Heavy Chain Diseases: Current Findings and Concepts

Séligmann, M; Mihaesco, Edith; Preud’homme, Jean-Louis; Danon, Franqoise; Brouet, Jean‐Claude

doi:10.1111/j.1600-065x.1979.tb00302.x

Cited by 145 publications

(90 citation statements)

References 49 publications

(26 reference statements)

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“…The dependence of ⌬V cells on nonspecific factors is reminiscent of the situation observed in the most common form of H chain disease, namely ␣-chain disease, which can be treated by antibiotics (46). It is also of interest to note that ⌬V mature B cells are eliminated by competition with normal B cells (17), as are autoreactive B cells (47), raising the possibility that, in the latter case, competition occurs for T cell-derived factors.…”

Section: Discussionmentioning

confidence: 99%

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Corcos

Grandien

Vázquez

et al. 2001

The Journal of Immunology

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Neoplastic B cells from H chain disease patients express a truncated B cell receptor (BCR), comprising a membrane Ig that lacks part of its extracellular domain. It has been speculated that deletion of the Ag binding domain would confer a constitutive activity on the BCR, as it has been shown for oncogenic growth factor receptors. A V region-less BCR has constitutive activity, because in transgenic mice it causes inhibition of endogenous H chain gene rearrangements and relieves the requirement for surrogate L chain in pre-B cell development. However, it has been speculated that normal Ag receptors also display constitutive activity. Here we show that transgenic B cells expressing a membrane H chain disease protein on their surface are phenotypically and functionally similar to B cells developing in the presence of their cognate Ag and that cells with normal levels of mutant BCR are eliminated in spleen via a bcl-2 sensitive pathway while progressing toward the mature stage. In contrast, cells with lower levels of mutant receptors develop as mature B cells. These findings support the view that the truncated BCR has a constitutive activity that mimics ligand binding, in analogy to what has been shown for oncogenic growth factor receptors.

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Section: Discussionmentioning

confidence: 99%

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Corcos

Grandien

Vázquez

et al. 2001

The Journal of Immunology

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“…Many different deletion mutants of.heavy chains have been described (10)(11)(12)(25)(26)(27)(28)(29). One y H chain mutant, IF2, with an internal deletion of the entire CH1 domain (27,30) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…H chain disease proteins in which deleted H chain is produced in the absence of L chain have been described in man and in mouse (10,11). In man, the steps that lead to the production ofdeleted H chains are not precisely defined; however, in the murine example, the H chain disease arose in two steps: first, a deleted H (AH) and a normal L chain were synthesized, and then a secondary variant synthesizing only AH was identified (12).…”

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confidence: 99%

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Two alpha heavy chain disease proteins with different genomic deletions demonstrate that nonexpressed alpha heavy chain genes contain methylated bases.

Dackowski¹,

Morrison²

1981

Proc. Natl. Acad. Sci. U.S.A.

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Two independently arising a heavy chain mutants have been found to synthesize heavy chains with CH, deletions ofapproximately equal extent. Both were isolated from heavy chain-producing variants of the mouse myeloma W3129 and demonstrate that it is possible to arrive at the heavy chain disease phenotype by the pathway H + L -e H -+ AH. Analysis of genomic DNA by digestion with restriction endonucleases followed by molecular hybridization showed that one mutant (A37) had a deletion of approximately 0.2 kilobase and the second mutant (A15) had a deletion of approximately 0.5 kilobase. Mouse myeloma cells contain several a chain alleles but only one is expressed; the presence of the deletion in A37 and A15 made it possible to identify the restriction fragments from the expressed allele. Analysis of the fragments produced after cleavage with an isoschizomeric pair of restriction enzymes, Map I and Hpa H, indicated that, in the W3129 cell line and its variants, the unexpressed a alleles contain methylated bases. The influence of methylation on gene expression remains to be elucidated.

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“…Previously, we demonstrated that 16 mutants in the H chain framework region 2 and CDR2 region of the T15 and PCG1-1 anti-phenylphosphocholine antibodies have severe defects in secretion (6,7). The molecular basis of the secretion defect in several mutants was traced to a single substitution (Ile 51 to Arg or Lys) in the H chain of the PCG1-1 antibody (8). Mutant H chains co-immunoprecipitate with chaperones BiP and GRP94 and remain endoglycosidase H-sensitive, consistent with retention in the endoplasmic reticulum (ER).…”

Section: Engineered Antibodies and Variable Region (V-region)mentioning

confidence: 99%

Recovering Antibody Secretion Using a Hapten Ligand as a Chemical Chaperone

Wiens¹,

O’Hare²,

Rittenberg³

2001

Journal of Biological Chemistry

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Engineered antibodies have come to the forefront as research reagents and clinical therapeutics. However, reduced stability or expression levels pose a major problem with many engineered antibodies. As a model for understanding functional consequences of variable region mutation, we have studied the assembly and trafficking of anti-phenylphosphocholine antibodies. Previously, we identified severe secretion defects because of mutations in the heavy chain second complementarity determining region, which is involved in antigen binding. Here we demonstrate that immunoglobulin secretion is increased up to 27-fold by incubating stably transfected PCG1-1 cells with cognate hapten p-nitrophenylphosphocholine. Secretion was unaffected by nonbinding analogs. Radiotracer and metabolic labeling experiments demonstrated specific cellular uptake of p-nitrophenylphosphocholine and increased intracellular heavy and light chain assembly. Brefeldin A inhibited hapten-mediated immunoglobulin secretion but not assembly, indicating that assembly occurs early within the biosynthetic pathway. Recovery of secretion correlated with antigen binding capacity, suggesting that the rescue mechanism involves stabilization of heavy and light chain variable domains. This model system provides the first demonstration that cognate ligands can increase intracellular assembly of functional anti-hapten antibody within mammalian cells and suggests that small molecules of appropriate specificity and affinity acting as chemical chaperones may find application for increasing or regulating immunoglobulin expression.

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Heavy Chain Diseases: Current Findings and Concepts

Cited by 145 publications

References 49 publications

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Expression of a V Region-Less B Cell Receptor Confers a Tolerance-Like Phenotype on Transgenic B Cells

Two alpha heavy chain disease proteins with different genomic deletions demonstrate that nonexpressed alpha heavy chain genes contain methylated bases.

Recovering Antibody Secretion Using a Hapten Ligand as a Chemical Chaperone

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