The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous.

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Presentation transcript:

The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice Chiara Bacchelli, PhD, Karen F. Buckland, PhD, Sylvie Buckridge, BSc, Ulrich Salzer, MD, Pascal Schneider, PhD, Adrian J. Thrasher, MD, PhD, H. Bobby Gaspar, MD, PhD Journal of Allergy and Clinical Immunology Volume 127, Issue 5, Pages 1253-1259.e13 (May 2011) DOI: 10.1016/j.jaci.2011.02.037 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Dual-Luciferase reporter assays for detection of NF-κB–specific transcriptional activity in 293T cells. A, Cells were cotransfected with either WT or mutant TACI plasmids together with full-length APRIL (gray bars) or BAFF (black bars) plasmids or without stimulating ligand (white bars) and along with NF-κB luciferase reporter plasmid and Renilla plasmid. B, Activation of NF-κB transcription by titration of WT and C104R mutant hTACI performed as in Fig 1, A, except that cells were transfected with a total of 2 ng of plasmids at the indicated ratio. WT and C104R data displayed are representative of 3 experiments, and 187N, Y79C, A181E, and R202H data are representative of 2 experiments. Triplicate data are shown as means ± SDs. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TACI expression on MZ B cells from C76R TACI homozygous (HOMO), heterozygous (HET), and WT mice. A, Representative histogram plots. The blue line indicates labeling with anti-mouse TACI antibody, and the red line indicates isotype control staining. B, Data shown are means ± SEMs (n = 6). FI, Fluorescence intensity. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Immunologic phenotyping. A, Percentage of B220+, CD4+, and CD8+ lymphocytes in peripheral blood. B, Spleen mass. C-H, Quantification of splenic B-cell populations. Fig 3, A, Mean ± SEM (n = 6-7). Fig 3, B-H, Individual values are shown; bars represents means. Het, Heterozygous, Homo, homozygous. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 C76R TACI mutant mice have reduced naive serum immunoglobulin levels. Levels of immunoglobulin subtypes in C76R homozygous (Homo), heterozygous (Het), and WT naive serum measured by means of ELISA. Individual values are shown; bars indicates means. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Defective TI type II humoral immune responses. The time course of TNP-specific immunoglobulin responses is shown. IgM and IgG levels were measured at 1:8100 dilution of sera, and IgA levels were measured at 1:900 dilution of sera. IgG1, IgG2a, IgG2b, and IgG3 IgG subclass antibodies were measured at 1:80, 1:160, 1:160, and 1:1250 dilutions, respectively. Data shown are means ± SEMs from 2 independent experiments (n = 7). P values are given for comparisons with WT mice. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 In vitro immunoglobulin production. Purified murine splenic B cells were cultured with APRIL in the presence of IL-4. IgM and IgG levels were measured in culture supernatants by using ELISA. Data shown are means ± SEMs of triplicate means from 3 independent experiments. Het, Heterozygous; Homo, homozygous. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Position of residues C104, C76, Y79, and I87 in the TACI domain structure. TACI is shown as a ribbon representation (dark gray). Y79, I87 and C104 are shown in black. In mTACI the residue corresponding to C104 is C76. The surface of the 2 adjacent subunits of the ligand are shown in 2 different shades of light gray. The illustration was drawn with PyMol by using atomic coordinates of pdb entry 1xu1. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Generation of C76R TACI mutant mice Generation of C76R TACI mutant mice. A, Amino acid sequence homology between hTACI and mTACI. Colons indicate identical amino acid residues, and single dots indicate similar residues. The black box highlights the CRD2 domain. Arrows indicate the position of the murine C76R point mutation (red arrow) and its corresponding human mutation, C104R (black arrow), in the CRD2 domain. The blue bold triangle indicates the arginine 49 residue. A schematic diagram of TACI protein structure is also shown. TM, Transmembrane domain. B, Generation of C76R TACI mutant mice by means of homologous recombination. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Transfected 293T cells and EBV-transformed patient B-lymphoblastic cell lines expressing mutant forms of TACI show reduced TACI expression and APRIL binding. A and B, 293T cells were transfected with plasmids expressing WT and mutant forms of hTACI. C-E, EBV-transformed patient B-lymphoblastic cell lines expressing homozygous (Homo), heterozygous (Het), and compound heterozygous TNFRSF13B mutations. TACI expression was measured by staining with a polyclonal anti-human TACI antibody (P166) directed against the extracellular domain of hTACI. Fig E3, A, Representative plots showing TACI expression (green) and isotype control antibody (red) of 293T cells. Fig E3, B, Mean fluorescence intensity (MFI) of TACI expression of 293T cells. Fig E3, C, Level of TACI expression on patients’ lymphoblastic cell lines. APRIL (Fig E3, D) and BAFF (Fig E3, E) binding to lymphoblastic cell lines or transfected 293T cells were determined by means of incubation of cells with Flag-tagged recombinant APRIL or BAFF and detection with anti-Flag mAb. Fig E3, A and B, Data displayed are representative of at least 3 independent experiments. Fig E3, C, E, and F, Symbols represent MFI of cell lines from individual patients, and bars indicate means of group. WT, Healthy control expressing WT TACI. ∗P ≤ .05. ∗∗P ≤ .01. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Genotyping of C76R knock-in mice and WT littermates Genotyping of C76R knock-in mice and WT littermates. A, Partial cDNA sequence of TNFRSF13B exon 3 (NM_021349.1). Point mutation c.226T>C (C76R) and synonymous change c.207G>A (R49R) are indicated by red and black arrows, respectively. B, Fluorescence-based DNA sequencing of generated knock-in and littermate mice was performed by means of capillary electrophoresis. Representative electropherograms are shown for DNA from WT, heterozygous (Het), and homozygous (Homo) mice. The orange box indicates the position of the point mutation c.226T>C (C76R). Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

TACI expression on splenocytes from C76R TACI homozygous (HOMO), heterozygous (HET), and WT mice. A and B, Representative dot plots (Fig E5, A) and histograms (Fig E5, B) showing levels of TACI expression on splenic B cells. The blue line indicates labeling with anti-mouse TACI antibody, the red line indicates isotype control staining, and plots are representative of n = 6. C and D, TACI expression on total follicular B cells. Data are shown as means ± SEMs (n = 6). Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Immunologic phenotyping Immunologic phenotyping. Percentage of B220+, CD4+, and CD8+ lymphocytes in peripheral blood (A) and facial and cervical lymph nodes (B). Data are shown as means ± SEMs (n = 4-7). Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

C76R TACI mutant mice have reduced naive serum immunoglobulin levels C76R TACI mutant mice have reduced naive serum immunoglobulin levels. Levels of total IgG in C76R homozygous (Homo), heterozygous (Het), and WT naive serum measured by means of ELISA. Individual values are shown, and bars indicates means. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Defective T-independent type II humoral immune responses Defective T-independent type II humoral immune responses. Mice were immunized with TNP-FICOLL or NP-CGG. A, Time course of TNP-specific immunoglobulin response showing IgM and IgG levels measured at 1:8100 dilution and IgA at 1:900 dilution of sera. IgG1, IgG2a, IgG2b, and IgG3 IgG subclass antibody levels were measured at 1:80, 1:160, 1:160, and 1:1250 dilutions, respectively. B, Time course of NP-specific immunoglobulin response showing IgM and total IgG levels measured at 1:300 dilution. IgA, IgG1, IgG2a, IgG2b, and IgG3 levels were measured at 1:25, 1:160, 1:80, 1:640, and 1:1280 dilutions, respectively. Data shown are means ± SEMs from 2 independent experiments (Fig E8, A, n = 7; Fig E8, B, n = 6). P values given are for comparisons with WT, with the exception of IgA and IgG2a in Fig E8, B. het, Heterozygous; homo, homozygous. Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

In vitro immunoglobulin production In vitro immunoglobulin production. Purified murine splenic B cells were cultured with anti-CD40 in the presence of IL-4. IgM and IgG levels were measured in culture supernatants by means of ELISA. Data are shown as means ± SEMs (n = 3). Journal of Allergy and Clinical Immunology 2011 127, 1253-1259.e13DOI: (10.1016/j.jaci.2011.02.037) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions