The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency

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Presentation transcript:

The C104R mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) through haploinsufficiency John J. Lee, MD, Haifa H. Jabara, BS, Lilit Garibyan, MD, PhD, Ingrid Rauter, PhD, Tatyana Sannikova, BS, Stacey R. Dillon, PhD, Richard Bram, MD, PhD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 126, Issue 6, Pages 1234-1241.e2 (December 2010) DOI: 10.1016/j.jaci.2010.08.017 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Characterization of C76R/TACI+/− transgenic mice. A, Schematic representation of the murine C76R TACI (mTACI) transgene. EC, extracellular; IC, intracellular; TM, transmembrane. B and C, Representative FACS analysis of splenocytes from TACI+/+, TACI−/−, C76R/TACI+/−, and TACI+/− mice for B220 and TACI surface expression. Relevant quadrant percentages and MFIs are provided. TACI expression on B220+ B cells (Fig 1, B) and CD4 and B220 expression (Fig 1, C) are shown. Fig 1, B, also shows TACI surface expression on WT Tg/TACI+/− mice, which were not further studied because the percentage of their B cells that expressed TACI and the intensity of TACI expression on these B cells were significantly higher than in TACI+/+ mice and C76R/TACI+/− mice. Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Serum immunoglobulins and antibody responses to TNP-Ficoll in C76R/TACI+/− transgenic mice. A, Serum IgM, IgG, and IgA levels from nonimmunized 8- to 12-week-old TACI+/+, TACI−/−, TACI+/−, and C76R/TACI+/− mice. The median (center line), 25th to 75th percentiles (box), and lowest and highest values (bars) are shown for each group. B, IgM and IgG anti-TNP antibody responses to TNP-Ficoll. Bars represent SEMs. The Mann-Whitney test was used in Fig 2, A, and 2-way ANOVA was used in Fig 2, B, to calculate significance (n = 10-12 mice per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Proliferation and immunoglobulin synthesis in vitro by naive B cells from C76R/TACI+/− transgenic mice. Proliferation (A) and IgG1 synthesis (B) in response to APRIL are shown. B cells were stimulated with anti-CD40 plus IL-4 as a control for proliferation and IgG1 production (n = 5-9 mice per group). The Mann-Whitney test was used to calculate significance. MED, Medium alone. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Decreased serum IgA levels and impaired antibody responses to TNP-Ficoll in TACI+/− mice on the C57BL/6 background. A, TACI and B220 expression on splenocytes from TACI+/+, TACI+/−, and TACI−/− mice on the C57BL/6 background. B, Serum IgM, IgG, and IgA levels from nonimmunized 8- to 12-week-old mice. C, IgM and IgG anti-TNP antibody responses to TNP-Ficoll. The results in Fig 4, B and C, are presented and analyzed as in Fig 2 (n = 10-12 mice per group). Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Proliferation and immunoglobulin synthesis in vitro by purified B cells from TACI+/− mice on the C57BL/6 background. Proliferation (A) and IgG1 synthesis (B) in response to APRIL are shown (n = 5-9 mice per group). Results were analyzed as in Fig 3. MED, medium alone. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

TACI surface expression of C76R transgenic mice TACI surface expression of C76R transgenic mice. A representative biexponential FACS plot of TACI expression on C76R/TACI−/− mice is shown. Single-cell suspensions were stained with fluorochrome-conjugated antibodies in PBS containing 1% BSA and Fc-block (BD PharMingen), washed, and analyzed on a FACSCanto cytometer (Becton Dickinson). Conjugated anti-mouse mAbs used were fluorescein isothiocyanate–labeled anti-B220 (RA3-6B2, BD PharMingen) and phycoerythrin-labeled anti-mouse TACI (R&D Systems). Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Antibody responses to KLH in C76R/TACI+/− transgenic mice Antibody responses to KLH in C76R/TACI+/− transgenic mice. Mice (n = 4 per group) were immunized on day 0 with 200 μg of KLH administered intraperitoneally and 200 μg of KLH administered subcutaneously, boosted on day 14 with 25 μg of KLH, and bled on day 21. Plates were coated with KLH (10 μg/mL) in sodium carbonate buffer (pH 9.0) to measure anti-KLH–specific antibody. The wells were blocked with 2% BSA for 2 hours and incubated with diluted sera overnight at 4°C. Alkaline phosphatase–conjugated isotype-specific antibodies (BD PharMingen) were used as revealing antibodies. None of the differences between groups were significant, as analyzed with the Mann-Whitney test. Journal of Allergy and Clinical Immunology 2010 126, 1234-1241.e2DOI: (10.1016/j.jaci.2010.08.017) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions