beneficial effect explains the in vivo antibody maturation process favoring VHH domains with an interloop disulfide bond. ..
- Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119:521-9 pubmed publisher..NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. ..
- Kalinina O, Doyle Cooper C, Miksanek J, Meng W, Prak E, Weigert M. Alternative mechanisms of receptor editing in autoreactive B cells. Proc Natl Acad Sci U S A. 2011;108:7125-30 pubmed publisher..The editing mechanisms in the case of ?-expressing B cells include L chain allelic inclusion and V(H) replacement. ..
- Xi L, Arons E, Navarro W, Calvo K, Stetler Stevenson M, Raffeld M, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012;119:3330-2 pubmed publisher..Our results suggest that HCLv and IGHV4-34(+) HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600. ..
- Rapaka R, Ricks D, Alcorn J, Chen K, Khader S, Zheng M, et al. Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina. J Exp Med. 2010;207:2907-19 pubmed publisher..We outline a mechanism whereby serum IgM, containing ancient specificities against conserved fungal antigens, bridges innate and adaptive immunity against fungal organisms. ..
- Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a master regulator of B cell development and leukemogenesis. Adv Immunol. 2011;111:179-206 pubmed publisher..Pax5 has also been implicated in human B cell malignancies because it can function as a haploinsufficient tumor suppressor or oncogenic translocation fusion protein in B cell precursor acute lymphoblastic leukemia. ..
- Chelius D, Ruf P, Gruber P, Plöscher M, Liedtke R, Gansberger E, et al. Structural and functional characterization of the trifunctional antibody catumaxomab. MAbs. 2010;2:309-19 pubmed..Binding measurement revealed the unique trifunctional features of catumaxomab. Other analytical tools were used to evaluate characteristics of catumaxomab preparations, including the presence of isoforms and aggregates. ..
- Zimmermann J, Romesberg F, Brooks C, Thorpe I. Molecular description of flexibility in an antibody combining site. J Phys Chem B. 2010;114:7359-70 pubmed publisher..The results suggest that 3PEPS spectroscopy in combination with molecular dynamics simulations can provide a detailed description of protein dynamics and, in this case, how it is evolved for biological function. ..
- Xiao F, Wang Y, Yan W, Chang M, Yao W, Xu Q, et al. Ig heavy chain genes and their locus in grass carp Ctenopharyngodon idella. Fish Shellfish Immunol. 2010;29:594-9 pubmed publisher..The transcriptional enhancer located at the mu-delta intergenic region was also analyzed and it seems possible that this enhancer is functional as verified in zebrafish and channel catfish...
- Lanasa M, Allgood S, Volkheimer A, Gockerman J, Whitesides J, Goodman B, et al. Single-cell analysis reveals oligoclonality among 'low-count' monoclonal B-cell lymphocytosis. Leukemia. 2010;24:133-40 pubmed publisher..We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL...
- Magadán Mompó S, Sánchez Espinel C, Gambón Deza F. Immunoglobulin heavy chains in medaka (Oryzias latipes). BMC Evol Biol. 2011;11:165 pubmed publisher..The publication of whole genome sequences and the availability of several cDNA libraries for medaka (Oryzias latipes) permitted us to perform a thorough analysis of immunoglobulin heavy chains present in this teleost.
- Forconi F, Potter K, Wheatley I, Darzentas N, Sozzi E, Stamatopoulos K, et al. The normal IGHV1-69-derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL. Blood. 2010;115:71-7 pubmed publisher..Conserved patterns in the 51p1-encoded immunoglobulin M of normal B cells suggest a restricted sequence repertoire shaped by evolution to recognize common pathogens. Proliferative pressure on these cells is the likely route to U-CLL. ..
- Dunnick W, Collins J, Shi J, Westfield G, Fontaine C, Hakimpour P, et al. Switch recombination and somatic hypermutation are controlled by the heavy chain 3' enhancer region. J Exp Med. 2009;206:2613-23 pubmed publisher..Finally, we find that in B cells with a transgene lacking the 3' enhancers, interchromosomal recombination between the transgenic VDJ exon and the endogenous heavy chain C genes is more easily detected than CSR within the transgene. ..
- Chen W, Zhu Z, Feng Y, Dimitrov D. A large human domain antibody library combining heavy and light chain CDR3 diversity. Mol Immunol. 2010;47:912-21 pubmed publisher..The new library could be used not only for the selection of such dAbs thus complementing existing libraries but also as a research tool for the exploration of the mechanisms determining folding and stability of human antibody domains. ..
- Degner S, Verma Gaur J, Wong T, Bossen C, Iverson G, Torkamani A, et al. CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells. Proc Natl Acad Sci U S A. 2011;108:9566-71 pubmed publisher..Together, our findings demonstrate that CTCF plays an important role in the 3D structure of the Igh locus and in the regulation of antisense germline transcription and that it contributes to the compaction of the Igh locus. ..
- Malcikova J, Smardova J, Rocnova L, Tichy B, Kuglik P, Vranova V, et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood. 2009;114:5307-14 pubmed publisher..Mutation analysis of the TP53 should be performed before each treatment initiation because novel defects may be selected by previous therapies. ..
- Wei Z, Wu Q, Ren L, Hu X, Guo Y, Warr G, et al. Expression of IgM, IgD, and IgY in a reptile, Anolis carolinensis. J Immunol. 2009;183:3858-64 pubmed publisher..The absence of an IgA-encoding gene in the lizard IGH locus suggests a complex evolutionary history for IgA in the saurian lineage leading to modern birds, lizards, and their relatives...