The Journal of allergy and clinical immunology · 2007
B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Jabara Haifa H, Chaudhuri Jayanta, Dutt Shilpee, Dedeoglu Fatma, Weng Yu, Murphy Michael M, Franco Sonia, Alt Fredrick W, Manis John, Geha Raif S
Аннотация
BACKGROUND: During differentiation, B cells receive signals by antigen through the B-cell receptor (BCR) and signals that induce isotype switching.
OBJECTIVE: We sought to investigate the effects of BCR ligation on isotype switching.
METHODS: Naive B cells from BALB/c mice were stimulated with LPS plus IL-4 alone or plus anti-IgM (0.1-10 mug/mL). IgE and IgG1 levels in supernatants were measured by means of ELISA on day 6. Cmu or Cvarepsilon germline transcripts, activation-induced cytidine deaminase (AID), and Imu-Cvarepsilon postswitch transcripts were measured by means of RT-PCR. Deletional switch recombination was assessed by means of digestion circularization PCR of Smu-Svarepsilon products.
RESULTS: BCR cross-linking inhibited IgE and IgG1 switching in a dose-dependent fashion. This was not due to inhibition of proliferation, increased apoptosis, or cell death. BCR cross-linking had no effect on Cmu or Cvarepsilon germline transcripts but suppressed the generation of Smu-Svarepsilon switch products and Imu-Cvarepsilon postswitch transcripts and caused a delay in the expression of AID mRNA, with decreased expression on days 2 and 3 after stimulation. Concomitantly, the number of DNA repair foci at the IgH locus on day 3 was significantly decreased. AID expression and activity became normal on day 4, but isotype switching remained profoundly diminished 8 days after stimulation.
CONCLUSION: BCR cross-linking delays AID expression. This might interfere with class-switch recombination by disrupting the temporal coordination of signals that lead to class-switch recombination.
OBJECTIVE: We sought to investigate the effects of BCR ligation on isotype switching.
METHODS: Naive B cells from BALB/c mice were stimulated with LPS plus IL-4 alone or plus anti-IgM (0.1-10 mug/mL). IgE and IgG1 levels in supernatants were measured by means of ELISA on day 6. Cmu or Cvarepsilon germline transcripts, activation-induced cytidine deaminase (AID), and Imu-Cvarepsilon postswitch transcripts were measured by means of RT-PCR. Deletional switch recombination was assessed by means of digestion circularization PCR of Smu-Svarepsilon products.
RESULTS: BCR cross-linking inhibited IgE and IgG1 switching in a dose-dependent fashion. This was not due to inhibition of proliferation, increased apoptosis, or cell death. BCR cross-linking had no effect on Cmu or Cvarepsilon germline transcripts but suppressed the generation of Smu-Svarepsilon switch products and Imu-Cvarepsilon postswitch transcripts and caused a delay in the expression of AID mRNA, with decreased expression on days 2 and 3 after stimulation. Concomitantly, the number of DNA repair foci at the IgH locus on day 3 was significantly decreased. AID expression and activity became normal on day 4, but isotype switching remained profoundly diminished 8 days after stimulation.
CONCLUSION: BCR cross-linking delays AID expression. This might interfere with class-switch recombination by disrupting the temporal coordination of signals that lead to class-switch recombination.