Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes

Sakano, Hitoshi; Maki, Richard A.; Kurosawa, Yoshikazu; Roeder, William; Tonegawa, Susumu

doi:10.1038/286676a0

Cited by 786 publications

(437 citation statements)

References 39 publications

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“…The normal molecular mechanism of isotype class switch involves a nonhomologous recombination event during which the intervening DNA between two S regions is excised as circular DNA (21). To provide direct evidence that the induction of IgG 1 and IgG 3 production by rIL-21 is associated with this type of DNA recombination, the presence of circular switch DNA in activated B cells was analyzed.…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Pène

Gauchat

Lécart

et al. 2004

The Journal of Immunology

279

211

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IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40. In this study, we show that rIL-21 strongly induces the production of all IgG isotypes by purified CD19+ human spleen or peripheral blood B cells stimulated with anti-CD40 mAb. Moreover, it was found to specifically induce the production of IgG1 and IgG3 by CD40-activated CD19+CD27− naive human B cells. Although stimulation of CD19+ B cells via CD40 alone induced γ1 and γ3 germline transcripts, as well as the expression of activation-induced cytidine deaminase, only stimulation with both anti-CD40 mAb and rIL-21 resulted in the production of Sγ/Sμ switch circular DNA. These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG1 and IgG3.

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Section: Resultsmentioning

confidence: 99%

Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Pène

Gauchat

Lécart

et al. 2004

The Journal of Immunology

279

211

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“…The HindIII filter was hybridized with a J-b2 probe (Malissen et al, 1984) to obtain a spectrum of TCR-b gene rearrangement, and the obtained rearrangements were further confirmed by hybridizing the PvuII filter with a J-b1 probe (Malissen et al, 1984). For IgH rearrangement analysis, genomic DNA isolated from spleen, liver and lymph node was digested with BglII and hybridized with a-32 P-labeled J H probe (Sakano et al, 1980). The rearranged IgH gene bands detected in the BglII filters were further confirmed by using Sac I digestion.…”

Section: Tcr and Igh Rearrangement Analysismentioning

confidence: 99%

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

et al. 2007

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LYL1, a member of the class II basic helix-loop-helix transcription factors, is aberrantly expressed in a fraction of human T-cell acute lymphoblastic leukemia. Here, we generated transgenic mice ubiquitously overexpressing LYL1 using a construct expressing full-length cDNA driven by a human elongation factor 1a promoter. Four independent lines exhibiting high LYL1 expression were established. Of these transgenic mice, 96% displayed loss of hair with a short kinked tail. Furthermore, 30% of them developed malignant lymphoma, with an average latent period of 352 days. In these mice, histological examination revealed tumor cell infiltration in multiple organs and immunohistochemical analysis showed that the infiltrated tumor cells were either CD3 or CD45R/B220-positive; fluorescence-activated cell sorter analysis indicated that each tumor consisted either of mainly CD4, CD8 double-positive T cells or mature B cells; the clonality of LYL1-induced lymphoma was confirmed by T-cell receptor rearrangement and immunoglobulin heavychain gene rearrangement analyses. Mammalian twohybrid analysis and luciferase assay suggested that excess LYL1 blocked the dimerization of E2A and thus inhibited the regulatory activity of E2A on the CD4 promoter. Reverse transcription-polymerase chain reaction results showed that the expression of certain E2A/HEB target genes was downregulated. Taken together, our results provide direct evidence that aberrant expression of LYL1 plays a role in lymphomagenesis.

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“…For example, it is unclear whether recognition and cleavage requires a pair of RSS or whether cleavage occurs independently at an individual RSS under physiological conditions. Moreover, while it has been established that efficient recombination requires a pair of RSS of different spacer lengths (Early et al 1980;Sakano et al 1980;Hesse et al 1989;Lewis & Hesse 1991;Akamatsu et al 1994), it has not been determined at which step (cleavage or joining) this '12/23 rule' is enforced.…”

Section: Introductionmentioning

confidence: 99%

The 12/23 rule is enforced at the cleavage step of V(D)J recombination in vivo

1996

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Background: V(D)J recombination is initiated by the introduction of double-stranded breaks (DSB) adjacent to recombination signal sequences (RSS). Each RSS contains a conserved heptamer and a conserved nonamer element separated by a 12 or 23 nucleotide spacer. In vivo, efficient recombination requires one RSS of each spacer length, although it has been unclear whether this '12/23 rule' regulates cleavage, joining, or both.

show abstract

Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes

Cited by 786 publications

References 39 publications

Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Cutting Edge: IL-21 Is a Switch Factor for the Production of IgG1 and IgG3 by Human B Cells

Overexpression of a transcription factor LYL1 induces T- and B-cell lymphoma in mice

The 12/23 rule is enforced at the cleavage step of V(D)J recombination in vivo

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