Truncation of the μ heavy chain alters BCR signalling and allows recruitment of CD5+ B cells

Zou, Xiangang; Ayling, Christine; Jian, Xian; Piper, Tony A.; Barker, Paul D.; Brüggemann, Marianne

doi:10.1093/intimm/13.12.1489

Cited by 13 publications

(22 citation statements)

References 52 publications

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“…The derivation of LC-deficient (L Ϫ/Ϫ ), 23 C truncation (knock-in NR), 24 NRL Ϫ/Ϫ , 25 and C H deletion (C⌬) 26 mice has been described. Animals were housed in the Babraham barrier facility, and procedures were carried out under project license PPL 80/1872, approved by the United Kingdom Home Office.…”

Section: Mice and Hybridoma Productionmentioning

confidence: 99%

“…42 This contrasts with the situation in L Ϫ/Ϫ mice, in which chains lacking C H 1 and C H 2 do not form polymers. 24 In L Ϫ/Ϫ mice, RB formation is observed for all Ig classes with diverse V H regions, and this may account for the differences when in vitro transfection is compared with mouse strains that produce diverse HC in truncated form.The promotion of RB formation by LC deficiency could be accounted for by its effect on HC aggregation, because in the absence of LC, HCs aggregate in solution 44 and RBs are composed of aggregated protein. 6 HC aggregation followed by apoptosis has been observed when insufficient LC is produced and upon faulty HC and LC association due to strand charge repulsion.…”

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confidence: 99%

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confidence: 99%

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Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Corcos

Osborn

Matheson

et al. 2010

Blood

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IntroductionIn the healthy organism, immunoglobulin (Ig) is present in membrane form, as part of the B-cell receptor (BCR), and in secreted form, as antibody. During B-cell development, V H DJ H rearrangement of a heavy chain (HC) precedes V L J L rearrangement of a light chain (LC). Nascent HC polypeptides are associated with the HC-binding protein (BiP, or GRP78) in the endoplasmic reticulum (ER) awaiting LC association, processing (eg, carbohydrate association), and export. [1][2][3] The key function of the BiP chaperone is to provide a scaffold to native or unfolded polypeptides, which prevents aggregation and establishes the appropriate conformation. Abnormal plasma cells called Mott cells, containing Ig aggregates, termed Russell bodies (RBs), have been found in nonsecretory myeloma, inflammatory diseases, and autoimmune disorders. 4,5 RB formation appears to indicate cellular indigestion due to a failure to eliminate misfolded or incorrectly assembled proteins. 6 An unsolved question is whether the inability to degrade or to export leads to Ig aggregation. It is possible that the production of large quantities of Ig as well as structural alterations may prevent appropriate processing.In the absence of LC, HC dissociation from chaperones and export is facilitated by deletions in the V H and/or C H 1 domain, a feature seen in pathology and also in cultured cell lines. [7][8][9] Shortened HC is produced in various lymphoid malignancies. In heavy-chain diseases (HCDs), HC is not associated with LC, lacks all or part of V H , and frequently shows deletion(s) in its C H domain(s). 7 In heavy-chain deposition disease (HCDD), a kidney disease secondary to plasma cell dyscrasia, deletions of C H 1 or of both C H 1 and C H 2 domains are found. 10,11 LCs are associated with HCs in HCDD serum antibodies but are missing from the deposits. 10,11 Expression studies showed that full-length HC cannot reach the cell surface in the absence of LC or surrogate LC, 12,13 although more recent experiments demonstrated that this is not always the case. 14-17 At the pre-B cell stage, HC pairing with surrogate LC results in surface expression and oligomerization of the pre-BCR, regarded as important for pre-BCR signaling. 18,19 HC-LC pairing permits a high level of surface IgM expression but appears to inhibit basal signaling, 20 possibly by preventing auto-aggregation.We previously found that ␥ and ␣ HCs lacking C H 1, similar to the proteins produced in HCDD, are present in the serum of LC-deficient (L Ϫ/Ϫ ) mice, which appear to be healthy. 21,22 HCs are encoded by mRNAs transcribed from somatically truncated HC genes with deletions extending from the switch region. Although membrane is required for these class-switch isotypes to be produced, no secreted HC could be detected.Here, we report that in L Ϫ/Ϫ mice, deletions in C result in the production of short HC transcripts and proteins by plasma cells; however, truncated proteins are only found in serum from older mice. In addition to this defect of secretion, a large majority ...

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Section: Mice and Hybridoma Productionmentioning

confidence: 99%

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confidence: 99%

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Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Corcos

Osborn

Matheson

et al. 2010

Blood

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“…With the lack of L chain, -H chain is retained in the cytoplasm of immature bone marrow B cells, and their further development, with subsequent migration and colonization of the spleen, is prevented (4). Targeted modification of the IgH locus has permitted expression of truncated Ig polypeptides (5), and introduction of Ig transgenes consisting of shorter chains or removed domains has allowed single chain expression (6 -8). Recently, it has also been shown that entire -H chains in association with the Ig␣ coreceptor, but lacking surrogate or conventional L chain, can be expressed on the cell surface of pre-B cells.…”

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Expression of a Dromedary Heavy Chain-Only Antibody and B Cell Development in the Mouse

Zou

Smith

Nguyen

et al. 2005

The Journal of Immunology

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“…Several targeted insertions of a neomycin (neo) resistance cassette in the J H -C intron resulted in complex phenotypes, which accommodate the idea that insertions downstream to E do not significantly affect IgH recombination and expression (9,10). By contrast, a neo insertion within E, in between the 5Ј MAR and the core enhancer, disrupted the architecture of the intronic enhancer and altered both accessibility to V(D)J recombination and germline J H transcription (9).…”

Section: B Cell Development Arrest Upon Insertion Of a Neomentioning

confidence: 99%

B Cell Development Arrest Upon Insertion of a neo Gene Between JH and Eμ: Promoter Competition Results in Transcriptional Silencing of Germline JH and Complete V(D)J Rearrangements

Delpy

Decourt

Bert

et al. 2002

The Journal of Immunology

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Previous targeting experiments within the IgH locus have shown that V(D)J recombination was affected by an insertion of a neo gene within Eμ upstream of the core enhancer, but not by insertions downstream of the enhancer. Similarly, class switch recombination to a given (C) gene was affected only by interposition of neo in between that gene and the 3′ IgH enhancers. Here we show that insertion of neo upstream Eμ only marginally impairs V(D)J recombination, but results in an altered D and JH gene usage and completely blocks transcription of the germline JH region and the rearranged VDJ segments. Although transcriptional silencing of JH occurs upstream of the insertion and results in the lack of mature B cells in homozygous mutant animals, IgH transcription is maintained downstream of the insertion together with neo transcription and can be up-regulated by LPS stimulation or upon fusion with plasmacytoma cells. Altogether these data argue for a polarized “neo effect” involving promoter competition and further show that V(D)J rearrangement can be uncoupled from transcription.

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Truncation of the μ heavy chain alters BCR signalling and allows recruitment of CD5+ B cells

Cited by 13 publications

References 52 publications

Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Expression of a Dromedary Heavy Chain-Only Antibody and B Cell Development in the Mouse

B Cell Development Arrest Upon Insertion of a neo Gene Between JH and Eμ: Promoter Competition Results in Transcriptional Silencing of Germline JH and Complete V(D)J Rearrangements

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