Ting-ting Zhang, MSc, Klaus Okkenhaug, PhD, Baher F

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Presentation transcript:

Genetic or pharmaceutical blockade of p110δ phosphoinositide 3-kinase enhances IgE production Ting-ting Zhang, MSc, Klaus Okkenhaug, PhD, Baher F. Nashed, MD, PhD, Kamal D. Puri, PhD, Zachary A. Knight, PhD, Kevan M. Shokat, PhD, Bart Vanhaesebroeck, PhD, Aaron J. Marshall, PhD Journal of Allergy and Clinical Immunology Volume 122, Issue 4, Pages 811-819.e2 (October 2008) DOI: 10.1016/j.jaci.2008.08.008 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 p110δ-D910A mice have selectively increased IgE levels after OVA immunization. Mice were immunized with OVA/alum and boosted at day 14. Sera collected before immunization (A) or 7 days after challenge (B) were assessed for the indicated antibody isotypes by means of ELISA. C, Levels of antigen-binding IgM, IgG1, or IgE antibodies were assessed after immunization. Squares represent WT mice, and circles represent p110δ-D910A mice. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 p110δ-D910A B cells show increased class switch to IgE and IgG1 in vitro. WT or p110δ-D910A B cells were stimulated with anti-CD40 plus IL-4 (A) or with LPS plus IL-4 (B). After 3 days of culture, cells were stained for intracellular IgG1 or IgE. The average percentage of IgE+(C) or IgG1+(D) cells and SEMs from 3 independent experiments are shown. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 p110δ inhibitor potently enhances generation of IgG1- and IgE-switched cells. A, WT B cells were stimulated with anti-CD40 plus IL-4 in the presence of the indicated doses of the p110δ selective inhibitor IC87114. At day 3, cells were stained for IgM, IgG1, or IgE. FACS data are representative of 3 independent experiments. B, The percentage of IgE+ cells from 1 representative experiment is shown. C, The percentage of IgG1+ and IgM+ cells is shown. D, PI-103, PIK-90, TGX-115, and TGX-221 inhibitors were added at 0.1, 1, or 10 μmol/L, and the percentage of IgE+ cells was assessed. IC87114 was used at 10 μmol/L and rapamycin was used at 0.01 μmol/L. E, Effect of PI3K inhibitors on secreted IgE levels was determined by means of ELISA. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Blockade of p110δ leads to deregulated sequential switching from IgG1 to IgE. A, WT or p110δ-D910A B cells cultured for 3 days with anti-CD40 plus IL-4 were double-stained for IgE and IgG1. The indicated inhibitors were used at 1 μmol/L. B, WT or p110δ-D910A B cells were labeled with CFSE before culture. At day 4, cells were harvested and stained with PE-labeled anti-IgE. Vertical lines mark cell divisions, as assessed by means of 2-fold dilutions of CFSE. C, Graph showing the frequency of IgE+ cells at divisions 1 to 5. Data represent means and SEs from 3 independent experiments. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 p110δ regulates ɛ germline transcription and AID expression. RNA was extracted from B cells stimulated under the indicated conditions, and levels of the indicated transcripts were determined by using LightCycler RT-PCR. A, ɛGLTs measured at 24 or 72 hours of culture. B, γ1GLTs measured at 24 or 72 hours of culture. C, ɛ and γ1 postswitch transcripts measured at 72 hours of culture. D, AID transcripts measured at 24 and 72 hours of culture. Data are expressed as normalized expression relative to the corresponding β-actin control and represent the average and SEM of at least 3 independent cultures. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Pharmacologic p110δ inhibition in vivo selectively generates higher IgE production after OVA immunization. Mice were orally treated with IC87114 1 hour before OVA immunization and then twice per day for 12 days. At day 12, sera and splenocytes were collected. Solid squares represent vehicle-treated mice, and open circles represent IC87114-treated mice. A, The frequency of B220+Fas+GL7+ GC cells in the spleen was analyzed by means of FACS, illustrating a significant reduction in the IC87114-treated group. B, Sera were analyzed by means of ELISA to determine total IgM, IgG1, and IgE levels. C, Sera were analyzed by means of ELISA to determine OVA-binding IgM, IgG1, and IgE levels. D, Spleen cells were restimulated in vitro with 300 μg/mL OVA with or without IC87114. Culture supernatants were analyzed for IFN-γ, IL-12p40, IL-4, and IL-13 by means of ELISA. VEH/VEH, Cells from vehicle-treated mice cultured with no inhibitor; IC/VEH, cells from IC87114-treated mice cultured with no inhibitor; IC/IC, cells from IC87114-treated mice cultured in the presence of 10 μmol/L IC87114; Ab, antibody. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Inhibition of p110δ activity potentiates IgE class switch in vitro Inhibition of p110δ activity potentiates IgE class switch in vitro. B cells were cultured for 3 days with anti-CD40 plus IL-4 and then stained for IgE with an independent fluorescein isothiocyanate–labeled anti-IgE mAb. A, WT or p110δ-D910A B cells. B, WT B cells cultured with the indicated doses of the p110δ-selective inhibitor IC87114. Results are comparable with those obtained in Figs 2, A, and 3, A. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Effect of p110δ blockade on IL-4–induced ɛ germline transcription and AID expression. RNA was extracted from B cells cultured in the indicated conditions, and ɛGLT or AID expression was determined by using LightCycler RT-PCR. ∗P < .05, ∗∗P < .005, and ∗∗∗P < .001 (Student t test) compared with WT B cells with no inhibitor under the same stimulation conditions. Journal of Allergy and Clinical Immunology 2008 122, 811-819.e2DOI: (10.1016/j.jaci.2008.08.008) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions