Journal Article
. 2020 May; 21(9):.
doi: 10.3390/ijms21093205.

Mechanisms of Wheat Allergenicity in Mice: Comparison of Adjuvant-Free vs. Alum-Adjuvant Models

Yining Jin 1 Haoran Gao 1 Rick Jorgensen 1 Jillian Salloum 1 Dan Ioan Jian 1 Perry K W Ng 2 Venugopal Gangur 1 
  • PMID: 32369940
  •     72 References


Wheat protein is considered a major type of food allergen in many countries including the USA. The mechanisms of allergenicity of wheat proteins are not well understood at present. Both adjuvant-based and adjuvant-free mouse models are reported for this food allergy. However, it is unclear whether the mechanisms underlying wheat allergenicity in these two types of models are similar or different. Therefore, we compared the molecular mechanisms in a novel adjuvant-free (AF) model vs. a conventional alum-adjuvant (AA) model of wheat allergy using salt-soluble wheat protein (SSWP). In the AF model, Balb/cJ mice were sensitized with SSWP via skin exposure. In the AA model, mice were sensitized by an intraperitoneal injection of SSWP with alum. In both models, allergic reactions were elicited using an identical protocol. Robust IgE as well as mucosal mast cell protein-1 responses were elicited similarly in both models. However, an analysis of the spleen immune markers identified strikingly different molecular activation patterns in these two models. Furthermore, a number of immune markers associated with intrinsic allergenicity were also identified in both models. Since the AF model uses skin exposure without an adjuvant, the mechanisms in the AF model may more closely simulate the human wheat allergenicity mechanisms from skin exposure in occupational settings such as in the baking industry.

Keywords: adjuvant; food allergy; food safety; immune markers; intrinsic allergenicity; mouse model; risk assessment; skin sensitization; wheat allergy; wheat protein allergenicity.

Racial Differences in Food Allergy Phenotype and Health Care Utilization among US Children.
Mahboobeh Mahdavinia, Susan R Fox, +7 authors, Ruchi S Gupta.
J Allergy Clin Immunol Pract, 2016 Nov 27; 5(2). PMID: 27888035    Free PMC article.
Evaluation of reduced allergenicity of deamidated gliadin in a mouse model of wheat-gliadin allergy using an antibody prepared by a peptide containing three epitopes.
Ryosuke Abe, Shiori Shimizu, +6 authors, Hitomi Kumagai.
J Agric Food Chem, 2014 Mar 13; 62(13). PMID: 24617642
Masked type I wheat allergy. Relation to exercise-induced anaphylaxis.
H Kushimoto, T Aoki.
Arch Dermatol, 1985 Mar 01; 121(3). PMID: 3977357
Integrins in pulmonary inflammatory diseases.
S Bazan-Socha, A Bukiej, C Marcinkiewicz, J Musial.
Curr Pharm Des, 2005 Mar 22; 11(7). PMID: 15777242
An adjuvant-free mouse model to evaluate the allergenicity of milk whey protein.
B Gonipeta, S Parvataneni, R J Tempelman, V Gangur.
J Dairy Sci, 2009 Sep 19; 92(10). PMID: 19762789
Wheat-dependent exercise-induced anaphylaxis in mice is caused by gliadin and glutenin treatments.
Hana Kozai, Hiromi Yano, Tsukasa Matsuda, Yasuko Kato.
Immunol Lett, 2005 Sep 13; 102(1). PMID: 16154206
A murine model of peanut anaphylaxis: T- and B-cell responses to a major peanut allergen mimic human responses.
X M Li, D Serebrisky, +7 authors, H A Sampson.
J Allergy Clin Immunol, 2000 Jul 11; 106(1 Pt 1). PMID: 10887318
CTLA-4 signaling regulates the intensity of hypersensitivity responses to food antigens, but is not decisive in the induction of sensitization.
Femke van Wijk, Sanne Hoeks, +5 authors, Raymond Pieters.
J Immunol, 2004 Dec 22; 174(1). PMID: 15611239
The economic impact of childhood food allergy in the United States.
Ruchi Gupta, David Holdford, +3 authors, David Meltzer.
JAMA Pediatr, 2013 Sep 18; 167(11). PMID: 24042236
Highly Cited.
Th17 cells are not required for maintenance of IL-17A-producing γδ T cells in vivo.
Pawan K Gupta, Sarah R Wagner, Qiang Wu, Rebecca A Shilling.
Immunol Cell Biol, 2016 Sep 22; 95(3). PMID: 27649780    Free PMC article.
Cellular and noncellular bloodborne biomarkers in asthma.
Hannah Sinz, Harald Renz, Chrysanthi Skevaki.
Ann Allergy Asthma Immunol, 2017 Jun 07; 118(6). PMID: 28583261
Rhinoconjunctival sensitization to hydrolyzed wheat protein in facial soap can induce wheat-dependent exercise-induced anaphylaxis.
Yuma Fukutomi, Yasuharu Itagaki, +6 authors, Kazuo Akiyama.
J Allergy Clin Immunol, 2010 Nov 26; 127(2). PMID: 21094523
Cytokines and Chemokines as Biomarkers of Future Asthma.
Andrew Bush.
Front Pediatr, 2019 Apr 04; 7. PMID: 30941335    Free PMC article.
C-reactive protein and lung diseases.
Marianna Agassandian, Galina V Shurin, Yang Ma, Michael R Shurin.
Int J Biochem Cell Biol, 2014 May 24; 53. PMID: 24853773
Food-dependent exercise-induced anaphylaxis in childhood.
George Du Toit.
Pediatr Allergy Immunol, 2007 Jul 10; 18(5). PMID: 17617816
Public perception of food allergy.
D R Altman, L T Chiaramonte.
J Allergy Clin Immunol, 1996 Jun 01; 97(6). PMID: 8648020
Long-term characteristics of hazelnut allergy in an adjuvant-free mouse model.
Babu Gonipeta, Sitaram Parvataneni, Pranati Paruchuri, Venu Gangur.
Int Arch Allergy Immunol, 2010 Feb 11; 152(3). PMID: 20145410    Free PMC article.
Wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat protein in soap.
Yuko Chinuki, Eishin Morita.
Allergol Int, 2012 Oct 25; 61(4). PMID: 23093796
Food allergy.
Harald Renz, Katrina J Allen, +4 authors, Hans C Oettgen.
Nat Rev Dis Primers, 2018 Jan 05; 4. PMID: 29300005
Highly Cited. Review.
Prevalence of self-reported food allergy in American adults and use of food labels.
Katherine A Vierk, Kathleen M Koehler, Sara B Fein, Debra A Street.
J Allergy Clin Immunol, 2007 Apr 25; 119(6). PMID: 17451802
Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis.
Marat V Khodoun, Richard Strait, +2 authors, Fred D Finkelman.
Proc Natl Acad Sci U S A, 2011 Jul 13; 108(30). PMID: 21746933    Free PMC article.
Evaluation of the prevalence of antiwheat-, anti-flour dust, and anti-alpha-amylase specific IgE antibodies in US blood donors.
Raymond E Biagini, Barbara A MacKenzie, +4 authors, John E Snawder.
Ann Allergy Asthma Immunol, 2004 Jul 09; 92(6). PMID: 15239172
Integrins as Therapeutic Targets for Respiratory Diseases.
C M Teoh, S S L Tan, T Tran.
Curr Mol Med, 2015 Sep 24; 15(8). PMID: 26391549    Free PMC article.
C5a receptor 1-/- mice are protected from the development of IgE-mediated experimental food allergy.
Anna Kordowski, Anna T Reinicke, +7 authors, Jörg Köhl.
Allergy, 2018 Oct 21; 74(4). PMID: 30341777
Hydrolysed wheat proteins present in cosmetics can induce immediate hypersensitivities.
Michel Laurière, Catherine Pecquet, +4 authors, Martine Vigan.
Contact Dermatitis, 2006 May 13; 54(5). PMID: 16689814
Are chemokines essential or secondary participants in allergic responses?
V Gangur, J J Oppenheim.
Ann Allergy Asthma Immunol, 2000 Jun 30; 84(6). PMID: 10875484
A molecular insight of CTLA-4 in food allergy.
Sandeep Kumar, Alok Kumar Verma, Mukul Das, Premendra D Dwivedi.
Immunol Lett, 2012 Dec 21; 149(1-2). PMID: 23254121
The dog as a model for food allergy.
Bob B Buchanan, Oscar L Frick.
Ann N Y Acad Sci, 2002 May 23; 964. PMID: 12023204
Severe allergic reaction to gluten hydrolysate without reaction to wheat.
Anna S Pelkonen, Soili Mäkinen-Kiljunen, +2 authors, Mika J Mäkelä.
Ann Allergy Asthma Immunol, 2011 Apr 05; 106(4). PMID: 21457885
Development of an adjuvant-free cashew nut allergy mouse model.
Sitaram Parvataneni, Babu Gonipeta, Robert J Tempelman, Venu Gangur.
Int Arch Allergy Immunol, 2009 Mar 20; 149(4). PMID: 19295233
IgE and IgA produced by OX40-OX40L or CD40-CD40L interaction in B cells-mast cells re-activate FcεRI or FcαRI on mast cells in mouse allergic asthma.
Gwan Ui Hong, Ji Yeun Lim, +2 authors, Jai Youl Ro.
Eur J Pharmacol, 2015 Feb 24; 754. PMID: 25704619
An Animal Model for Wheat Allergy Skin Sensitisation: A Comparative Study in Naive versus Tolerant Brown Norway Rats.
Anne-Sofie Ravn Ballegaard, Charlotte Bernhard Madsen, Katrine Lindholm Bøgh.
Int Arch Allergy Immunol, 2018 Dec 06; 178(2). PMID: 30517928    Free PMC article.
Prevalence of sensitization to food allergens in adult Swedes.
E Björnsson, C Janson, +2 authors, O Sjöberg.
Ann Allergy Asthma Immunol, 1996 Oct 01; 77(4). PMID: 8885811
Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management.
Scott H Sicherer, Hugh A Sampson.
J Allergy Clin Immunol, 2017 Nov 22; 141(1). PMID: 29157945
Highly Cited. Review.
Do ancient types of wheat have health benefits compared with modern bread wheat?
Peter R Shewry.
J Cereal Sci, 2018 Mar 03; 79. PMID: 29497244    Free PMC article.
Mouse models of food allergy: how well do they simulate the human disorder?
Babu Gonipeta, Eunjung Kim, Venu Gangur.
Crit Rev Food Sci Nutr, 2014 Jun 11; 55(3). PMID: 24915373
Prevalence of food allergies in young adults and their relationship to asthma, nasal allergies, and eczema.
Rosalie K Woods, Frank Thien, +2 authors, Michael Abramson.
Ann Allergy Asthma Immunol, 2002 Mar 01; 88(2). PMID: 11868923
Sensitization and elicitation of an allergic reaction to wheat gliadins in mice.
M Bodinier, M Leroy, +5 authors, K Adel-Patient.
J Agric Food Chem, 2009 Jan 28; 57(4). PMID: 19170508
Wheat-dependent exercise-induced anaphylaxis.
K A Scherf, K Brockow, +2 authors, H Wieser.
Clin Exp Allergy, 2015 Sep 19; 46(1). PMID: 26381478
An adjuvant-free mouse model of tree nut allergy using hazelnut as a model tree nut.
Neil Patrick Birmingham, Sitaram Parvataneni, +5 authors, Venu Gangur.
Int Arch Allergy Immunol, 2007 Jun 16; 144(3). PMID: 17570928
T lymphocytes in food allergy: overview of an intricate network of circulating and organ-resident cells.
Philippe A Eigenmann.
Pediatr Allergy Immunol, 2002 Jul 30; 13(3). PMID: 12144637
Wheat gliadins modified by deamidation are more efficient than native gliadins in inducing a Th2 response in Balb/c mice experimentally sensitized to wheat allergens.
Pascal Gourbeyre, Sandra Denery-Papini, +3 authors, Marie Bodinier.
Mol Nutr Food Res, 2011 Dec 08; 56(2). PMID: 22147540
Allergic and anaphylactic response to sesame seeds in mice: identification of Ses i 3 and basic subunit of 11s globulins as allergens.
Lalitha Navuluri, Sitaram Parvataneni, +3 authors, Venu Gangur.
Int Arch Allergy Immunol, 2006 May 16; 140(3). PMID: 16699288
Murine model of atopic dermatitis associated with food hypersensitivity.
X M Li, G Kleiner, +4 authors, H A Sampson.
J Allergy Clin Immunol, 2001 Apr 11; 107(4). PMID: 11295660
Development and validation of a mouse-based primary screening method for testing relative allergenicity of proteins from different wheat genotypes.
Haoran Gao, Yining Jin, +3 authors, Venu Gangur.
J Immunol Methods, 2018 Nov 06; 464. PMID: 30395814
Sensitization to airborne and food allergens in Reykjavík (Iceland) and Uppsala (Sweden) - a comparative study.
D Gislason, E Björnsson, +4 authors, G Boman.
Allergy, 1999 Dec 22; 54(11). PMID: 10604551
CCR3 and CXCR3 as drug targets for allergy: principles and potential.
Venu Gangur, Neil P Birmingham, Sirinart Thanesvorakul, Shama Joseph.
Curr Drug Targets Inflamm Allergy, 2003 Oct 17; 2(1). PMID: 14561176
The prevalence, severity, and distribution of childhood food allergy in the United States.
Ruchi S Gupta, Elizabeth E Springston, +4 authors, Jane L Holl.
Pediatrics, 2011 Jun 22; 128(1). PMID: 21690110
Highly Cited.
The prevalence of food hypersensitivity in an unselected population of children and adults.
M Osterballe, T K Hansen, +2 authors, C Bindslev-Jensen.
Pediatr Allergy Immunol, 2005 Oct 22; 16(7). PMID: 16238581
Characterization of a hypoallergenic wheat line lacking ω-5 gliadin.
Kunie Kohno, Hitoshi Takahashi, +3 authors, Eishin Morita.
Allergol Int, 2016 Apr 23; 65(4). PMID: 27103182
An Adjuvant-Free Mouse Model of Transdermal Sensitization and Oral Elicitation of Anaphylaxis to Shellfish.
Sitaram Parvataneni, Babu Gonipeta, Harini G Acharya, Venu Gangur.
Int Arch Allergy Immunol, 2016 Feb 20; 168(4). PMID: 26895004
Food-dependent exercise-induced anaphylaxis--update and current data.
E Beaudouin, J M Renaudin, +3 authors, D A Moneret-Vautrin.
Eur Ann Allergy Clin Immunol, 2006 May 23; 38(2). PMID: 16711535
Immunoglobulin-E-binding epitopes of wheat allergens in patients with food allergy to wheat and in mice experimentally sensitized to wheat proteins.
S Denery-Papini, M Bodinier, +9 authors, D Kasarda.
Clin Exp Allergy, 2011 Jul 21; 41(10). PMID: 21771117
Novel Bread Wheat Lines Enriched in Carotenoids Carrying Hordeum chilense Chromosome Arms in the ph1b Background.
María-Dolores Rey, María-Carmen Calderón, +3 authors, Pilar Prieto.
PLoS One, 2015 Aug 05; 10(8). PMID: 26241856    Free PMC article.
Impact of ω-5 gliadin on wheat-dependent exercise-induced anaphylaxis in mice.
Mamoru Tanaka, Takao Nagano, +4 authors, Yasuko Kato.
Biosci Biotechnol Biochem, 2011 Feb 11; 75(2). PMID: 21307596
Identification of Soluble Mediators in IgG-Mediated Anaphylaxis via Fcγ Receptor: A Meta-Analysis.
Audrey Siew Foong Kow, Azirah Chik, +3 authors, Chau Ling Tham.
Front Immunol, 2019 Feb 28; 10. PMID: 30809224    Free PMC article.
Oral food challenge to wheat: a near-fatal anaphylaxis and review of 93 food challenges in children.
Antonella Cianferoni, Karishma Khullar, +4 authors, Jonathan M Spergel.
World Allergy Organ J, 2013 Aug 24; 6(1). PMID: 23965733    Free PMC article.
Wheat allergy: diagnosis and management.
Antonella Cianferoni.
J Asthma Allergy, 2016 Feb 19; 9. PMID: 26889090    Free PMC article.
Allergenicity Assessment of Transgenic Wheat Lines In Silico.
Ankita Mishra, Naveen Arora.
Methods Mol Biol, 2017 Sep 16; 1679. PMID: 28913796
Genetic and biochemical markers of obstructive lung disease in the general population.
Morten Dahl.
Clin Respir J, 2010 Mar 20; 3(2). PMID: 20298391
A Mouse Model of Anaphylaxis and Atopic Dermatitis to Salt-Soluble Wheat Protein Extract.
Yining Jin, Sarah Ebaugh, +4 authors, Venu Gangur.
Int Arch Allergy Immunol, 2017 Sep 28; 174(1). PMID: 28950276
Characterization of causative allergens for wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat proteins in facial soap.
Tomoharu Yokooji, Saki Kurihara, +8 authors, Hiroaki Matsuo.
Allergol Int, 2013 Aug 22; 62(4). PMID: 23963475
Effect of extrusion processing on immune activation properties of hazelnut protein in a mouse model.
Tina Ortiz, Radhakrishna Para, +5 authors, Venu Gangur.
Int J Food Sci Nutr, 2016 Jun 03; 67(6). PMID: 27251648
Innate and adaptive type 2 immunity in lung allergic inflammation.
Masato Kubo.
Immunol Rev, 2017 Jun 29; 278(1). PMID: 28658559
Highly Cited. Review.
An ELISA-based method for measurement of food-specific IgE antibody in mouse serum: an alternative to the passive cutaneous anaphylaxis assay.
Neil Birmingham, Sandhya Payankaulam, +3 authors, Venu Gangur.
J Immunol Methods, 2003 Apr 02; 275(1-2). PMID: 12667673
Assessment of the sensitizing potential of processed peanut proteins in Brown Norway rats: roasting does not enhance allergenicity.
Stine Kroghsbo, Neil M Rigby, +5 authors, Charlotte B Madsen.
PLoS One, 2014 May 09; 9(5). PMID: 24805813    Free PMC article.
Sensitization to acid-hydrolyzed wheat protein by transdermal administration to BALB/c mice, and comparison with gluten.
R Adachi, R Nakamura, +2 authors, R Teshima.
Allergy, 2012 Sep 22; 67(11). PMID: 22994386
Thioredoxin-linked mitigation of allergic responses to wheat.
B B Buchanan, C Adamidi, +5 authors, O L Frick.
Proc Natl Acad Sci U S A, 1997 May 13; 94(10). PMID: 9144244    Free PMC article.
Polydesensitisation with reducing elevated serum total IgE by IFN-gamma therapy in atopic dermatitis: IFN-gamma and polydesensitisation (PDS).
Jae Ho Lee, Geunwoong Noh.
Cytokine, 2013 Jun 22; 64(1). PMID: 23786862
IL-10 is critical for Th2 responses in a murine model of allergic dermatitis.
Dhafer Laouini, Harri Alenius, +3 authors, Raif S Geha.
J Clin Invest, 2003 Oct 03; 112(7). PMID: 14523043    Free PMC article.
IL-25 in allergic inflammation.
Miao Xu, Chen Dong.
Immunol Rev, 2017 Jun 29; 278(1). PMID: 28658555
Advances in Molecular Mechanisms of Wheat Allergenicity in Animal Models: A Comprehensive Review.
Yining Jin, Harini G Acharya, +5 authors, Venugopal Gangur.
Molecules, 2019 Mar 27; 24(6). PMID: 30909404    Free PMC article.