Match!

Genomic Organization of Murine and Human Immunoglobulin Light Chain Loci

Published on Jan 1, 2016
· DOI :10.1016/B978-0-12-374279-7.05007-4
Abstract
Antibodies in humans and mice typically consist of two identical immunoglobulin heavy chains paired with two identical light chains, either kappa (Igκ) or lambda (Igλ), joined by disulfide bonds. B cells normally produce antibodies derived from a single heavy and a single light chain that recognize a single antigen, and thus are monospecific. The germ line Igκ and Igλ loci are complex units that coordinate ordered, cell- and stage-specific functions including chromatin structure and epigenetic state, variable rearrangement, gene expression, allelic exclusion, and somatic hypermutation. Although the Igκ and Igλ light chains are functionally analogous, the loci for Igκ and Igλ light chains possess distinct structures and functions that differ between chain type (Igκ vs Igλ) and species (mouse vs human). The diverse functions of the Igκ and Igλ light chain loci reflect the complex regulation necessary for antibody production in B cells for humoral immunity.
  • References (44)
  • Citations (0)
📖 Papers frequently viewed together
2015
1 Author (Magdalena Rother)
12 Citations
75 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References44
Newest
#1Keith M. Hamel (U of C: University of Chicago)H-Index: 6
#2Malay Mandal (U of C: University of Chicago)H-Index: 19
Last. Marcus R. Clark (U of C: University of Chicago)H-Index: 38
view all 4 authors...
The essential events of B-cell development are the stochastic and sequential rearrangement of immunoglobulin heavy (Igμ) and then light chain (Igκ followed by Igλ) loci. The counterpoint to recombination is proliferation, which both maintains populations of pro-B cells undergoing Igμ recombination and expands the pool of pre-B cells expressing the Igμ protein available for subsequent Igκ recombination. Proliferation and recombination must be segregated into distinct and mutually exclusive develo...
5 CitationsSource
#1Jean-Marie Buerstedde (Yale University)H-Index: 9
#2Jukka Alinikula (Yale University)H-Index: 8
Last. David G. Schatz (Yale University)H-Index: 63
view all 5 authors...
Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neig...
30 CitationsSource
#1Nancy M. Choi (Scripps Research Institute)H-Index: 3
#2Ann J. Feeney (Scripps Research Institute)H-Index: 34
At both the immunoglobulin (Ig) heavy and kappa light chain loci, there are >100 functional variable (V) genes spread over >2 Mb that must move into close proximity in 3D space to the (D)J genes to create a diverse repertoire of antibodies. Similar events take place at the T cell receptor (TCR) loci to create a wide repertoire of TCRs. In this review, we will discuss the role of CTCF in forming rosette-like structures at the antigen receptor (AgR) loci, and the varied roles it plays in alternate...
20 CitationsSource
#1Syeda F.Y. HaqueH-Index: 1
#2Sarah L. Bevington (University of Leeds)H-Index: 5
Last. Joan Boyes (University of Leeds)H-Index: 14
view all 3 authors...
Enhancers are essential for long range chromatin opening and the activation of V(D)J recombination at the antigen receptor loci. The murine immunoglobulin lambda light chain locus is a duplicated locus and, using a bacterial artificial chromosome spanning the 3′ half of the locus to generate transgenic mice, we have identified a critical enhancer element for lambda locus recombination. Four hypersensitive sites had been previously mapped downstream of the JCλ1 gene segment (HS1-4). Systematic de...
2 CitationsSource
#1Xiaorong Zhou (Nantong University)H-Index: 4
#2Yougui Xiang (UTSW: University of Texas Southwestern Medical Center)H-Index: 7
Last. William T. Garrard (UTSW: University of Texas Southwestern Medical Center)H-Index: 28
view all 4 authors...
The mouse Igκ gene locus has three known transcriptional enhancers: an intronic enhancer (Ei), a 3′ enhancer (E3′), and a further downstream enhancer (Ed). We previously discovered, using the chromosome conformation-capture technique, that Ei and E3′ interact with a novel DNA sequence near the 3′ end of the Igκ locus, specifically in B cells. In the present investigation, we examined the function of this far downstream element. The sequence is evolutionarily conserved and exhibits a plasmacytoma...
7 CitationsSource
#1Christian Vettermann (University of California, Berkeley)H-Index: 9
#2Mark S. Schlissel (University of California, Berkeley)H-Index: 81
The allelic exclusion of immunoglobulin (Ig) genes is one of the most evolutionarily conserved features of the adaptive immune system and underlies the monospecificity of B cells. While much has been learned about how Ig allelic exclusion is established during B-cell development, the relevance of monospecificity to B-cell function remains enigmatic. Here, we review the theoretical models that have been proposed to explain the establishment of Ig allelic exclusion and focus on the molecular mecha...
82 CitationsSource
#1Sabyasachi Das (PSU: Pennsylvania State University)H-Index: 17
#2Nikolas Nikolaidis (CSUF: California State University, Fullerton)H-Index: 22
Last. Masatoshi Nei (PSU: Pennsylvania State University)H-Index: 110
view all 3 authors...
We have studied the genomic structure and evolutionary pattern of immunoglobulin kappa deleting element (KDE) and three kappa enhancers (KE5′, KE3′P, and KE3′D) in eleven mammalian genomic sequences. Our results show that the relative positions and the genomic organization of the KDE and the kappa enhancers are conserved in all mammals studied and have not been affected by the local rearrangements in the immunoglobulin kappa (IGK) light chain locus over a long evolutionary time (∼120 million yea...
12 CitationsSource
#1Susannah L. Hewitt (NYU: New York University)H-Index: 10
#2Bu Yin (UPenn: University of Pennsylvania)H-Index: 9
Last. Jane A. Skok (UCL: University College London)H-Index: 29
view all 16 authors...
Immunoglobulin gene rearrangements occur in an organized, temporal way. Skok and colleagues show that immunoglobulin alleles 'pair' to coordinate cleavage and allelic availability.
127 CitationsSource
#1Cheng-Ran Xu (Scripps Research Institute)H-Index: 8
#2Ann J. Feeney (Scripps Research Institute)H-Index: 34
Ag receptor loci poised for V(D)J rearrangement undergo germline transcription (GT) of unrearranged genes, and the accessible gene segments are associated with posttranslational modifications (PTM) on histones. In this study, we performed a comprehensive analysis of the dynamic changes of four PTM throughout B and T cell differentiation in freshly isolated ex vivo cells. Methylation of lysines 4 and 79 of histone H3, and acetylation of H3, demonstrated stage and lineage specificity, and were mos...
46 CitationsSource
#1Susannah L. HewittH-Index: 10
#2Deborah FarmerH-Index: 4
Last. Jane A. SkokH-Index: 29
view all 8 authors...
V(D)J recombination at Igh and Igk loci takes place sequentially during successive stages in B cell development. Using 3-dimensional DNA fluorescence in situ hybridization (FISH), we identified a lineage- and stage-specific interchromosomal association between these two loci which marks the transition between Igh and Igk recombination. Co-localization occured between pericentromerically located alleles in pre-B cells, and was mediated by the 3’ Igk enhancer. Deletion of this regulatory element p...
40 CitationsSource
Cited By0
Newest