The false alarm hypothesis: Food allergy is associated with high dietary advanced glycation end-products and proglycating dietary sugars that mimic alarmins
Authors: Peter K. Smith, Madhan Masilamani, Xiu-Min Li, Hugh A. Sampson
Journal: Journal of Allergy and Clinical Immunology (2016)

Current hypotheses and models of food allergy do not adequately explain the dramatic increase in food allergy in westernized countries in the last 30 years. Dietary AGEs and AGE-forming sugars might be the missing link, and this hypothesis is supported by geographic and regional consumption and patterns of allergy appearing to match AGE consumption, fetal exposure to higher AGE levels in late pregnancy being associated with an increased incidence of atopic dermatitis and food sensitization, and allergy-protective microbiota interventional animal models and in vitro data on the effect of AGEs and activation of the RAGE receptor. The supporting materials discussed in this article are presented in Table I, ∗References 24Bianchi M.E. DAMPs, PAMPs and alarmins: all we need to know about danger.J Leukoc Biol. 2007; 81: 1-5Crossref PubMed Scopus (1258) Google Scholar, 25Dumitriu I.E. Baruah P. Valentinis B. Voll R.E. Herrmann M. 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Global findings from the International Study of Asthma and Allergies in Childhood (ISAAC) phase three.Thorax. 2013; 68: 351-360Crossref PubMed Scopus (48) Google Scholar, 115Thornley S. Stewart A. Marshall R. Jackson R. Per capita sugar consumption is associated with severe childhood asthma: an ecological study of 53 countries.Prim Care Respir J. 2011; 20: 75-78Crossref PubMed Scopus (0) Google Scholar, 116DeChristopher L.R. Uribarri J. Tucker K.L. Intakes of apple juice, fruit drinks and soda are associated with prevalent asthma in US children aged 2-9 years.Public Health Nutr. 2016; 19: 123-130Crossref PubMed Scopus (0) Google Scholar. and key points are provided in Table II, which provides credence to but does not prove a false alarmin hypothesis caused by dietary changes in the Western world. This theory integrates knowledge of the effects of the hygiene hypothesis and nutritional aspects. Proof needs to be established of the biological relevance of dietary AGEs on immune responses with prospective epidemiologic and observational studies and specific laboratory research both in vivo and in vitro.Table IEvidence supporting the false alarm hypothesisEvidence supporting the false alarm hypothesisReferenceAlarmins, AGE, and RAGE1.In vitro dataA.DCsI.Require HMGB1 for maturation and migrationII.Release HMGB1 when signaling antigenB.T-cell activationI.Requires DC HMGB1 (or AGE) to activate, proliferate, and migrateC.DNAI.HMGB1 and AGEs cause DNA damage and dysfunctionD.Mast cellsI.RAGE ligation causes mast cell activation and release of histamine and oxidative mediatorsE.Bacterial evidenceI.Lactobacillus species make glyoxalaseII.Escherichia coli produces AGEs that contribute to inflammationIII.High-AGE diet does not favor probiotic flora2.In vivo animal model studiesA.Glycation reduction compounds blocking the development of food allergyB.RAGE knockout reduced response to allergens24Bianchi M.E. DAMPs, PAMPs and alarmins: all we need to know about danger.J Leukoc Biol. 2007; 81: 1-5Crossref PubMed Scopus (1258) Google Scholar, 26Price C.L. Sharp P.S. North M.E. Rainbow S.J. Knight S.C. Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells.Diabetes. 2004; 53: 1452-1458Crossref PubMed Scopus (0) Google Scholar, 27Ge J. Jia Q. Liang C. Luo Y. Huang D. Sun A. et al.Advanced glycosylation end products might promote atherosclerosis through inducing the immune maturation of dendritic cells.Arterioscler Thromb Vasc Biol. 2005; 25: 2157-2163Crossref PubMed Scopus (0) Google Scholar, 28Agresti A. Bianchi M.E. HMGB proteins and gene expression.Curr Opin Genet Dev. 2003; 13: 170-178Crossref PubMed Scopus (246) Google Scholar, 50Manfredi A.A. Capobianco A. Esposito A. De Cobelli F. Canu T. Monno A. et al.Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes.J Immunol. 2008; 180: 2270-2275Crossref PubMed Google Scholar24Bianchi M.E. DAMPs, PAMPs and alarmins: all we need to know about danger.J Leukoc Biol. 2007; 81: 1-5Crossref PubMed Scopus (1258) Google Scholar25Dumitriu I.E. Baruah P. Valentinis B. Voll R.E. Herrmann M. Nawroth P.P. et al.Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products.J Immunol. 2005; 174: 7506-7515Crossref PubMed Google Scholar42Yim H.S. Kang S.O. Hah Y.C. Chock P.B. Yim M.B. Free radicals generated during the glycation reaction of amino acids by methylglyoxal. A model study of protein-cross-linked free radicals.J Biol Chem. 1995; 270: 28228-28233Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Kang J.H. Oxidative damage of DNA induced by methylglyoxal in vitro.Toxicol Lett. 2003; 145: 181-187Crossref PubMed Scopus (0) Google Scholar, 45Kalapos M.P. The tandem of free radicals and methylglyoxal.Chem Biol Interact. 2008; 171: 251-271Crossref PubMed Scopus (111) Google Scholar49Sick E. Brehin S. Andre P. Coupin G. Landry Y. Takeda K. et al.Advanced glycation end products (AGEs) activate mast cells.Br J Pharmacol. 2010; 161: 442-455Crossref PubMed Scopus (0) Google Scholar92Kant R. Blom J. Palva A. Siezen R.J. de Vos W.M. Comparative genomics of Lactobacillus.Microb Biotechnol. 2011; 4: 323-332Crossref PubMed Scopus (0) Google Scholar97Cohen-Or I. Katz C. Ron E.Z. AGEs secreted by bacteria are involved in the inflammatory response.PLoS One. 2011; 6: e17974Crossref PubMed Scopus (0) Google Scholar98Mills D.J. Tuohy K.M. Booth J. Buck M. Crabbe M.J. Gibson G.R. et al.Dietary glycated protein modulates the colonic microbiota towards a more detrimental composition in ulcerative colitis patients and non-ulcerative colitis subjects.J Appl Microbiol. 2008; 105: 706-714Crossref PubMed Scopus (0) Google Scholar103Okada Y. Oh-oka K. Nakamura Y. Ishimaru K. Matsuoka S. Okumura K. et al.Dietary resveratrol prevents the development of food allergy in mice.PLoS One. 2012; 7: e44338Crossref PubMed Scopus (22) Google Scholar, 104Masilamani M. Wei J. Bhatt S. Paul M. Yakir S. Sampson H.A. Soybean isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut.J Allergy Clin Immunol. 2011; 128: 1242-1250.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar37Milutinovic P.S. Alcorn J.F. Englert J.M. Crum L.T. Oury T.D. The receptor for advanced glycation end products is a central mediator of asthma pathogenesis.Am J Pathol. 2012; 181: 1215-1225Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 38Oczypok E.A. Milutinovic P.S. Alcorn J.F. Khare A. Crum L.T. Manni M.L. et al.Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells.J Allergy Clin Immunol. 2015; 136: 747-756.e4Abstract Full Text Full Text PDF PubMed Scopus (9) Google ScholarWestern diet high in AGEs can induce alarmin signaling1.Epidemiologic studies: increased rate of food allergy and anaphylaxisA.Association with:I.Australian and US fast food outletsII.US sugar consumption∗Australia has similar patterns of consumption of sugar and fructose to the United States.III.US fructose consumption∗Australia has similar patterns of consumption of sugar and fructose to the United States.B.Increased food allergy inI.Urban vs rural areas (less consumption of AGEs/sugar in rural areas)II.Urban food deserts2.Observational studiesIncreased eczema and food sensitization in offspring of mothers with gestational diabetes3.Allergic march dataA.Association of asthma with sugar intake in early lifeB.Association of asthma with excess free fructose from fruit juices and soft drinks in 2- to 9-year-oldsC.Association with asthma, rhinoconjunctivitis, and eczema with fast food and protection with healthy eating (fruit and vegetables)Current paper87Steyn N.P. Myburgh N.G. Nel J.H. Evidence to support a food-based dietary guideline on sugar consumption in South Africa.Bull World Health Org. 2003; 81: 599-608PubMed Google Scholar, 88McNaughton S, Crawford D, Campbell K, Abbott G, Ball K. Eating behaviours of urban and rural children from disadvantaged backgrounds. Deakin University. Available at: https://www.deakin.edu.au/__data/assets/pdf_file/0017/307007/book-6.pdf. Accessed July 28, 2016.Google Scholar90Humphrey A.L. Wilson B.C. Reddy M. Shroba J.A. Ciaccio C.E. An association between pediatric food allergy and food deserts [abstract].J Allergy Clin Immunol. 2015; 135: AB255Abstract Full Text Full Text PDF Google Scholar78Kumar R. Ouyang F. Story R.E. Pongracic J.A. Hong X. Wang G. et al.Gestational diabetes, atopic dermatitis, and allergen sensitization in early childhood.J Allergy Clin Immunol. 2009; 124 (e1-4): 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar115Thornley S. Stewart A. Marshall R. Jackson R. Per capita sugar consumption is associated with severe childhood asthma: an ecological study of 53 countries.Prim Care Respir J. 2011; 20: 75-78Crossref PubMed Scopus (0) Google Scholar116DeChristopher L.R. Uribarri J. Tucker K.L. Intakes of apple juice, fruit drinks and soda are associated with prevalent asthma in US children aged 2-9 years.Public Health Nutr. 2016; 19: 123-130Crossref PubMed Scopus (0) Google Scholar69Robertson C.F. Roberts M.F. Kappers J.H. Asthma prevalence in Melbourne schoolchildren: have we reached the peak?.Med J Aust. 2004; 180: 273-276PubMed Google Scholar, 111Ellwood P. Asher M.I. Bjorksten B. Burr M. Pearce N. Robertson C.F. Diet and asthma, allergic rhinoconjunctivitis and atopic eczema symptom prevalence: an ecological analysis of the International Study of Asthma and Allergies in Childhood (ISAAC) data. ISAAC Phase One Study Group.Eur Respir J. 2001; 17: 436-443Crossref PubMed Scopus (0) Google Scholar, 112Nagel G. Weinmayr G. Kleiner A. Garcia-Marcos L. Strachan D.P. Effect of diet on asthma and allergic sensitisation in the International Study on Allergies and Asthma in Childhood (ISAAC) Phase Two.Thorax. 2010; 65: 516-522Crossref PubMed Scopus (0) Google Scholar, 113Ellwood P. Asher M.I. Garcia-Marcos L. Williams H. Keil U. Robertson C. et al.Do fast foods cause asthma, rhinoconjunctivitis and eczema? Global findings from the International Study of Asthma and Allergies in Childhood (ISAAC) phase three.Thorax. 2013; 68: 351-360Crossref PubMed Scopus (48) Google ScholarIn vitro studies and epidemiologic, statistical, and clinical data add to the understanding of the known mechanisms that have been associated with food allergy.∗ Australia has similar patterns of consumption of sugar and fructose to the United States. Open table in a new tab Table IIKey points1. HMBG1 is a major alarmin that promotes TH2 responses and appears critical for directing antigen responses.2. HMBG1 binds to RAGE.3. HMGB1/RAGE alarmin signaling is critical for allergic reactions.4. Western diet high in AGEs can induce alarmin signaling.5. Western diet has the potential to mimic tissue damage through glycation/AGEs.6. Mitigation of AGE-induced reactions are beneficial.7. We hypothesize that a diet high in AGEs can mimic innate alarms and skew toward allergic responses in genetic and environmentally predisposed subjects. Open table in a new tab