Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in.

Slides:

Advertisements

Similar presentations

Therapeutic reversal of food allergen sensitivity by mature retinoic acid–differentiated dendritic cell induction of LAG3+CD49b−Foxp3− regulatory T cells

Advertisements

A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency Haifa H. Jabara, BSc, Toshiro Ohsumi, PhD,

Lentiviral-mediated gene therapy leads to improvement of B-cell functionality in a murine model of Wiskott-Aldrich syndrome Marita Bosticardo, PhD, Elena.

Antigen-driven basophil activation is indicative of early Necator americanus infection in IgE-seronegative patients Franco H. Falcone, PhD, Gary Telford,

Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells Youwen Yang, PhD, Hans Michael Haitchi, MD,

Umasundari Sivaprasad, PhD, David J. Askew, PhD, Mark B

IL-25 and CD4+ TH2 cells enhance type 2 innate lymphoid cell–derived IL-13 production, which promotes IgE-mediated experimental food allergy Jee-Boong.

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

Oral immunotherapy induces IgG antibodies that act through FcγRIIb to suppress IgE- mediated hypersensitivity Oliver T. Burton, PhD, Stephanie L. Logsdon,

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

Frank Kirstein, PhD, Natalie E

B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE Haifa H. Jabara,

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival Jyoti Balhara, MSc, Lianyu Shan,

Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells Jun Young Hong, MS, J. Kelley.

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association Christina S. Yee,

CD19 controls Toll-like receptor 9 responses in human B cells

Functional analysis of protective IL1RL1 variants associated with asthma risk Vladimir Ramirez-Carrozzi, PhD, Amy Dressen, MS, Patrick Lupardus, PhD,

Human dendritic cell subset 4 (DC4) correlates to a subset of CD14dim/−CD16++ monocytes Federica Calzetti, BS, Nicola Tamassia, PhD, Alessandra Micheletti,

Leucine-rich repeat containing 8A (LRRC8A)–dependent volume-regulated anion channel activity is dispensable for T-cell development and function Craig.

TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of.

Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang,

Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α John T. Schroeder, PhD,

Frank Kirstein, PhD, Natalie E

Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to.

Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome Javier Chinen,

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

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

Balthazar B Cazac, Jürgen Roes Immunity

Positive Regulation of Lyn Kinase by CD148 Is Required for B Cell Receptor Signaling in B1 but Not B2 B Cells Katarzyna M. Skrzypczynska, Jing W. Zhu,

Volume 24, Issue 3, Pages (March 2006)

Jürgen Ruland, Gordon S Duncan, Andrew Wakeham, Tak W Mak Immunity

Jia Guo, MD, Xin Lin, PhD, Marc A

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

B-1a and B-1b Cells Exhibit Distinct Developmental Requirements and Have Unique Functional Roles in Innate and Adaptive Immunity to S. pneumoniae Karen.

Takao Kobayashi, PhD, Koji Iijima, PhD, Alexander L

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells Osamu Kaminuma, DVM, PhD, Fujiko Kitamura,

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

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells Elizabeth.

Inhibition of human B-cell development into plasmablasts by histone deacetylase inhibitor valproic acid Anne-Kathrin Kienzler, MSc, Marta Rizzi, MD,

CD22 is a negative regulator of B-cell receptor signalling

IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells Claire Galand, PhD, Juan Manuel Leyva-Castillo, PhD, Juhan.

3-Methyl-4-nitrophenol triggers nasal allergy by modulating dendritic cell properties Xiao-Yu Liu, PhD, Yong-Jin Wu, MD, PhD, Li-Juan Song, MD, Xian-Hai.

Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales,

Fibronectin is a TH1-specific molecule in human subjects

Β2 integrins rather than β1 integrins mediate Alternaria-induced group 2 innate lymphoid cell trafficking to the lung Maya R. Karta, PhD, Peter S. Rosenthal,

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

A peptide derived from the Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization.

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: Clinical and immunologic outcomes.

Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization Haoli Jin, MD, PhD, Lalit Kumar, PhD, Clinton Mathias, PhD, David Zurakowski,

Role of B cells in TH cell responses in a mouse model of asthma

Induction of long-lived allergen-specific plasma cells by mucosal allergen challenge Elke O. Luger, PhD, Verena Fokuhl, MSc, Michael Wegmann, PhD, Melanie.

Fibronectin is a TH1-specific molecule in human subjects

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Chen Yao, BS, Sandra M. Zurawski, PhD, Elizabeth S

Josée Lamoureux, PhD, Jana Stankova, PhD, Marek Rola-Pleszczynski, MD

Novel allergic asthma model demonstrates ST2-dependent dendritic cell targeting by cypress pollen Lucia Gabriele, BS, Giovanna Schiavoni, BS, Fabrizio.

Xin-Zi Tang, PhD, James B. Jung, BS, Christopher D.C. Allen, PhD

Impaired intestinal tolerance in the absence of a functional complement system Pirkka T. Pekkarinen, MD, Kirsi Vaali, PhD, Hanna Jarva, MD, PhD, Eliisa.

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects Polina Stepensky, MD,

Duy Pham, PhD, Sarita Sehra, PhD, Xin Sun, PhD, Mark H. Kaplan, PhD

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency Douglas.

Prostaglandin E2–EP3 signaling suppresses skin inflammation in murine contact hypersensitivity Tetsuya Honda, MD, PhD, Toshiyuki Matsuoka, MD, PhD, Mayumi.

Volume 28, Issue 5, Pages (May 2008)

IgG4 production is confined to human IL-10–producing regulatory B cells that suppress antigen-specific immune responses Willem van de Veen, MSc, Barbara.

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

Presentation transcript:

Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice Haifa H. Jabara, BSc, John J. Lee, MD, Erin Janssen, MD, PhD, Sumana Ullas, MS, Kyriaki Liadaki, PhD, Lilit Garibyan, MD, PhD, Halli Benson, BS, Tatyana Sannikova, BS, Richard Bram, MD, PhD, Lennart Hammarstrom, MD, Anthony C. Cruz, BS, Richard Siegel, MD, PhD, John Manis, MD, Richard Malley, MD, Raif S. Geha, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 4, Pages 1293-1301.e4 (April 2017) DOI: 10.1016/j.jaci.2016.07.028 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Blood donor carriers of the TACI A181E mutation have impaired natural antibody responses. A, Phosphocholine (PC)–specific IgM and IgG antibody. B, Inhibition of anti-PC IgG binding to PC by increasing concentrations of sodium thiocyanate (NaSCN; left panel) and NaSCN molarity, resulting in 50% inhibition of the OD (right panel). C and D, E coli–specific IgM (Fig 1, C) and tetanus toxoid (TT)–specific IgG (Fig 1, D) in sera from Swedish asymptomatic subjects carrying a heterozygous TACI A181E mutation (n = 14) and healthy control subjects (n = 20). Data are expressed as OD at 405 nm or international units per milliliter. Sera were used at 1:100 dilution in Fig 1, A (for IgM), B, and D, and 1:500 dilution in Fig 1, A (for IgG). Columns or symbols and bars represent means ± SEMs. *P < .05, **P < .01, and ***P < .001, Student t test. ns, Not significant. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The A144E mutation impairs TACI surface expression, but not mRNA expression, in mouse B cells. A, Quantitative RT-PCR analysis of Tnfrsf13b mRNA levels in purified B220+ splenic B cells from TACI+/+ (+/+), TACI+/− (+/−), TACI+/A144E (+/mut), TACIA144E/A144E (mut/mut), and TACI−/− (−/−) mice. mRNA expression of Tnfrsf13b compared with that of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (Gapdh) is shown as a percentage of the ratio in B cells from TACI+/+ WT control mice. B and C, Representative fluorescence-activated cell sorting analysis (Fig 2, B) and pooled data (Fig 2, C) of the mean fluorescence intensity (MFI) of TACI surface expression on gated B220+ splenic B cells. D and E, Representative fluorescence-activated cell sorting analysis (Fig 2, D) and pooled data (Fig 2, E) of intracellular TACI expression in gated B220+ peripheral B cells. MFI data presented are the net value of TACI expression (MFI of TACI minus MFI of isotype control). Columns and bars in Fig 2, A, C, and E, represent means ± SEMs (n = 3-5 mice per group). *P < .05, **P < .01, and ***P < .001, Student t test. n.d., Not detected. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Proliferation and in vitro immunoglobulin production in response to APRIL are impaired in B cells from A144E TACI mutant mice. Proliferation in response to APRIL (A) and IgG1 secretion in response to APRIL plus IL-4 (B) by splenic B cells from TACI+/+ (+/+) TACI+/− (+/−), TACI+/A144E (+/mut), TACIA144E/A144E (mut/mut), and TACI−/− (−/−) mice. Stimulation with anti-CD40 plus IL-4 was used as a control. Columns and bars represent means ± SEMs (n = 5-7 mice per group). *P < .05 and **P < .01, Student t test. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Serum immunoglobulin levels and antibody responses to TNP-Ficoll in A144E TACI mutant mice. A, Serum IgM, IgG, and IgA levels from nonimmunized 8- to 12-week-old TACI+/+ (+/+), TACI+/− (+/−), TACI+/A144E (+/mut), TACIA144E/A144E (mut/mut), and TACI−/− (−/−) mice. Each symbol represents an individual mouse, and horizontal lines indicate means (n = 11-15 mice per group). B, IgM and IgG anti-TNP responses 14 days after immunization with TNP-Ficoll. C, IgG anti-NP response after immunization with NP-OVA. Data in Fig 4, B and C, are presented as OD readings at 405 nm. Symbols and bars represent means ± SEMs (n = 5-11 mice per group). *P < .05, **P < .01, and ***P < .001. ns, Not significant. The Student t test was used in Fig 4, A, and 2-way ANOVA was used in Fig 4, B. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Decreased levels of natural antibodies to phosphocholine (PC) and increased susceptibility to pneumococcal inhalation challenge in TACI A144E mutant mice. A, IgM (left) and IgG (right) PC-specific antibody levels in sera from nonimmunized 8- to 12-week-old TACI+/+ (+/+), TACI+/− (+/−), TACI+/A144E (+/mut), and TACI−/− (−/−) mice expressed as OD at 405 nm (n = 7 for each group). B, Kaplan-Meier survival curves after intranasal challenge of 8- to 12-week-old unimmunized naive TACI+/+ (+/+), TACI+/− (+/−), TACI+/A144E (+/mut), and TACI−/− (−/−) mice with an S pneumoniae serotype 3 strain (n = 12-23 per group). Symbols and bars in Fig 5, A, indicate means ± SEMs, and symbols in Fig 5, B, represent the percentage of surviving mice. *P < .05, **P < .01, and ***P < .001. Two-way ANOVA was used in Fig 5, A, and the log-rank (Mantel-Cox) test was used in Fig 5, B. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Strategy for the generation of TACI A144E knock-in mice. A, Genomic structure of murine Tnfrsf13b and the targeting construct, predicted structure of the targeted allele after homologous recombination, and predicted structure of the targeted allele after Cre-mediated removal of the neo gene by breeding with EIIa-Cre mice. Exons are represented by blue boxes, the neomycin resistance gene (neo) is represented by the red box, and the thymidine kinase gene (tk) is represented by the green box. Black triangles represent loxP sites. Primers a and b were used for genotyping. B, PCR analysis of tail genomic DNA from TACI+/+ (+/+), TACIA144E/A144E (mut/mut), and TACI+/A144E (+/mut) mice. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 TACI A181E and A144E mutants assemble with their WT counterparts and act as dominant-negative mutations in 293T cell transfectants. A and B, Representative immunoblots showing the association of WT and A181E hTACI (Fig E2, A) and WT and A144E mTACI in 293T cell transfectants (Fig E2, B). C and D, NF-κB induction by APRIL in 293T cells transfected with WT hTACI, A181E hTACI or both (Fig E2, A) or with WT mTACI, A144E mTACI, or both (Fig E2, B). Fold induction was calculated by dividing the normalized NF-κB luciferase result of APRIL-treated samples by the NF-κB luciferase result of untreated samples. Blots in Fig E2, A and B, are representative of 3 independent experiments. Results in Fig E2, C and D, represent means and SDs of 3 independent experiments. *P < .05 and ***P < .001, Student t test. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Normal B-cell development in TACI A144E mice. B-cell subpopulations were examined in the bone marrow, spleen, and peritoneal cavity of 6- to 8-week-old TACI+/+ (+/+), TACI+/− (+/−), TACI+/A144E (+/mut), TACIA144E/A144E (mut/mut), and TACI−/− (−/−) mice. A, Percentages of B-cell subpopulations in the bone marrow. Left panel, CD43+B220hiIgM− pro-B, CD43−B220hiIgM− pre-B, and CD43−B220hiIgMmed immature B cells. Right panel, Mature B220hiIgM+ B cells. B, Percentages of CD3+ T cells and B220+ B cells in the spleen. C, Subpopulations of CD23−CD21hi marginal zone (MZ), CD23hiCD21lo follicular (FO), CD24+CD21− transitional 1 (T1), and CD23+CD21+ transitional 2 (T2) cells among the B220+IgM+ splenic B cells. D, Percentages of subpopulations of CD23− B-1, CD23+ B-2, and CD23-CD5+CD11b+ B-1a cells within the B220+ cell population in the peritoneal lavage cavity. Columns and bars represent means ± SEMs (n = 5 mice per group). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1293-1301.e4DOI: (10.1016/j.jaci.2016.07.028) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions