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Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation  Esra.

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Presentation on theme: "Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation  Esra."— Presentation transcript:

1 Toll-like receptor 9, transmembrane activator and calcium-modulating cyclophilin ligand interactor, and CD40 synergize in causing B-cell activation  Esra Ozcan, MD, Ingrid Rauter, PhD, Lilit Garibyan, MD, PhD, Stacey R. Dillon, PhD, Raif S. Geha, MD  Journal of Allergy and Clinical Immunology  Volume 128, Issue 3, Pages e4 (September 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 TLR9 synergizes with CD40 in activating naive B cells. A and B, Synergy between CpG and anti-CD40 in driving IgG1 and IgE production (Fig 1, A) and proliferation (Fig 1, B) in naive B cells cultured with IL-4. C, Effect of addition of CpG to anti-CD40 mAb on B-cell survival. Values represent means ± SDs of at least 3 experiments. ∗P < .05, ∗∗P < .01, ∗∗∗P < Note that in this and subsequent figures, not all bars representing SDs are readily visible. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 TLR9 synergizes with CD40 in driving isotype switching. A, sIgG1 expression. B, Expression of Cε GLT, Iμ-Cε, Cγ1 GLT, Iμ-Cγ1, and AICDA mRNA measured by means of RT-PCR. Similar results were obtained in 3 independent experiments. C, CD138 surface expression. D, Blimp-1 mRNA expression. Values in Fig 2, A, C, and D, represent means ± SDs of at least 3 experiments. ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 TLR9 synergizes with TACI in driving immunoglobulin production and proliferation. A and B, Synergy between CpG and APRIL in driving IgG1 and IgE production (Fig 3, A) and proliferation (Fig 3, B) in naive B cells stimulated with IL-4. C, Effect of addition of CpG to APRIL on B-cell survival. Values represent means ± SDs of at least 3 experiments. ∗P < .05, ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 TLR9 and TACI synergize in driving isotype switching and have an additive effect on plasma cell differentiation. A, sIgG1 expression. B, Expression of Cε GLT, Iμ-Cε, Cγ1 GLT, Iμ-Cγ1, and AICDA mRNA. Similar results were obtained in 3 independent experiments. C, CD138 surface expression. D, Blimp-1 mRNA expression. Values in Fig 4, A, C, and D, represent means ± SDs of at least 3 experiments. ∗P < .05, ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Triple synergy between TLR9, CD40, and TACI in driving B-cell activation and differentiation in the presence of IL-4. IgG1 and IgE production (A) and proliferation (B), sIgG1 expression (C), molecular events involved in CSR (D), CD138 expression (E), and Blimp-1 mRNA expression (F) by naive B cells cultured with IL-4 are shown. Values in Fig 5, A, B, C, E, and F, represent means ± SDs of at least 3 experiments. Fig 5, D, is representative 3 independent experiments. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Synergy between CpG, anti-CD40, and APRIL in PBMCs from healthy subjects. Synergy between CpG and anti-CD40 (A, n = 3) and between CpG and APRIL (B, n = 13) in driving IgG production by IL-4–stimulated PBMCs. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E1 IgG1 and IgE production by naive B cells in response to stimulation with different concentrations of anti-CD40 mAb plus IL-4. The experiment shown is representative of 3. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E2 IgG1 and IgE production by naive B cells in response to stimulation with different concentrations of CpG plus IL-4. The experiment shown is representative of 3. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E3 CpG synergizes with TACI ligation in driving IgM and IgG3 production and proliferation. A and B, Synergy between CpG and APRIL in driving IgM and IgG3 production (Fig E3, A) and proliferation (Fig E3, B) in naive B cells. C, Effect of addition of CpG to APRIL on B-cell survival. Values represent means ± SDs of at least 3 experiments. ∗P < .05, ∗∗P < .01. At the scale used, not all bars representing SDs are readily visible. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E4 APRIL enhancement of CpG-driven immunoglobulin production is dependent on TACI. Effect of APRIL (1 μg/mL) on IgG1 and IgE production by naive B cells from TACI−/− mice, BCMA−/− mice, and genetically matched wild-type control animals. Values represent means ± SDs of at least 3 experiments. ∗P < .05, ∗∗P < .01. At the scale used, not all bars representing SDs are readily visible. Variations in absolute amounts of immunoglobulins secreted by B cells from the 3 groups of mice studied likely reflect their mixed Sv129xC57Bl6 background. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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