Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring Phoebe K. Richgels, MS, Amnah.

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Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring Phoebe K. Richgels, MS, Amnah Yamani, MS, Claire A. Chougnet, PhD, Ian P. Lewkowich, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 5, Pages 1404-1415.e9 (November 2017) DOI: 10.1016/j.jaci.2016.12.972 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Maternal HDM exposure increases the severity of AHR and airway inflammation in HDM-exposed offspring. Pregnant female mice were exposed to HDM or PBS on days 0, 4, and 10 of pregnancy. Offspring of PBS- and HDM-exposed mothers were exposed to PBS or HDM at age 6, 8, and 9 weeks and development of AHR was assessed (A). After sacrifice, BAL fluid was collected to assess total BAL cellularity (B) and the number of lymphocytes (C), eosinophils (D), neutrophils (E), and macrophages (F). BAL, Bronchoalveolar lavage. Mean + SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Increased TH2 cytokine production in HDM-exposed offspring of HDM-exposed mothers. Offspring of PBS- and HDM-exposed mothers were treated with PBS or HDM as described in the Methods section. Single-cell suspensions of lung cells were restimulated with HDM, and production of IL-4 (A), IL-5 (B), IL-13 (C), and IL-17A (D) was assessed by ELISA. The frequency of CD4+ cells producing IL-13 (E) and IL-17A (F) was assessed by flow cytometry. Mean + SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Increased total and HDM-specific IgG production in HDM-exposed offspring of HDM-exposed mothers. Offspring of PBS- and HDM-exposed mothers were treated with PBS or HDM as described in the Methods section. Serum isolated at time of sacrifice was assayed for total IgE (A), HDM-sp IgG1 (B), and HDM-sp IgG2a (C) by ELISA. Lowest dilution on plate indicated. sp, Specific. Mean + SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Minimal changes in allergen uptake by pulmonary DC populations were observed in HDM-exposed offspring of HDM-exposed mothers. Offspring of PBS- and HDM-exposed mothers were treated with PBS or HDM as described in the Methods section. Amount of HDM phagocytosed (MFI) and frequency of HDM-bearing (% of total lung cells) myeloid DCs (A) and alveolar macrophages (B) were assessed by flow cytometry. Macs, Macrophages; MFI, mean fluorescence intensity. Mean + SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Maternal HDM exposure does not increase the severity of AHR and airway inflammation in A fumigatus–exposed offspring. Offspring of PBS- and HDM-exposed mothers were exposed to PBS, HDM, or A fumigatus extract at age 6, 8, and 9 weeks. After sacrifice, BAL fluid was collected to assess total bronchoalveolar lavage cellularity (A) and the number of eosinophils (B), lymphocytes (C), neutrophils (D), andmacrophages (E). AF, A fumigatus. ∗∗P < .01 and ∗∗∗P < .001. Mean + SEM shown. Data represent 2 to 5 mice pooled from 2 experiments. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Maternal HDM exposure does not increase the magnitude of the TH2 response or the magnitude of the immunoglobulin response following exposure of offspring to A fumigatus. Offspring of PBS- and HDM-exposed mothers were exposed to PBS, HDM, or A fumigatus extract at age 6, 8, and 9 weeks. Single-cell suspensions of lung cells were restimulated with ConA, and production of IL-4 (A), IL-5 (B), and IL-13 (C) was assessed by ELISA. D, The frequency of CD4+ cells producing IL-13 was assessed by flow cytometry. E, Serum isolated at time of sacrifice was assayed for total IgE. AF, A fumigatus. Mean + SEM shown. Data represent 2 to 5 mice pooled from 2 experiments. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Offspring of HDM-exposed μMT dams demonstrate increased severity of AHR and airway inflammation. Male C57Bl/6 mice were mated with female C57Bl/6 dams (left column) or B-cell–deficient μMT dams (right columns) and pregnant female mice were exposed to HDM or PBS on days 0, 4, and 10 of pregnancy. Offspring of PBS- and HDM-exposed mothers were exposed to intraperitoneal PBS or HDM at age 6 and 7 weeks, and challenged with intratracheal PBS or HDM at age 8 and 9 weeks and the development of AHR was assessed 72 hours later (A). After sacrifice, BAL fluid was collected to assess total BAL cellularity (B) and the number of macrophages (C), eosinophils (D), lymphocytes (E), and neutrophils (F). BAL, Bronchoalveolar lavage. Mean + SEM shown. Data represent 3 to 13 mice pooled from 3 experiments. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Maternal HDM exposure increases the severity of AHR in male and female offspring of HDM-exposed mothers. Pregnant female mice were exposed to HDM or PBS on days 0, 4, and 10 of pregnancy. Offspring of PBS- and HDM-exposed mothers were exposed to PBS or HDM at age 6, 8, and 9 weeks and development of AHR was assessed in female (A) and male (B) offspring. Mean ± SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. *P < .05 between PBS Mom HDM Pup and HDM Mom HDM Pup groups. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Similar magnitude of cytokine production in TH2 and TH17 cells in control offspring and offspring of HDM-exposed dams. Offspring of PBS- and HDM-exposed mothers were treated with PBS or HDM as described in the Methods section. The MFI of IL-13 (left panel) and IL-17A (right panel) in IL-13+ CD4+ T cells and IL-17A+ CD4+ T cells was assessed by flow cytometry. MFI, Mean fluorescence intensity. Mean + SEM shown. Data represent 2 to 7 mice in a single representative experiment of 3 performed. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 No changes in pulmonary DC numbers in HDM-challenged offspring of HDM-exposed mothers. Offspring of PBS- and HDM-exposed mothers were treated with PBS or HDM as described in the Methods section. Total numbers (mean fluorescence intensity) and % of HDM-bearing CD103+ DCs (A), inflammatory DCs (B), myeloid DCs (C), alveolar macrophages (D), and plasmacytoid DCs (E) were assessed by flow cytometry. Mean + SEM shown. Data represent 7 to 18 mice pooled from 4 experiments. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 BMDCs from offspring of HDM-exposed mothers do not display altered capacity for allergen uptake or allergen-stimulated costimultory molecule expression. BMDCs were generated from control offspring (blue histograms) or offspring of HDM-exposed mothers (red histrograms). BMDCs were cultured with PBS or HDM at the indicated concentrations and live DCs were identified by expression of CD11c and CD11b (A). Uptake of fluorescently labeled HDM (B) and expression of CD80 (C), CD86 (D), and MHC class II (E) were assessed. Plots show representative analysis from 1 of 3 cultures performed. BMDC, Bone marrow–derived DCs; FSC, forward scatter. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 After maternal HDM exposure, HDM is not detectable in fetal tissues, placental tissues, of amniotic fluid cells. Pregnant female mice were exposed to HDM or PBS on days 0 and 4 of pregnancy, and with AF405-labeled HDM on day 10 of pregnancy. Mice were sacrificed on day 12 of pregnancy and the presence of HDM was assessed in fetal tissue (A), placental tissue (B), and cells from the amniotic fluid (C) of control offspring (blue histograms) and offspring of HDM-exposed mothers (red histograms). Top panels in Fig E5, A and B, show strategy to identify CD11c and CD11b-expressing cells, and lower panels show AF405 histograms. Fig E5, C, represents cells pooled from all control offspring and offspring of HDM-exposed mothers. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Offspring of HDM-exposed μMT dams demonstrate increased TH2 cell recruitment. Naive μMT dams (right graphs) or wild-type C57Bl/6 dams (left graphs) were mated with naive C57Bl/6 sires and pregnant female mice were exposed to HDM or PBS on days 0, 4, and 10 of pregnancy. Offspring of PBS- and HDM-exposed mothers were exposed to intraperitoneal PBS or HDM at age 6 and 7 weeks, and challenged with intratracheal PBS or HDM at age 8 and 9 weeks and sacrificed 72 hours later. Single-cell suspensions of lung cells were restimulated with HDM, and the frequency of CD4+ cells producing IL-13 (A) and IL-17A (B) was assessed by flow cytometry. Mean + SEM shown. Data represent 3 to 13 mice pooled from 3 experiments. *P < .05. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Offspring of HDM-exposed μMT dams demonstrate increased total IgE production. Male C57Bl/6 mice were mated with female C57Bl/6 dams (left column) or B-cell–deficient μMT dams (right columns) and pregnant female mice were exposed to HDM or PBS on days 0, 4, and 10 of pregnancy. Offspring of PBS- and HDM-exposed mothers were exposed to intraperitoneal PBS or HDM at age 6 and 7 weeks, and challenged with intratracheal PBS or HDM at age 8 and 9 weeks and sacrificed 72 hours later. Levels of HDM-specific IgG1 (A) and total IgE (B) were assessed in the serum by ELISA. Sp, Specific. Mean + SEM shown. Data represent 3 to 13 mice pooled from 3 experiments. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Kinetics of HDM-specific immunoglobulin levels in offspring of HDM-exposed mothers. Naive A/J offspring of HDM-exposed dams were bled at the indicated times, and the levels of HDM-specific IgG1 (A) and IgG2a (B) present in the serum were assessed by ELISA. Dotted line indicates background titers present in naive animal run at the same time as serum from offspring of HDM-exposed mother. Each time point consists of 2 or 3 independent animals. Sp, Specific. Journal of Allergy and Clinical Immunology 2017 140, 1404-1415.e9DOI: (10.1016/j.jaci.2016.12.972) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions