A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency

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Presentation transcript:

A common single nucleotide polymorphism impairs B-cell activating factor receptor's multimerization, contributing to common variable immunodeficiency Kathrin Pieper, PhD, Marta Rizzi, MD, PhD, Matthaios Speletas, MD, PhD, Cristian R. Smulski, PhD, Heiko Sic, PhD, Helene Kraus, MSc, Ulrich Salzer, MD, Gina J. Fiala, MSc, Wolfgang W. Schamel, PhD, Vassilios Lougaris, MD, Alessandro Plebani, MD, Lennart Hammarstrom, MD, PhD, Mike Recher, MD, Anastasios E. Germenis, MD, PhD, Bodo Grimbacher, MD, Klaus Warnatz, MD, PhD, Antonius G. Rolink, PhD, Pascal Schneider, PhD, Luigi D. Notarangelo, MD, Hermann Eibel, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 4, Pages 1222-1225.e10 (April 2014) DOI: 10.1016/j.jaci.2013.11.021 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 BAFF binding to (A) and BAFFR expression (B) by B cells from healthy donors. C, BAFFR immunoblots of 2-dimensional gel electrophoresis performed with EBV cell lines (n ≥ 3). Cell numbers (D) and IgM secretion (E) of primary B cells activated with CpG DNA, anti-IgM, and BAFF. Fig 1, D and E show mean ± SD of triplicates. *P < .05; **P < .01; and ***P < .001. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Dose-dependent BAFF binding to primary B cells from healthy donors with heterozygous or homozygous P21R BAFFR mutations or WT BAFFR. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 BAFF binding (A), BAFFR expression (B), and dose-dependent BAFF binding plots of primary B cells isolated from patients with CVID with either WT BAFFR or a heterozygous P21R BAFFR mutation. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A, Structural modeling of BAFF (orange) bound to BAFFR (cyan); green: P21. B, Superimposition of BAFFR (cyan) and CRD1 of TNFR1 (violet); green: P21 of BAFFR; magenta: Q46 of TNFR1. C, Portion of TNFR1 dimer (violet and blue). Residues close to Q46 shown in yellow. Figures were drawn with PyMol by using the pdb files 1OQE and 1NCF. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, BAFFR-specific immunoblots of 2D gel electrophoresis (1-dimensional, BN-PAGE; 2D, SDS-PAGE) with primary B cells. B, 2D-PAGE of HEK293T cells expressing PLAD-containing (Fas17-227) or PLAD-deleted Fas (Fas59-227). Fas was detected by immunoblotting. C, Fluorescence microscopy of Fas17-227 and Fas59-227 YFP fusion proteins expressed in HEK293T cells; scale bar 10 μm. BN, Blue-native; 2D, 2-dimensional. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Decreased FRET in P21R-coexpressing cells. BAFFR WT, P21R, and Fas were C-terminally fused to eYFP and eCFP. Percentage of FRET-positive cells was recorded by flow cytometry of coexpressing HEK293T cells. C+, eCFP-eYFP fusion proteins; C−, separate expression of eCFP and eYFP. Results shown are means ± SD of 8 independent experiments. The dotted line indicates background. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 B-cell subsets of individuals with BAFFR WT (BAFFRWT/WT), homozygous P21R (BAFFRP21R/P21R) (A), or heterozygous BAFFR deletion mutation (BAFFRWT/DEL) (B). Histograms show percentages of B cells in PBMCs. FACS plots display CD19+ B cells and percentages of CD19+IgM+CD38high transitional, CD19+IgM+CD27− follicular, CD19+IgMhighCD27+ MZ, and CD19+IgM-CD27+ switched-memory B cells. C, BAFFR expression on CD19+ B cells; ***P < .001. FACS, Fluorescence-activated cell sorting. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 A, Immunoblot analysis of NF-κB2 processing in BAFFR transduced ST2 cells cultivated with (+) or without (−) BAFF. B, Concentration-dependent p52/p100 NF-κB2 ratio. Mean ± SD of 4 independent experiments. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Primary B cells from a healthy donor (A) and a patient with CVID (B) were activated in vitro with CpG DNA, anti-IgM, and BAFF as indicated. Cell numbers were analyzed in the beginning (d0) and after 6 days of cultivation. Plots show mean ± SD of triplicates. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 CD19+ human B cells expressing BAFFR WT or homozygous P21R were cultivated in vitro for 6 days with the CD40 ligand and IL21. A, Development of plasmablasts was analyzed by using flow cytometry. Numbers indicate percentages of CD27+CD38+ plasmablasts. B, Immunoglobulin secretion was measured by using ELISA. Data represent means ± SD of triplicates. Journal of Allergy and Clinical Immunology 2014 133, 1222-1225.e10DOI: (10.1016/j.jaci.2013.11.021) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions