Exposure to nonmicrobial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis Remo Frei, PhD, Ruth Ferstl, PhD,

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Exposure to nonmicrobial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis Remo Frei, PhD, Ruth Ferstl, PhD, Caroline Roduit, PhD, Mario Ziegler, Dipl-Ing, Elisa Schiavi, PhD, Weronika Barcik, MSc, Noelia Rodriguez-Perez, PhD, Oliver F. Wirz, MSc, Marcin Wawrzyniak, PhD, Benoit Pugin, PhD, Dirk Nehrbass, PhD, Marek Jutel, MD, PhD, Sylwia Smolinska, PhD, Patrycja Konieczna, PhD, Christian Bieli, PhD, Susanne Loeliger, MLS, Marco Waser, PhD, Göran Pershagen, MD, PhD, Josef Riedler, MD, Martin Depner, PhD, Bianca Schaub, MD, Jon Genuneit, MD, Harald Renz, MD, Juha Pekkanen, MD, Anne M. Karvonen, PhD, Jean-Charles Dalphin, MD, PhD, Marianne van Hage, MD, PhD, Gert Doekes, PhD, Mübeccel Akdis, MD, Charlotte Braun-Fahrländer, MD, Cezmi A. Akdis, MD, Erika von Mutius, MD, Liam O’Mahony, PhD, Roger P. Lauener, MD Tobias Alfvén, Johan Alm, Anna Bergström, Lars Engstrand, Helen Rosenlund, Niclas Hakansson, Gunnar Lilja, Frederik Nyberg, Jackie Swartz, Magnus Wickman, Johannes Wildhaber, Alex Möller, Bert Brunekreef, Mirian Boeve, Jeroen Douwes, Machteld Huber, Mirjam Matze Gertraud Weiss, Mynda Schreue, Karin B. Michles, Felix Sennhauser, Annika Scheynius Maija-Riitta Hirvonen, Sami Remes, Marjut Roponen, Pekka Tiittanen, Marie-Laure Dalphin, Vincent Kaulek Gisela Buchele, Markus Ege, Michael Kabesch, Petra Pfefferle, Georg Loss, Anne Hyvärinen Remo Frei, PhD, Ruth Ferstl, PhD, Caroline Roduit, PhD, Mario Ziegler, Dipl-Ing, Elisa Schiavi, PhD, Weronika Barcik, MSc, Noelia Rodriguez-Perez, PhD, Oliver F. Wirz, MSc, Marcin Wawrzyniak, PhD, Benoit Pugin, PhD, Dirk Nehrbass, PhD, Marek Jutel, MD, PhD, Sylwia Smolinska, PhD, Patrycja Konieczna, PhD, Christian Bieli, PhD, Susanne Loeliger, MLS, Marco Waser, PhD, Göran Pershagen, MD, PhD, Josef Riedler, MD, Martin Depner, PhD, Bianca Schaub, MD, Jon Genuneit, MD, Harald Renz, MD, Juha Pekkanen, MD, Anne M. Karvonen, PhD, Jean-Charles Dalphin, MD, PhD, Marianne van Hage, MD, PhD, Gert Doekes, PhD, Mübeccel Akdis, MD, Charlotte Braun-Fahrländer, MD, Cezmi A. Akdis, MD, Erika von Mutius, MD, Liam O’Mahony, PhD, Roger P. Lauener, MD Tobias Alfvén, Johan Alm, Anna Bergström, Lars Engstrand, Helen Rosenlund, Niclas Hakansson, Gunnar Lilja, Frederik Nyberg, Jackie Swartz, Magnus Wickman, Johannes Wildhaber, Alex Möller, Bert Brunekreef, Mirian Boeve, Jeroen Douwes, Machteld Huber, Mirjam Matze Gertraud Weiss, Mynda Schreue, Karin B. Michles, Felix Sennhauser, Annika Scheynius Maija-Riitta Hirvonen, Sami Remes, Marjut Roponen, Pekka Tiittanen, Marie-Laure Dalphin, Vincent Kaulek Gisela Buchele, Markus Ege, Michael Kabesch, Petra Pfefferle, Georg Loss, Anne Hyvärinen Remo Frei, PhD, Ruth Ferstl, PhD, Caroline Roduit, PhD, Mario Ziegler, Dipl-Ing, Elisa Schiavi, PhD, Weronika Barcik, MSc, Noelia Rodriguez-Perez, PhD, Oliver F. Wirz, MSc, Marcin Wawrzyniak, PhD, Benoit Pugin, PhD, Dirk Nehrbass, PhD, Marek Jutel, MD, PhD, Sylwia Smolinska, PhD, Patrycja Konieczna, PhD, Christian Bieli, PhD, Susanne Loeliger, MLS, Marco Waser, PhD, Göran Pershagen, MD, PhD, Josef Riedler, MD, Martin Depner, PhD, Bianca Schaub, MD, Jon Genuneit, MD, Harald Renz, MD, Juha Pekkanen, MD, Anne M. Karvonen, PhD, Jean-Charles Dalphin, MD, PhD, Marianne van Hage, MD, PhD, Gert Doekes, PhD, Mübeccel Akdis, MD, Charlotte Braun-Fahrländer, MD, Cezmi A. Akdis, MD, Erika von Mutius, MD, Liam O’Mahony, PhD, Roger P. Lauener, MD Tobias Alfvén, Johan Alm, Anna Bergström, Lars Engstrand, Helen Rosenlund, Niclas Hakansson, Gunnar Lilja, Frederik Nyberg, Jackie Swartz, Magnus Wickman, Johannes Wildhaber, Alex Möller, Bert Brunekreef, Mirian Boeve, Jeroen Douwes, Machteld Huber, Mirjam Matze Gertraud Weiss, Mynda Schreue, Karin B. Michles, Felix Sennhauser, Annika Scheynius Maija-Riitta Hirvonen, Sami Remes, Marjut Roponen, Pekka Tiittanen, Marie-Laure Dalphin, Vincent Kaulek Gisela Buchele, Markus Ege, Michael Kabesch, Petra Pfefferle, Georg Loss, Anne Hyvärinen Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 382-390.e7 (January 2018) DOI: 10.1016/j.jaci.2017.04.051 Copyright © 2017 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 382-390 Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig 1 Association between anti-Neu5Gc IgG levels in tertiles and wheeze or asthma. A, Cross-sectional PARSIFAL study (school-aged children): adjusted odds ratio for the incidence of asthma or wheezing of tertiles of anti-Neu5Gc IgG levels related to the lowest tertile as reference. B, Longitudinal PASTURE birth cohort (at age of 6 years): adjusted odds ratio for the incidence of nonatopic asthma or wheezing of tertiles of anti-Neu5Gc IgG levels related to the lowest tertile as reference. Odds ratios are adjusted for farming status, center, atopic parents, and sex. Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Oral application of Neu5Gc to CMAH-deficient mice reduced the severity of airway inflammation. A, Airway resistance in response to increasing doses of methacholine. B, Total and differential cell counts in BAL fluid. C, Representative hematoxylin and eosin (H&E)–stained lung tissue. D, Representative periodic acid–Schiff (PAS)–stained lung tissue. E, Quantification of IL-17 secretion by lung CD3+/CD4+ T helper cells. F, Quantification of lung CD25+Foxp3+ Treg cells and their IL-10 secretion. Each dot represents an individual animal. Data were assessed in 4 (ovalbumin model) and 4 (house dust mite model) independent experiments (means and SEMs). Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neut, neutrophils. Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Oral application of Neu5Gc reduced the severity of colitis in SCID mice. A, Symptom score. B, Body weight. C, Weight/length ratio of the colon. D, Quantification of IL-17 secretion by mesenteric lymph node CD3+/CD4+ T helper cells. E, Quantification of mesenteric lymph node CD25+Foxp3+ Treg cells and their IL-10 secretion. Each dot represents an individual animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Neu5Gc induces a regulatory phenotype in dendritic cells and leads to less IL-17–producing T helper cells and induction of Treg cells in T helper cell–dendritic cell cocultures. A, Expression of indoleamine 2,3-dioxygenase (IDO) and retinaldehyde dehydrogenase 2 (RALDH2) genes and secretion of IL-10 by human monocyte-derived dendritic cells stimulated with Neu5Gc. B, IL-17 production of T helper cells. C, Quantification of CD25+Foxp3+ Treg cells and their IL-10 secretion. Each dot represents an individual donor/animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Short-term oral application of Neu5Gc to CMAH-deficient mice did not reduce the severity of airway inflammation. Total and differential cell counts in BAL fluid. Each dot represents an individual animal. Data were assessed in 1 experiment (mean and SEMs). Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neut, neutrophils. Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Oral application of Neu5Gc to CMAH-deficient mice reduced the severity of airway inflammation in a model using ovalbumin as an allergen. A, Quantification of cytokine secretion by lung CD3+/CD4+ T helper cells. B, Quantification of total and ovalbumin-specific IgE in sera. Each dot represents an individual animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Oral application of Neu5Gc to CMAH-deficient mice reduced the severity of airway inflammation in a model using house dust mite as an allergen. A, Quantification of cytokine secretion by lung CD3+/CD4+ T helper cells. B, Quantification of lung CD25+Foxp3+ Treg cell subsets and their IL-10 secretion. C, Quantification of total IgE and house dust mite–specific IgG1 in sera. Each dot represents an individual animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig E4 Oral application of Neu5Gc to wild-type mice reduced the severity of airway inflammation in a model using house dust mite as an allergen. A, Airway resistance in response to increasing doses of methacholine. Eos, Eosinophils; Lymph, lymphocytes; Mac, macrophages; Neut, neutrophils. B, Total and differential cell counts in BAL fluid. C, Quantification of cytokine secretion by lung CD3+/CD4+ T helper cells. D, Quantification of lung CD25+Foxp3+ Treg cells and their IL-10 secretion. Each dot represents an individual animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions

Fig E5 Oral application of Neu5Gc prevented the onset of colitis in SCID mice. A, Quantification of cytokine secretion by mesenteric lymph node CD3+CD4+ T helper cells. B, Representative hematoxylin and eosin (H&E)–stained gut tissue. Each dot represents an individual animal. Data were assessed in 2 independent experiments (means and SEMs). Journal of Allergy and Clinical Immunology 2018 141, 382-390.e7DOI: (10.1016/j.jaci.2017.04.051) Copyright © 2017 The Authors Terms and Conditions