B Cell Development under the Condition of Allelic Inclusion

Sonoda, Eiichiro; Pewzner-Jung, Yael; Schwers, Stephan; Taki, Shinsuke; Jung, Steffen; Eilat, Dan; Rajewsky, Klaus

doi:10.1016/s1074-7613(00)80325-8

Cited by 223 publications

(248 citation statements)

References 46 publications

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“…3). Two of the hybridomas, originating from two separate splenocytes gave two productive HCAb, confirming that expression of two antibodies in one B cell is not toxic (37). However, the prediction (37) that they would loose in competition with single antibody-producing cells under antigen challenge is not borne out by finding two double antibody-expressing cells of five hybridomas.…”

Section: Discussionmentioning

confidence: 70%

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: Discussionmentioning

confidence: 70%

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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“…5). The paucity of pro-B cells in mice expressing a rearranged heavychain gene early in their development has been previously described and attributed to rapid transit through the early precursor stages (36). This accelerated development of IgH-tg cells might also explain the lower levels of BP-1 expression on their surface (shown in Fig.…”

Section: Tslp Supports the Proliferation Of Adult Large Pre-b But Nomentioning

confidence: 66%

Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment

Vosshenrich

Cumano

Müller

et al. 2004

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

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IL-7 and thymic stromal lymphopoietin (TSLP) are two major cytokines controlling murine B cell development. IL-7 has been studied extensively, but only recently has it become possible to unravel the role of TSLP in detail. We studied the biological activities of TSLP in B cell development at distinct ages in the mouse. On the one hand, TSLP is able to give rise to a measurable B1 cell compartment derived from fetal liver pro-B cells, although, as is the case for B2 cells, it does not play a prevalent role in the development of this subset. On the other hand, TSLP drives the proliferation of pro-B cells from the fetal and neonatal liver, but in the bone marrow environment, B cell precursors require pre-B cell receptor expression for TSLP responsiveness.

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“…To verify our results from the K46 cells, we used primary splenocytes from the B1-8i knock-in mouse strain, which expresses the B1-8 transgenic IgH (41). When paired with an Igl L chain, the B1-8 H chain produces an NP-specific BCR (51).…”

Section: Differences Between Anti-bcr-and Ligand-induced Signaling Inmentioning

confidence: 99%

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

Štěpánek

Dráber

Drobek

et al. 2013

The Journal of Immunology

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When a BCR on a mature B cell is engaged by its ligand, the cell becomes activated, and the Ab-mediated immune response can be triggered. The initiation of BCR signaling is orchestrated by kinases of the Src and Syk families. However, the proximal BCR-induced phosphorylation remains incompletely understood. According to a model of sequential activation of kinases, Syk acts downstream of Src family kinases (SFKs). In addition, signaling independent of SFKs and initiated by Syk has been proposed. Both hypotheses lack sufficient evidence from relevant B cell models, mainly because of the redundancy of Src family members and the importance of BCR signaling for B cell development. We addressed this issue by analyzing controlled BCR triggering ex vivo on primary murine B cells and on murine and chicken B cell lines. Chemical and Csk-based genetic inhibitor treatments revealed that SFKs are required for signal initiation and Syk activation. In addition, ligand and anti-BCR Ab–induced signaling differ in their sensitivity to the inhibition of SFKs.

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B Cell Development under the Condition of Allelic Inclusion

Cited by 223 publications

References 46 publications

Generation of heavy-chain-only antibodies in mice

Generation of heavy-chain-only antibodies in mice

Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment

Nonredundant Roles of Src-Family Kinases and Syk in the Initiation of B-Cell Antigen Receptor Signaling

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