Rearrangement of Mouse Immunoglobulin Kappa Deleting Element Recombining Sequence Promotes Immune Tolerance and Lambda B Cell Production

Vela, José Luis; Aït-Azzouzene, Djemel; Duong, Bao; Ota, Takayuki; Nemazee, David

doi:10.1016/j.immuni.2007.12.011

Cited by 46 publications

(53 citation statements)

References 54 publications

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“…This suggests that transitioning or maturing B cells are involved in tolerance induction and/or maintenance; alternatively, these cells may be suppressed by immunosuppression. Studies have shown that mature B cells in transition after antigen stimulation undergo receptor editing as means of promoting tolerance to self antigens (29,30). Although receptor editing is believed to take place centrally in the bone marrow, it is possible that this mechanism is used peripherally in transplant recipients, as also shown in autoimmune models (31).…”

Section: Figurementioning

confidence: 99%

Identification of a B cell signature associated with renal transplant tolerance in humans

et al. 2010

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Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.

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Section: Figurementioning

confidence: 99%

Identification of a B cell signature associated with renal transplant tolerance in humans

et al. 2010

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“…The Ig locus undergoes rearrangement next in pre-B cells, where a V gene is joined to a J region. If Ig V-J joining is productively unsuccessful because of out-of-reading frame recombination junctions, then the Ig locus becomes activated for rearrangement and expression, which in wild-type (WT) mice accounts for production of only approximately 5% of the total IgL chains (2).…”

mentioning

confidence: 99%

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Zhou

Xiang

Ding

et al. 2013

Molecular and Cellular Biology

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bWe address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Ig gene's downstream enhancers, E3= and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3= in mature B cells that possessed Ed ؊/؊ alleles. Upon E3= deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Ig gene rearrangements. We conclude that the Ig gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery. During B cell development, the mouse IgH and IgL loci become activated in a stepwise fashion for gene rearrangement (1). The IgH gene rearranges first, by sequential D-J and then by V-(D)J joining, leading to the pro-and pre-B cell stages of development, respectively. The Ig locus undergoes rearrangement next in pre-B cells, where a V gene is joined to a J region. If Ig V-J joining is productively unsuccessful because of out-of-reading frame recombination junctions, then the Ig locus becomes activated for rearrangement and expression, which in wild-type (WT) mice accounts for production of only approximately 5% of the total IgL chains (2).In order to characterize chromatin structure-function relationships in a model system, research in our laboratory has focused on the mouse Ig locus because it offers the opportunity to identify changes in chromatin structure that may precede gene rearrangement and transcriptional activation during B lymphocyte differentiation, as well as to visualize chromatin remodeling events that are linked to gene activation (reference 3 and references therein). Rearrangement of the Ig locus deposits a V gene carrying its own promoter into a chromatin domain containing three powerful enhancers: an intronic enhancer (Ei) within the transcription unit (4), and two enhancers downstream of the transcription termination region, termed E3= and Ed (3, 5). The results of chromosome conformation capture experiments have revealed that in activated B cells, the three enhancers exhibit all possible pairwise interactions with themselves and rearranged V gene promoters, with the looping out of the intervening DNA sequences (6). However, in unstimulated B cells, rearranged...

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“…Recombination of Kde with either an upstream V k or an isolated RSS heptamer recombination element (RE) in the J k eC k intron results in the physical deletion of the C k exon and silencing of the k locus [19]. Kde sequences have been identified in mice and humans [20e22] and more recently in the genomes of several additional mammals including the platypus [23].…”

Section: Palindromic Heptamers In Zebrafish C Lmentioning

confidence: 99%

Targeted annotation of immunoglobulin light chain (IgL) genes in zebrafish from BAC clones reveals kappa-like recombining/deleting elements within IgL constant regions

Zimmerman

Romanowski

Maddox

2011

Fish & Shellfish Immunology

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Rearrangement of Mouse Immunoglobulin Kappa Deleting Element Recombining Sequence Promotes Immune Tolerance and Lambda B Cell Production

Cited by 46 publications

References 54 publications

Identification of a B cell signature associated with renal transplant tolerance in humans

Identification of a B cell signature associated with renal transplant tolerance in humans

Loss of an Igκ Gene Enhancer in Mature B Cells Results in Rapid Gene Silencing and Partial Reversible Dedifferentiation

Targeted annotation of immunoglobulin light chain (IgL) genes in zebrafish from BAC clones reveals kappa-like recombining/deleting elements within IgL constant regions

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