Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.

Iglesias, Antonio; Köpf, Manfred; Williams, G. Stuart; Bühler, Bernd; Köhler, Georges

doi:10.1002/j.1460-2075.1991.tb07749.x

Cited by 64 publications

(44 citation statements)

References 50 publications

(38 reference statements)

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“…The difference in our results and those of Zou et al (13) may be explained by the level of expression of the locus (and, thus, signaling) because of the LCR on our constructs. Our results confirm that truncated HCAb lacking CH1 (24) or VH and CH1 (36) cannot associate with SLCs and fail to activate gene rearrangement.…”

Section: Discussionsupporting

confidence: 78%

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Generation of heavy-chain-only antibodies in mice

Janssens¹,

Dekker²,

Hendriks

et al. 2006

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

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We have generated transgenic mice containing hybrid llama͞ human antibody loci that contain two llama variable regions and the human D, J, and C and͞or C␥ constant regions. Such loci rearrange productively and rescue B cell development efficiently without LC rearrangement. Heavy-chain-only antibodies (HCAb) are expressed at high levels, provided that the CH1 domain is deleted from the constant regions. HCAb production does not require an IgM stage for effective pre-B cell signaling. Antigenspecific heavy-chain-only IgM or IgGs are produced upon immunization. The IgG is dimeric, whereas IgM is multimeric. The chimeric HCAb loci are subject to allelic exclusion, but several copies of the transgenic locus can be rearranged and expressed successfully on the same allele in the same cell. Such cells are not subject to negative selection. The mice produce a full antibody repertoire and provide a previously undescribed avenue to produce specific human HCAb in the future.immunoglobulin rearrangement ͉ transgenic C onventional antibodies contain two heavy and light chains (LC) coded for by heavy and LC loci. B cell development and antibody production starts in the bone marrow (BM) by heavy chain (HC) VDJ recombination and expression of IgM associated with a surrogate LC on the cell surface. In a second round of recombination, one of the LC rearranges in pre-B cells. If successful, the B cells undergo selection, affinity maturation, and switching to different HC constant regions to result in B cells, which express tetrameric antibodies of different isotypes (IgA, IgG, and IgE). Normally absence of HC or LC expression leads to arrest of B cell development. However, some species produce HC-only antibodies (HCAb) as part of their normal B cell development and repertoire. The best-known HCAb (i.e., no LC) are IgG2 and IgG3 in camelids (1). They undergo antigen-mediated selection and affinity maturation, and their variable domains are subject to somatic hypermutation (2, 3). HCAb are thought to recognize unusual epitopes, such as clefts on the antigen surface (4). The first domain of the constant region, CH1, is spliced out because of the loss of a consensus splice signal (5, 6). CH1 exon loss also has been described in other mammals, albeit associated with disease, e.g., in mouse myelomas (7) and human HC disease (HCD) (8-10).Camelid HCAbs contain a complete VDJ region. Its size, stability, specificity, and solubility have generated considerable biotechnological interest. The antigen-binding site, a single-variable domain (VHH), resembles VH of conventional Abs. However, differences in FR2 and CDR3 prevent VHH to pair with a variable LC, whereas hydrophilic amino acids provide solubility (11). HCAb of the IgM class have not been found in camelids, suggesting that the IgM ϩ stage of HCAb formation is very transient and͞or circumvented.Murine NSO myeloma cells can express a rearranged camelid VHH-␥2a gene (12) and, recently, the same gene was expressed in transgenic mice (13). Here, we describe transgenic mice containing various...

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Section: Discussionsupporting

confidence: 78%

“…In this respect, HCAb lacking CH1 mimic a BCR rather than a pre-BCR, probably because of a failure to bind pseudo-LC (24). Serum analysis.…”

Section: Mouse Light Chains Do Not Rearrange In M⌬g⌬ and G⌬ Micementioning

confidence: 99%

Generation of heavy-chain-only antibodies in mice

Janssens¹,

Dekker²,

Hendriks

et al. 2006

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

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“…High levels of HC germ-line transcripts are the first immunoglobulin transcripts detectable in fetal ontogeny; K germ-line transcripts generally are detected after the appearance of HC transcripts {Siden et al 1981; Lennon and Perry 1990). Analyses of transformed cell lines have correlated ~ HC expression with rearrangement of LC loci (Reth et al 1985;Iglesias et al 1991). The expression of ix HCs appears to promote the differentiation of pro-B-cells in the BM to a small pre-Bcell stage where K LC gene rearrangements are accumulated Hardy et al 1991, Kitamura et al 1991Chen et al 1993;Ehlich et al 1993;Li et al 1993).…”

Section: Expression Of Germ-line K Lc Transcripts Is Enhanced In Hc18mentioning

confidence: 99%

Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.

Young

Ardman²,

Shinkai³

et al. 1994

Genes Dev.

187

151

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“…The events that operate to restrict further V H (D)J H recombination are collectively referred to as allelic exclusion. However, arrest in the recombination process is selective, as transition into the pre-B window is accompanied by re-expression of RAG1 and RAG2 proteins and accessibility of the IgL loci for IgL recombination (15)(16)(17). Although it is well established that pre-BCR signals are necessary for transition to the pre-B stage, it is not clear if those signals directly affect IgL recombination (8, 12, 18 -21).…”

mentioning

confidence: 99%

Basal Igα/Igβ Signals Trigger the Coordinated Initiation of Pre-B Cell Antigen Receptor-Dependent Processes

Fuentes‐Pananá

Bannish

Shah

et al. 2004

The Journal of Immunology

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The pro-B to pre-B transition during B cell development is dependent upon surface expression of a signaling competent pre-B cell Ag receptor (pre-BCR). Although the mature form of the BCR requires ligand-induced aggregation to trigger responses, the requirement for ligand-induced pre-BCR aggregation in promoting B cell development remains a matter of significant debate. In this study, we used transmission electron microscopy on murine primary pro-B cells and pre-B cells to analyze the aggregation state of the pre-BCR. Although aggregation can be induced and visualized following cross-linking by Abs to the pre-BCR complex, our analyses indicate that the pre-BCR is expressed on the surface of resting cells primarily in a nonaggregated state. To evaluate the degree to which basal signals mediated through nonaggregated pre-BCR complexes can promote pre-BCR-dependent processes, we used a surrogate pre-BCR consisting of the cytoplasmic regions of Igα/Igβ that is targeted to the inner leaflet of the plasma membrane of primary pro-B cells. We observed enhanced proliferation in the presence of low IL-7, suppression of VH(D)JH recombination, and induced κ light (L) chain recombination and cytoplasmic κ L chain protein expression. Interestingly, Igα/Igβ-mediated allelic exclusion was restricted to the B cell lineage as we observed normal TCRαβ expression on CD8-expressing splenocytes. This study directly demonstrates that basal signaling initiated through Igα/Igβ-containing complexes facilitates the coordinated control of differentiation events that are associated with the pre-BCR-dependent transition through the pro-B to pre-B checkpoint. Furthermore, these results argue that pre-BCR aggregation is not a requirement for pre-BCR function.

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Molecular requirements for the mu-induced light chain gene rearrangement in pre-B cells.

Cited by 64 publications

References 50 publications

Generation of heavy-chain-only antibodies in mice

Generation of heavy-chain-only antibodies in mice

Influence of immunoglobulin heavy- and light-chain expression on B-cell differentiation.

Basal Igα/Igβ Signals Trigger the Coordinated Initiation of Pre-B Cell Antigen Receptor-Dependent Processes

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