B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE

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...

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Veröffentlicht in:Journal of allergy and clinical immunology 2008, Vol.121 (1), p.191-196.e2
Hauptverfasser: Jabara, Haifa H., BS, Chaudhuri, Jayanta, PhD, Dutt, Shilpee, PhD, Dedeoglu, Fatma, MD, Weng, Yu, BS, Murphy, Michael M., BS, Franco, Sonia, MD, PhD, Alt, Fredrick W., PhD, Manis, John, MD, Geha, Raif S., MD
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Sprache:eng
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Zusammenfassung: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 μg/mL). IgE and IgG1 levels in supernatants were measured by means of ELISA on day 6. Cμ or Cε germline transcripts, activation-induced cytidine deaminase (AID), and Iμ-Cε postswitch transcripts were measured by means of RT-PCR. Deletional switch recombination was assessed by means of digestion circularization PCR of Sμ-Sε 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 Cμ or Cε germline transcripts but suppressed the generation of Sμ-Sε switch products and Iμ-Cε 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.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2007.08.008