B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE Haifa H. Jabara,

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B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE Haifa H. Jabara, BS, Jayanta Chaudhuri, PhD, Shilpee Dutt, PhD, Fatma Dedeoglu, MD, Yu Weng, BS, Michael M. Murphy, BS, Sonia Franco, MD, PhD, Fredrick W. Alt, PhD, John Manis, MD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 121, Issue 1, Pages 191-196.e2 (January 2008) DOI: 10.1016/j.jaci.2007.08.008 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 BCR cross-linking inhibits LPS plus IL-4–induced IgG1 and IgE isotype switching by murine B cells. A, Effect of goat IgG F(ab′)2 anti-mouse IgM (α-μ; 0-10 μg/mL) and control (C) goat IgG F(ab′)2 (10 μg/mL) on IgG1 and IgE synthesis by purified splenic B cells. Results represent the mean ± SE of 5 experiments (n = 5). B, Surface IgG1 expression. Results are representative of 4 experiments; percentages of sIgG1+ B cells are indicated. Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 No effect of BCR cross-linking on B-cell viability or proliferation. A, Tritiated thymidine incorporation (n = 3). B, CFSE dilution on day 6. C, Annexin V staining. In Fig 2, B and C, a representative of 3 experiments is shown as overlay histograms of B cells stimulated with IL-4 plus LPS (green), IL-4 plus LPS plus α-μ (10 μg/mL; red), and IL-4 plus LPS plus control (10 μg/mL; blue). Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 BCR cross-linking inhibits LPS/IL-4–driven switch recombination and plasmablast generation. A, RT-PCR of Cɛ GLTs, AID, and Iμ-Cɛ. B, Sμ→Sɛ by means of digestion circularization PCR. C, Semiquantitative analysis of Iμ-Cμ and Cɛ GLT by using 4-fold dilution of cDNA. D, IgM secretion (n = 5). E, CD138 expression. β2-Microglobulin (β2 m) and nicotinic acetylcholine receptor β unit (nAChR) are loading controls. Results represent 3 experiments in Fig 3, A through C, and 2 experiments in Fig 3, E. Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 BCR cross-linking causes a decrease in DNA repair foci. A, Immuno-FISH with 53BP1 and IgH locus bacterial artificial chromosome (BAC) probes. Representative B cell showing colocalization (white arrow) of IgH BAC probe (green) and 53BP1 protein (red). B, Quantitative analysis of immuno-FISH assay performed on primary B cells after 72 hours of culture (n = 3). ∗∗P < .01. Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 BCR cross-linking delays AID mRNA expression. A, Quantitative PCR analysis of AID mRNA expression on days 2, 3, and 4 after stimulation. AID mRNA levels in α-μ or control treated cultures are expressed as a percentage of AID induced by LPS plus IL-4 (n = 4). ∗P < .05; ∗∗P < .01. B, Effect of BCR cross-linking on IgE and IgG1 production 8 days after stimulation (n = 3). Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 BCR cross-linking has no effect on AID. A, Western blot of AID in B-cell lysates (15 μg per lane) on day 4, with Ku70 as a control. B, Assay of B-cell extracts (5 μg) for DNA CDA, with LPS-stimulated AID−/− B cells as a negative control. C, JNK phosphorylation (0.5 × 106 cells per lane). Results represent 3 experiments for Fig 6, A, and 2 experiments for Fig 2, B and C. Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Effect of BCR cross-linking on IgG1 and IgE isotype switching by murine B cells negatively sorted for IgG, IgA, and IgE and stimulated with LPS plus IL-4. Effect of goat IgG F(ab′)2 anti-mouse IgM (α-μ; 0-10 mg/mL) and control (C) goat IgG F(ab′)2 (10 mg/mL) on IgG1 and IgE synthesis by sorted splenic B cells. Results shown are representative of 3 independent experiments. Mouse splenic B cells were purified by means of negative sorting with biotinylated mAbs to IgG1, IgG2a, IgG2b, IgG3, IgA, IgE, CD138, CD43, CD11b, and Thy-1.2 (PharMingen) and Dynabeads M-280 streptavidin (Dynal). Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Two-color region FISH to detect chromosomal breaks at the IgH locus Two-color region FISH to detect chromosomal breaks at the IgH locus. A, Two-color IgH FISH strategy to detect chromosomal breaks. B, Metaphase spreads showing intact IgH locus with contiguous localization of 5′ IgH (green) and 3′ IgH (red) probes. C, Chromosomal breaks in B cells from BALB/c (wild-type) mice treated with LPS/IL-4 in the presence of medium, anti-IgM, or control IgG. Stimulated H2AX−/− B cells were used as a positive control for detection of chromosomal breaks. The 3′ end of the IgH locus was detected by using BAC199 and the 5′ end was detected by using BAC207 in metaphase spreads of B cells 96 hours after stimulation, as previously described.E1 Journal of Allergy and Clinical Immunology 2008 121, 191-196.e2DOI: (10.1016/j.jaci.2007.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions