Maternal allergy increases susceptibility to offspring allergy in association with TH2- biased epigenetic alterations in a mouse model of peanut allergy

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Maternal allergy increases susceptibility to offspring allergy in association with TH2- biased epigenetic alterations in a mouse model of peanut allergy Ying Song, MD, Changda Liu, PhD, Yiqun Hui, MD, PhD, Kamal Srivastava, PhD, Zhenwen Zhou, PhD, Jia Chen, ScD, Rachel L. Miller, MD, Fred D. Finkelman, MD, Xiu-Min Li, MD, MS Journal of Allergy and Clinical Immunology Volume 134, Issue 6, Pages 1339-1345.e7 (December 2014) DOI: 10.1016/j.jaci.2014.08.034 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Experimental protocols. Peanut-sensitized female mice were orally challenged with peanut and then mated with naive male mice 1 week later. Five-week-old O-PAM and O-NM mice were sensitized weekly for 3 weeks and challenged at week 4. Offspring of PBS-challenged naive mothers served as normal control animals. Breed., Breeding; Chall., challenge; i.g., intragastric; PN, peanut; Sensit., sensitization. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 O-PAM mice have an increased IgE response to peanut sensitization. Blood was collected from offspring after peanut sensitization at indicated time points, and serum peanut-specific IgE (A), peanut-specific IgG1 (B), and peanut-specific IgG2a (C) levels were determined by using ELISA. **P < .01 versus O-NM (n = 8-11 per group). PN, Peanut; W, week in sensitization protocol. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 O-PAM mice have anaphylaxis after peanut oral challenge. Thirty minutes after challenge, anaphylactic symptoms in both O-NM and O-PAM mice were scored (A), core body temperatures were measured (B), and plasma histamine levels were determined (C). Histamine levels are presented in log scale. *P < .05 and **P < .01 versus O-NM and #P < .05 versus normal control mice (n = 8-11 per group). Each dot represents an individual mouse. The horizontal bar indicates the mean. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Cytokine secretion by offspring splenocyte (SPC; A) and MLN (B) cultures. Splenocytes and MLN cells were prepared and cultured for 72 hours in the presence or absence of CPE. Culture supernatant IL-4, IFN-γ, and IL-10 levels were determined. Data are expressed as means ± SDs of each group. *P < .05 versus O-NM and #P < .05 versus normal control mice (n = 8-11 per group). Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Methylation at the CpG−408 and CpG−393 sites of the Il4 gene promoter. Purified DNA from sensitized and challenged offspring splenocytes (SPC) and MLN cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. Percentages of DNA methylation at the CpG−408 and CpG−393 sites of the Il4 gene promoters in offspring splenocytes (A and B) and MLN cells (C and D) are shown. Data are expressed as means ± SDs of each group. *P < .05 and **P < .01 versus O-NM and #P < .05 and ##P < .01 versus normal control mice (n = 5-8 per group). Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Correlation between DNA methylation at Il4 gene promoter and IL-4 production in SPC or MLN cells cultures from peanut sensitized offspring (A and C). Correlation between DNA methylation at Il4 gene promoter and PN specific IgE in serum from sensitized offspring (B and D). Nonparametric (Spearman) correlation was used. *P < .05 and **P < .01 (n = 10-12). Each dot represents an individual mouse. PN, Peanut; SPC, splenocyte. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 A-C, Neonatal offspring splenocyte IL-4 cytokine levels and CpG methylation at the CpG−408 and CpG−393 sites of the Il4 gene promoter. Splenocytes from unimmunized neonatal offspring were prepared and cultured for 72 hours in the presence of Con A. IL-4 levels in culture supernatants were determined by using ELISA. DNA methylation of the Il4 gene promoter from unimmunized neonatal splenocytes was determined as described in Fig 5. *P < .05 and ***P < .001 (n = 5-8 per group). Data are expressed as means ± SDs of each group. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Mothers with peanut allergy exhibited hypersensitivity reactions after oral peanut challenge and before mating. Blood was collected from PAMs and NMs 1 day before challenge. A, Serum peanut-specific IgE levels were measured by using ELISA. B-D, Anaphylaxis scores (Fig E1, B) and core body temperatures (Fig E1, C) were measured and plasma histamine levels (Fig E1, D) were determined 30 minutes after challenge. **P < .01 and ***P < .001 versus NMs (n = 5 per group). Each dot represents an individual mouse. Horizontal bars indicate means. Data shown are representative of 2 individual experiments. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Anaphylaxis scores and core body temperatures with or without anti-FcγRIIB/RIII mAb administration in peanut-sensitized O-PAM mice are shown after oral challenge (n = 5-6). Horizontal lines represent the means of each group. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A, Global methylation of MLN cells in O-PAM, O-NM, and normal control mice after challenge was measured by using the global DNA methylation ELISA kit (Epigentek). In this ELISA kit the methylated fraction of DNA is recognized by 5-methylcytosine antibody and quantified through an ELISA-like reaction (n = 6-7 per group). Both P > .05 for O-PAM versus O-NM and O-PAM versus naive mice. B, Purified DNA from sensitized and challenged offspring MLN cells underwent bisulfite treatment, PCR amplification, and pyrosequencing. B and C, Percentage of DNA methylation of the Ifng and foxp3 gene promoters in offspring MLN cells. Data are expressed as means ± SDs of each group (n = 5-6 per group). Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 DNA methylation at CpG−408 and CpG−393 sites of the Il4 gene promoter from PBLs of PAMs and NMs before breeding. Purified DNA from mothers' PBLs before breeding underwent bisulfite treatment, PCR amplification, and pyrosequencing. *P < .05 and ***P < .001 versus NMs (n = 5). Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Breast milk was collected from lactating PAMs and NMs when their offspring were 10 to 15 days old by using a mouse milking machine modified in our laboratory. An additional group of lactating PAM mice was inoculated intragastrically with 10 mg of peanut protein (PAM-PN). Milk was collected 2 hours after peanut protein feeding. Milk was diluted 1:2 in PBS, and peanut protein levels were detected with a commercial kit (Neogen Corp; n = 3-4). ***P < .001. Journal of Allergy and Clinical Immunology 2014 134, 1339-1345.e7DOI: (10.1016/j.jaci.2014.08.034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions