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

Slides:

Advertisements

Similar presentations

Exposure to allergen and diesel exhaust particles potentiates secondary allergen- specific memory responses, promoting asthma susceptibility Eric B. Brandt,

Advertisements

Surface availability of beta-glucans is critical determinant of host immune response to Cladosporium cladosporioides Rachael A. Mintz-Cole, PhD, Eric.

Sejal Saglani, MD, Stephen Lui, PhD, Nicola Ullmann, MD, Gaynor A

Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge Mei Ming, PhD, Baozhong Zhao, PhD, Christopher.

Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M

Weiguo Chen, MD, PhD, Yasuhiro Tabata, MD, PhD, Aaron M

Let-7 microRNA–mediated regulation of IL-13 and allergic airway inflammation Manish Kumar, MSc, Tanveer Ahmad, MSc, Amit Sharma, PhD, Ulaganathan Mabalirajan,

Robert J. Snelgrove, PhD, Lisa G

SERPINB3/B4 Contributes to Early Inflammation and Barrier Dysfunction in an Experimental Murine Model of Atopic Dermatitis Umasundari Sivaprasad, Kayla.

Calcitonin gene-related peptide– and vascular endothelial growth factor–positive inflammatory cells in late-phase allergic skin reactions in atopic subjects

Interferon response factor 3 is essential for house dust mite–induced airway allergy Thomas Marichal, DVM, Denis Bedoret, DVM, PhD, Claire Mesnil, DVM,

Innate IL-13–producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity Jillian L. Barlow, PhD, Agustin Bellosi,

Expression of IL-4 receptor α on smooth muscle cells is not necessary for development of experimental allergic asthma Frank Kirstein, PhD, William G.C.

Frank Kirstein, PhD, Natalie E

Exposure to allergen and diesel exhaust particles potentiates secondary allergen- specific memory responses, promoting asthma susceptibility Eric B. Brandt,

Allergen-dependent solubilization of IL-13 receptor α2 reveals a novel mechanism to regulate allergy Michael O. Daines, MD, Weiguo Chen, PhD, Yasuhiro.

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

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs Chien-Chang Chen, PhD, Takao Kobayashi, PhD, Koji Iijima,

Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn,

Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation Si-Yen Liu, PhD, Wei-Zhi Wang,

CD1d restricted natural killer T cells are not required for allergic skin inflammation Abdallah Elkhal, PhD, Muriel Pichavant, PhD, Rui He, PhD, Jordan.

Β-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses Zhonghua Zhang, MD, Jocelyn.

Allergic airway disease is unaffected by the absence of IL-4Rα–dependent alternatively activated macrophages Natalie E. Nieuwenhuizen, PhD, Frank Kirstein,

Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology Carla P. Jones, PhD, Lisa G. Gregory, PhD, Benjamin Causton, BSc, Gaynor A.

Dendritic cells and alveolar macrophages mediate IL-13–induced airway inflammation and chemokine production Margaret Crapster-Pregont, BS, Janice Yeo,

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice László Hortobágyi, MS, Sonja Kierstein, PhD, Kateryna Krytska,

Chang Xiao, MD, PhD, Jocelyn M

Heme oxygenase 1 attenuates the development of atopic dermatitis–like lesions in mice: Implications for human disease Mio Kirino, MD, Yohei Kirino, MD,

Experimental gastrointestinal allergy enhances pulmonary responses to specific and unrelated allergens Eric B. Brandt, PhD, Troy A. Scribner, MD, Hiroko.

Frank Kirstein, PhD, Natalie E

T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death Hye Young Kim,

Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization Zhi-Qiang Liu, MD, PhD, Ying Feng,

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,

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

Surface availability of beta-glucans is critical determinant of host immune response to Cladosporium cladosporioides Rachael A. Mintz-Cole, PhD, Eric.

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

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.

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

Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13 Rui He, MD, PhD, Hye Young Kim,

Jethe O. F. Nunes, PhD, Juliana de Souza Apostolico, MSc, David A. G

Prophylactic and therapeutic inhibition of allergic airway inflammation by probiotic Escherichia coli O83 Christian Zwicker, MSc, Priya Sarate, MSc,

Mast cell–derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma Ara Jo, PhD, Sun H.

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway Meiqin Wang, MD, PhD, Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi,

Protein disulfide isomerase–endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness

Cold temperature induces mucin hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin.

Allergen-induced IL-6 trans-signaling activates γδ T cells to promote type 2 and type 17 airway inflammation Md Ashik Ullah, MPharm, Joana A. Revez,

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,

Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? Marina Miller, MD, PhD, Christine Vuong,

The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation Stephen Sai Folmsbee, G.R. Scott Budinger,

Sarita Sehra, PhD, Weiguo Yao, PhD, Evelyn T. Nguyen, MS, Nicole L

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice Nicholas Venturelli, BS, Willem S. Lexmond, MD,

IL-17A enhances IL-13 activity by enhancing IL-13–induced signal transducer and activator of transcription 6 activation Sara L. Hall, MS, Theresa Baker,

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

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,

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

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,

DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma Stephanie Brand, PhD, Dörthe Andrea Kesper, PhD,

Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lung Christina C. Lewis, PhD, Bruce Aronow, PhD, John Hutton, MD,

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

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation Kentaro Takahashi, MD, Koichi.

MicroRNA-155 is essential for TH2-mediated allergen-induced eosinophilic inflammation in the lung Carina Malmhäll, BSc, Sahar Alawieh, BSc, You Lu, PhD,

Douglas A. Kuperman, PhD, Christina C. Lewis, PhD, Prescott G

Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation Takumi Kiwamoto,

Eric B. Brandt, PhD, Melissa K. Mingler, MS, Michelle D

The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice Martin Kohan, MSc, Andres F. Muro,

Junqing Cui, PhD, Stephen Pazdziorko, Joy S

Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation Takumi Kiwamoto,

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

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:

A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma Umasundari Sivaprasad, PhD, David J. Askew, PhD, Mark B. Ericksen, BS, Aaron M. Gibson, BS, Matthew T. Stier, Eric B. Brandt, PhD, Stacey A. Bass, Michael O. Daines, MD, Jamila Chakir, PhD, Keith F. Stringer, MD, Susan E. Wert, PhD, Jeffrey A. Whitsett, MD, Timothy D. Le Cras, PhD, Marsha Wills-Karp, PhD, Gary A. Silverman, MD, PhD, Gurjit K. Khurana Hershey, MD, PhD Journal of Allergy and Clinical Immunology Volume 127, Issue 1, Pages 254-261.e6 (January 2011) DOI: 10.1016/j.jaci.2010.10.009 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Generation and characterization of Serpinb3a-null mice. A, Schematic of the mouse and human SCCA locus (gray arrows indicate pseudogenes). B, Schematic of the targeting vector (top), WT (middle), and recombinant construct (bottom). B, BamH1; E, EcoR1 restriction sites. The probe used for Southern blotting is indicated in red. C, Genotyping by Southern blotting of BamH1-digested genomic DNA. The 2-kbp recombinant (red arrow) and 4.5-kbp WT alleles (black arrow) are indicated. The 6.5-kbp band is from WT Serpinb3b (green arrow). D, Expression of Serpinb3a (top), Serpinb3b (middle), and β-actin (bottom) in WT and Serpinb3a null (KO) mice. E, Percentage of B and T cells in the spleen. F, Percentage of B and T cells in the lymph node. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Serpinb3a-null mice show attenuated APTI after HDM challenge with no effect on sensitization APTI measurements (A), HDM-specific IgG1 levels (B), HDM-specific IgE levels in plasma (C), percentage of B cells (D), and percentage of CD3+ T cells (E) in the lymph node (LN). Experiments include 6 to 8 mice per group. P values are shown only for statistically significant differences. The horizontal bar for each group represents the mean. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Serpinb3a-null mice show no effect on inflammation after HDM challenge. A, Differential cell counts in BALF. B, H&E staining of airways, Experiments include 6 to 8 mice per group. P values are shown for statistically significant differences. Data shown are the means ± SDs. In B, the pictures were taken at ×200 magnification, and the inset panel was taken at ×1000 magnification. Eos, Eosinophils; KO, knock out; Lymph, lymphocytes; Macros, macrophages; Neut, neutrophils. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Decreased mucus production and goblet cell hyperplasia in Serpinb3a-null (KO) mice after HDM challenge. A, Representative images of Muc5AC staining (×200 magnification). B, Quantitation of Muc5AC staining. C, Representative images of CLCA3 staining. D, Quantitation of CLCA3 staining. B and D, Black bar, WT+HDM; white bar, KO+HDM. B, n = 10 for WT+HDM and n = 12 for KO+HDM. D, n = 9 for WT+HDM and n = 10 for KO+HDM. Frequency distribution across the groups was significantly different between the WT and KO mice for both Muc5AC (P = .005) and CLCA3 (P = .003). Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Decreased SPDEF expression in Serpinb3a-null mice after HDM challenge. A, SPDEF staining in WT and Serpinb3a-null (KO) mice after PBS or HDM challenge. A representative image at ×200 magnification from each treatment is shown. B, Quantitation of SPDEF staining. Black bar, WT+HDM; white bar, KO+HDM. n = 13 for WT+HDM and KO+HDM. Frequency distribution across the groups was significantly different between the WT and KO mice (P < .001). Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 The asthma phenotype is attenuated in the Serpinb3a-null mice (KO) after IL-13 treatment. A, APTI measurements (n = 11-13 per group). B, Differential BALF cell counts (n = 11-13 per group). P values are shown only for statistically significant differences. C, Representative images of Muc5AC staining (×200 magnification). Eos, Eosinophils; KO, knock out; Lymph, lymphocytes; Macros, macrophages; Neut, neutrophils; SAL, saline. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 SERPINB4 expression is induced by IL-13. A, Quantitative PCR for SERPINB4 in primary bronchial epithelial cells from controls and patients with asthma (6 subjects per group) treated with IL-13 for 24 hours. Data are presented as a fold increase in SERPINB4 expression in IL-13–treated cells compared with paired untreated controls. B, SERPINB4 expression after treatment with IL-4, IL-13, TNF-α, or IFN-γ. Data shown are representative of 3 independent experiments (each done in triplicate). The horizontal bar for each group represents the mean in A. B, Data shown are the means ± SDs. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

There are no differences in levels of total IgG1 (A) and IgE (B) in the plasma of Serpinb3a-null (KO) mice compared with WT mice after allergen challenge. Statistically significant differences are indicated with the P value. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Decreased FOXA3 expression in Serpinb3a-null (KO) mice after HDM challenge. A, FOXA3 staining in WT and Serpinb3a-null mice after PBS or HDM challenge. A representative image at ×200 magnification from each treatment is shown. B, Quantitation of FoxA3 staining. Black bar, WT+HDM; white bar, KO+HDM. P values are shown only for statistically significant differences. n = 13 for WT+HDM and KO+HDM. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative airways for each grade used to quantify immunohistochemistry. A, Representative grade 0, 1, 2, and 3 airways for Muc5AC staining after HDM treatment. B, Representative grade 0, 1, 2, and 3 airways for CLCA3 staining after HDM treatment. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative airways for each grade used to quantify immunohistochemistry. A, Representative grade 0, 1, 2, and 3 airways for SPDEF staining after HDM treatment. B, Representative grade 0, 1, 2, and 3 airways for FOXA3 staining after HDM treatment. C, Representative grade 0, 1, 2, and 3 airways for Muc5AC staining after IL-13 treatment. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Quantitative PCR shows a modest but insignificant decrease in SPDEF mRNA in the lungs of SerpinB3a-null (KO) mice after HDM challenge. Journal of Allergy and Clinical Immunology 2011 127, 254-261.e6DOI: (10.1016/j.jaci.2010.10.009) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions