Frequency and Characterization of Phenotypic Ig Heavy Chain Allelically Included IgM-Expressing B Cells in Mice

Barreto, Vasco M.; Cumano, Ana

doi:10.4049/jimmunol.164.2.893

Cited by 55 publications

(43 citation statements)

References 32 publications

(34 reference statements)

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“…However, it was shown that the onset of allelic exclusion after successful V H to DJ H recombination is accompanied by the transient downregulation of RAG (Grawunder et al, 1995), decontraction of the IgH locus (Roldán et al, 2005), and loss of accessibility correlates such as V H germline transcripts and marks of active chromatin (see below). It has been estimated that only 1 in 10,000 wild-type Blymphocytes actually escape allelic exclusion and express a functional μHC from both IgH alleles (Barreto and Cumano, 2000). Feedback regulation can explain cessation of V H to DJ H rearrangement but would be ineffective if both IgH alleles would rearrange simultaneously.…”

Section: Igh Rearrangements and Allelic Exclusionmentioning

confidence: 99%

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Perlot

Alt

2008

Advances in Immunology

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Immunoglobulin variable region exons are assembled from discontinuous variable (V), diversity (D), and joining (J) segments by the process of V(D)J recombination. V(D)J rearrangements of the immunoglobulin heavy chain (IgH) locus are tightly controlled in a tissue-specific, ordered and allele-specific manner by regulating accessibility of V, D, and J segments to the recombination activating gene proteins which are the specific components of the V(D)J recombinase. In this review we discuss recent advances and established models brought forward to explain the mechanisms underlying accessibility control of V(D)J recombination, including research on germline transcripts, spatial organization, and chromatin modifications of the immunoglobulin heavy chain (IgH) locus. Furthermore, we review the functions of well-described and potential new cis-regulatory elements with regard to processes such as V(D)J recombination, allelic exclusion, and IgH class switch recombination.

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Section: Igh Rearrangements and Allelic Exclusionmentioning

confidence: 99%

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Perlot

Alt

2008

Advances in Immunology

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“…RAG is turned off in B cells expressing a functional, self-tolerant Ig; although perhaps too simplistic, this by and large explains both allelic and isotypic exclusion at the L chain loci. Although it is tempting to propose analogous models for allelic exclusion of IgH and IgL chain genes, there are, in fact, great differences-not only in temporal sequence of gene assembly, but also in strictness of exclusion: a small percentage of B cells does express two different L chains (5), but only one in 10 4 cells expresses two H chains (6).…”

mentioning

confidence: 99%

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Lutz

Heideman

Roth

et al. 2011

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

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B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro-B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized μH mRNA that does not encode μH chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that μH mRNA may thus contribute to efficient H chain allelic exclusion.

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“…Contrary to the latter prediction, however, only about one in 10 3 -10 4 mature splenic B lymphocytes were found to express two heavy chains in the cytoplasm (23,44). The same level of allelic exclusion was found even in mice triallelic for the Ig heavy chain locus (9).…”

Section: Heavy Chainmentioning

confidence: 55%

Models for Antigen Receptor Gene Rearrangement. III. Heavy and Light Chain Allelic Exclusion

Kalmanovich

Mehr

2003

The Journal of Immunology

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The extent of allelic exclusion in Ig genes is very high, although not absolute. Thus far, it has not been clearly established whether rapid selection of the developing B cell as soon as it has achieved the first productively rearranged, functional heavy chain is the only mechanism responsible for allelic exclusion. Our computational models of Ag receptor gene rearrangement in B lymphocytes are hereby extended to calculate the expected fractions of heavy chain allelically included newly generated B cells as a function of the probability of heavy chain pairing with the surrogate light chain, and the probability that the cell would test this pairing immediately after the first rearrangement. The expected fractions for most values of these probabilities significantly exceed the levels of allelic inclusion in peripheral B cells, implying that in most cases productive rearrangement and subsequent cell surface expression of one allele of the heavy chain gene probably leads to prevention of rearrangement completion on the other allele, and that additional mechanisms, such as peripheral selection disfavoring cells with two productively rearranged heavy chain genes, may also play a role. Furthermore, we revisit light chain allelic exclusion by utilizing the first (to our knowledge) computational model which addresses and enumerates B cells maturing with two productively rearranged κ light chain genes. We show that, assuming that there are no selection mechanisms responsible for abolishing cells expressing two light chains, the repertoire of newly generated B lymphocytes exiting the bone marrow must contain a significant fraction of such κ double-productive B cells.

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Frequency and Characterization of Phenotypic Ig Heavy Chain Allelically Included IgM-Expressing B Cells in Mice

Cited by 55 publications

References 32 publications

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Chapter 1 Cis‐Regulatory Elements and Epigenetic Changes Control Genomic Rearrangements of the IgH Locus

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Models for Antigen Receptor Gene Rearrangement. III. Heavy and Light Chain Allelic Exclusion

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