scholarly journals Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination

2014 ◽  
Vol 15 (5) ◽  
pp. 341-346 ◽  
Author(s):  
B Laffleur ◽  
S M Bardet ◽  
A Garot ◽  
M Brousse ◽  
A Baylet ◽  
...  
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Immunoglobulin Genes ◽  
Class Switch ◽  
Human B Cells

scholarly journals DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

2015 ◽  
Vol 195 (12) ◽  
pp. 5608-5615 ◽  
Author(s):  
Andrea Björkman ◽  
Likun Du ◽  
Kerstin Felgentreff ◽  
Cornelia Rosner ◽  
Radhika Pankaj Kamdar ◽  
...  
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Human B Cells

scholarly journals IL-21 is a broad negative regulator of IgE class switch recombination in mouse and human B cells

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Zhiyong Yang ◽  
Chung-An M. Wu ◽  
Sasha Targ ◽  
Christopher D.C. Allen
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Primary Source ◽  
Negative Regulator ◽  
Class Switch ◽  
Cellular Analysis ◽  
Follicular Helper ◽  
Human B Cells

IgE antibodies may elicit potent allergic reactions, and their production is tightly controlled. The tendency to generate IgE has been thought to reflect the balance between type 1 and type 2 cytokines, with the latter promoting IgE. Here, we reevaluated this paradigm by a direct cellular analysis, demonstrating that IgE production was not limited to type 2 immune responses yet was generally constrained in vivo. IL-21 was a critical negative regulator of IgE responses, whereas IFN-γ, IL-6, and IL-10 were dispensable. Follicular helper T cells were the primary source of IL-21 that inhibited IgE responses by directly engaging the IL-21 receptor on B cells and triggering STAT3-dependent signaling. We reconciled previous discordant results between mouse and human B cells and revealed that the inhibition of IgE class switch recombination by IL-21 was attenuated by CD40 signaling, whereas IgG1 class switch recombination was potentiated by IL-21 in the context of limited IL-4. These findings establish key features of the extrinsic regulation of IgE production by cytokines.

scholarly journals Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

2015 ◽  
Vol 112 (7) ◽  
pp. 2157-2162 ◽  
Author(s):  
Andrea Björkman ◽  
Per Qvist ◽  
Likun Du ◽  
Margarita Bartish ◽  
Apostolos Zaravinos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Class Switch Recombination ◽  
Cancer Type ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Human B Cells ◽  
Breast Cancer Type

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.

The role of Apex2 in class-switch recombination of immunoglobulin genes

2010 ◽  
Vol 22 (3) ◽  
pp. 213-213 ◽  
Author(s):  
Jeroen E. J. Guikema ◽  
Janet Stavnezer ◽  
Carol E. Schrader
Keyword(s):  
Class Switch Recombination ◽  
Immunoglobulin Genes ◽  
Class Switch

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 ◽  
Vol 116 (11) ◽  
pp. 1895-1898 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Remi Fiancette ◽  
Eric Pinaud ◽  
Véronique Truffinet ◽  
Nadine Cogné ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Regulatory Region ◽  
Class Switch Recombination ◽  
B Cell Differentiation ◽  
Plasma Cell Differentiation ◽  
Heavy Chains ◽  
Class Switch ◽  
Transcriptional Changes

Abstract The immunoglobulin heavy chain locus (IgH) undergoes multiple changes along B-cell differentiation. In progenitor B cells, V(D)J assembly allows expression of μ heavy chains. In mature B cells, class switch recombination may replace the expressed constant (C)μ gene with a downstream CH gene. Finally, plasma cell differentiation strongly boosts IgH transcription. How the multiple IgH transcriptional enhancers tune these changes is unclear. Here we demonstrate that deletion of the whole IgH 3′ regulatory region (3′RR) allows normal maturation until the stage of IgM/IgD expressing lymphocytes, but nearly abrogates class switch recombination to all CH genes. Although plasma cell numbers are unaffected, we reveal the role of the 3′RR into the transcriptional burst normally associated with plasma cell differentiation. 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.

scholarly journals Mapping of a Functional Recombination Motif that Defines Isotype Specificity for μ→γ3 Switch Recombination Implicates NF-κB p50 as the Isotype-specific Switching Factor

2004 ◽  
Vol 199 (5) ◽  
pp. 617-627 ◽  
Author(s):  
Amy L. Kenter ◽  
Robert Wuerffel ◽  
Carmen Dominguez ◽  
Ananth Shanmugam ◽  
Hongmei Zhang
Keyword(s):  
B Cells ◽  
Binding Site ◽  
Class Switch Recombination ◽  
Interleukin 4 ◽  
Specific Factor ◽  
Wild Type ◽  
Class Switch ◽  
Activation Induced Deaminase ◽  
Necessary And Sufficient

Ig class switch recombination (CSR) requires expression of activation-induced deaminase (AID) and production of germline transcripts to target S regions for recombination. However, the mechanism of CSR remains unclear. Here we show that an extrachromosomal S plasmid assay is AID dependent and that a single consensus repeat is both necessary and sufficient for isotype-specific CSR. Transfected switch substrates specific for μ→γ3 and μ→γ1 are stimulated to switch with lipopolysaccharide (LPS) alone or LPS and interleukin-4, respectively. An Sγ3/Sγ1 substrate containing only three Sγ3-associated nucleotides reconstituted LPS responsiveness and permitted mapping of a functional recombination motif specific for μ→γ3 CSR. This functional recombination motif colocalized with a binding site for NF-κB p50, and p50 binding to this site was previously established. We show a p50 requirement for plasmid-based μ→γ3 CSR using p50-deficient B cells. Switch junctions from p50-deficient B cells showed decreased lengths of microhomology between Sμ and Sγ3 relative to wild-type cells, indicating a function for p50 in the mechanics of CSR. We note a striking parallel between the affects of p50 and Msh2 deficiency on Sμ/Sγ3 junctions. The data suggest that p50 may be the isotype-specific factor in μ→γ3 CSR and epistatic with Msh2.

MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Eric J. Wigton ◽  
Yohei Mikami ◽  
Ryan J. McMonigle ◽  
Carlos A. Castellanos ◽  
Adam K. Wade-Vallance ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
Cell Fate Decisions ◽  
Class Switch ◽  
Mrna Targets ◽  
Regulatory Circuit ◽  
Pathway Discovery

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.

scholarly journals Noncoding RNA transcription alters chromosomal topology to promote isotype-specific class switch recombination

2020 ◽  
Vol 5 (44) ◽  
pp. eaay5864 ◽  
Author(s):  
Gerson Rothschild ◽  
Wanwei Zhang ◽  
Junghyun Lim ◽  
Pankaj Kumar Giri ◽  
Brice Laffleur ◽  
...  
Keyword(s):  
B Cells ◽  
Regulatory Region ◽  
Noncoding Rnas ◽  
Class Switch Recombination ◽  
Regulatory Elements ◽  
Specific Class ◽  
Antibody Diversity ◽  
Variable Regions ◽  
Class Switch ◽  
Super Enhancer

B cells undergo two types of genomic alterations to increase antibody diversity: introduction of point mutations into immunoglobulin heavy- and light-chain (IgH and IgL) variable regions by somatic hypermutation (SHM) and alteration of antibody effector functions by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). SHM and CSR require the B cell–specific activation-induced cytidine deaminase (AID) protein, the transcription of germline noncoding RNAs, and the activity of the 3′ regulatory region (3′RR) super-enhancer. Although many transcription regulatory elements (e.g., promoters and enhancers) reside inside the IgH and IgL sequences, the question remains whether clusters of regulatory elements outside IgH control CSR. Using RNA exosome–deficient mouse B cells where long noncoding RNAs (lncRNAs) are easily detected, we identified a cluster of three RNA-expressing elements that includes lncCSRIgA (that expresses lncRNA-CSRIgA). B cells isolated from a mouse model lacking lncRNA-CSRIgA transcription fail to undergo normal levels of CSR to IgA both in B cells of the Peyer’s patches and grown in ex vivo culture conditions. lncRNA-CSRIgA is expressed from an enhancer site (lncCSRIgA) to facilitate the recruitment of regulatory proteins to a nearby CTCF site (CTCFlncCSR) that alters the chromosomal interactions inside the TADlncCSRIgA and long-range interactions with the 3′RR super-enhancer. Humans with IgA deficiency show polymorphisms in the lncCSRIgA locus compared with the normal population. Thus, we provide evidence for an evolutionarily conserved topologically associated domain (TADlncCSRIgA) that coordinates IgA CSR in Peyer’s patch B cells through an lncRNA (lncRNA-CSRIgA) transcription-dependent mechanism.

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