Innate immunostimulatory properties of allergens and their relevance to food allergy

Ruiter, Bert; Shreffler, Wayne G.

doi:10.1007/s00281-012-0334-8

Cited by 47Food Allergy and Anaphylaxis ResearchIL-33, ST2, and ILC PathwaysAsthma and respiratory diseases

Innate immunostimulatory properties of allergens and their relevance to food allergy

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Ruiter, Bert, Shreffler, Wayne G.·2012·Seminars in Immunopathology

DOI 10.1007/s00281-012-0334-8PMC PMC3459673

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Abstract

Food allergy is an increasingly prevalent disease of immune dysregulation directed to a small subset of proteins. Shared structural and functional features of allergens, such as glycosylation, lipid-binding and protease activity may provide insight into the mechanisms involved in the induction of primary Th2 immune responses. We review the literature of innate Th2-type immune activation as a context for better understanding the properties of allergens that contribute to the induction of Th2-biased immune responses in at least a subset of individuals. Th2-priming signals have been largely identified in the context of parasite immunity and wound healing. Some of the features of parasite antigens and the innate immune responses to them are now understood to play a role in allergic inflammation as well. These include both exogenous and endogenous activators of innate immunity and subsequent release of key cytokine mediators such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33. Moreover, numerous innate immune cells including epithelium, dendritic cells, basophils, innate lymphoid cells and others all interact to shape the adaptive Th2 immune response. Progress toward understanding Th2-inducing innate immune signals more completely may lead to novel strategies for primary prevention and therapy of respiratory and food allergies.

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Glycosylation is a common feature of many food allergens, and glycans may enhance immunogenicity through activation of innate Th2 responses.
“the fact that glycosylation is a common feature to many food allergens has prompted investigations that showed that glycans may enhance immunogenicity through the activation of innate Th2 responses [10].”
From Influence of the Carbohydrate Moieties on the Immunoreactivity and Digestibility of the Egg Allergen Ovomucoid (2013) · cites this paper as [10]

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Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes
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Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines
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Cutting Edge: IPSE/alpha-1, a Glycoprotein from Schistosoma mansoni Eggs, Induces IgE-Dependent, Antigen-Independent IL-4 Production by Murine Basophils In Vivo
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The proteolytic activity of the major dust mite allergen Der p 1 conditions dendritic cells to produce less interleukin‐12: allergen‐induced Th2 bias determined at the dendritic cell level
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What makes a food protein an allergen?
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Glucocorticoids drive human CD8+ T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production
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Peanuts can contribute to anaphylactic shock by activating complement
Khodoun, M. V., Strait, R. T., Orekov, T., Hogan, S. P., Karasuyama, H., Herbert, D. R., Köhl, J., & Finkelman, F. D. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2008.11.004 · Cited by 132 · cited 1× · see citing works
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New insights into innate immune mechanisms underlying allergenicity
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Effects of glycation of the model food allergen ovalbumin on antigen uptake and presentation by human dendritic cells
Hilmenyuk, T., Bellinghausen, I., Heydenreich, B., Ilchmann, A., Toda, M., Grabbe, S., & Saloga, J. (2009) · Immunology · doi:10.1111/j.1365-2567.2009.03199.x · Cited by 127 · see citing works
Immunology of TLR-independent vaccine adjuvants
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Chapter 6 Interleukin 5 in the Link Between the Innate and Acquired Immune Response
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Specificity of IgG and IgE antibodies against plant and insect glycoprotein glycans determined with artificial glycoforms of human transferrin
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“[15] directly demonstrated this by creating neo-conjugates of carrier proteins with specific glycans, which increased the allergic immunogenicity of these proteins.”
Basophils Are the Major Producers of IL-4 during Primary Helminth Infection
van Panhuys, N., Prout, M. S., Forbes, E., Min, B., Paul, W. E., & Gros, G. S. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1000940 · Cited by 119 · cited 1× · see citing works
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Schistosome N‐glycans containing core α3‐fucose and core β2‐xylose epitopes are strong inducers of Th2 responses in mice
Faveeuw, C., Mallevaey, T., Paschinger, K., Wilson, I. B. H., Fontaine, J., Mollicone, R., Oriol, R., Altmann, F., Lerouge, P., Capron, M., et al. (2003) · European Journal of Immunology · doi:10.1002/eji.200323717 · Cited by 117 · see citing works
Critical Role of IL-25 in Nematode Infection-Induced Alterations in Intestinal Function
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“TSLP, IL-25 and IL-33 are induced by exposure to a variety of aeorallergens including those of house dust mite (HDM) and cockroach.”
Influential
The Structure of the Dust Mite Allergen Der p 7 Reveals Similarities to Innate Immune Proteins
Mueller, G., Edwards, L. L., Aloor, J., Fessler, M., Glesner, J., Pomés, A., Chapman, M., London, R., & Pedersen, L. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.12.016 · Cited by 112 · cited 1× · see citing works
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Parasite Antigen-Driven Basophils Are a Major Source of IL-4 in Human Filarial Infections
Mitre, E., Taylor, R. T., Kubofcik, J., & Nutman, T. (2004) · Journal of Immunology · doi:10.4049/jimmunol.172.4.2439 · Cited by 111 · cited 12× · see citing works
“IL-13 functions as an effector molecule that mediates eosinophilic inflammation, airway hyperresponsiveness, and mucus hypersecretion [22].”
Influential
Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)–1/TIM4 interaction as a therapeutic strategy in a dendritic cell–induced peanut allergy model
Feng, B., Chen, X., He, S., Zheng, P., Foster, J. A., Xing, Z., Bienenstock, J., & Yang, P. (2008) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2008.04.036 · Cited by 107 · cited 1× · see citing works
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Tick Saliva Inhibits Dendritic Cell Migration, Maturation, and Function while Promoting Development of Th2 Responses1
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Mucosal Allergic Sensitization to Cockroach Allergens Is Dependent on Proteinase Activity and Proteinase-Activated Receptor-2 Activation
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“Because of this homology, Der p 2 in the presence of a very low concentration of LPS signals directly through TLR4, which plays an essential role in the induction of sensitization to Der p 2 and experimental allergic asthma [17].”
Influential
Functional Interaction of Common Allergens and a C-type Lectin Receptor, Dendritic Cell-specific ICAM3-grabbing Non-integrin (DC-SIGN), on Human Dendritic Cells*
Hsu, S.-C., Chen, C.-H., Tsai, S.-H., Kawasaki, H., Hung, C.-H., Chu, Y.-T., Chang, H.-W., Zhou, Y.-F., Fu, J.-R., Plunkett, B., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.058370 · Cited by 95 · see citing works
Epidemiology of food allergy
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New insights into basophil biology: initiators, regulators, and effectors of type 2 inflammation
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The role of dendritic cells in food allergy.
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Self-citation
Soybean isoflavones regulate dendritic cell function and suppress allergic sensitization to peanut
Masilamani, M., Wei, J., Bhatt, S., Paul, M., Yakir, S., & Sampson, H. A. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.05.009 · Cited by 91 · cited 1× · see citing works
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The effect of the food matrix on in vivo immune responses to purified peanut allergens.
van Wijk, F., Nierkens, S., Hassing, I., Feijen, M., Koppelman, S., de Jong, G. D., Pieters, R., & Knippels, L. (2005) · Toxicological Sciences · doi:10.1093/toxsci/kfi187 · Cited by 86 · cited 1×
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The Role of OX40 Ligand Interactions in the Development of the Th2 Response to the Gastrointestinal Nematode Parasite Heligmosomoides polygyrus1 2
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Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation
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“Nod activation in DCs did not initiate Th2 immunity but was required for antigen presentation and optimal antigen-specific Th2 responses [135].”
Cutting Edge: Polarized Th Cell Response Induction by Transferred Antigen-Pulsed Dendritic Cells Is Dependent on IL-4 or IL-12 Production by Recipient Cells
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TH2 adjuvants: Implications for food allergy
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“All these factors appear to be important in sensing of allergens by the innate immune system, and the resulting Th2-type response [99, 100].”
Self-citation
Immunoglobulin E (IgE) Responses to Paramyosin Predict Resistance to Reinfection with Schistosoma japonicum and Are Attenuated by IgG4
Jiz, M., Friedman, J., Leenstra, T., Jarilla, B., Pablo, A. O., Langdon, G., Pond-Tor, S., Wu, H.-W., Manalo, D., Olveda, R., et al. (2009) · Infection and Immunity · doi:10.1128/iai.00012-09 · Cited by 79
Innate immunity in allergic disease
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Structural biology of allergens
Thomas, W. R., Hales, B. J., & Smith, W.-A. (2005) · Current Allergy and Asthma Reports · doi:10.1007/s11882-005-0012-1 · Cited by 75 · cited 2× · see citing works
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Pollen-Derived E1-Phytoprostanes Signal via PPAR-γ and NF-κB-Dependent Mechanisms1
Gilles, S., Mariani, V., Bryce, M., Mueller, M. J., Ring, J., Jakob, T., Pastore, S., Behrendt, H., & Traidl-Hoffmann, C. (2009) · Journal of Immunology · doi:10.4049/jimmunol.0802613 · Cited by 72
Pollen metabolome analysis reveals adenosine as a major regulator of dendritic cell–primed TH cell responses
Gilles, S., Fekete, Á., Zhang, X., Beck, I., Blume, C., Ring, J., Schmidt‐Weber, C. B., Behrendt, H., Schmitt‐Kopplin, P., & Traidl‐Hoffmann, C. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.12.1082 · Cited by 71 · cited 1× · see citing works
“Another pollen-derived component, adenosine, was found to inhibit IL-12 release by DCs through induction of cAMP [132].”
Development and validation of a structured questionnaire for the diagnosis of oral allergy syndrome in subjects with seasonal allergic rhinitis during the UK birch pollen season
Skypala, I. J., Calderón, M. A., Leeds, A. R., Emery, P. W., Till, S. J., & Durham, S. R. (2011) · Clinical & Experimental Allergy · doi:10.1111/j.1365-2222.2011.03759.x · Cited by 71 · cited 1× · see citing works
“to inhalant, not ingested, allergens that subsequently provokes a secondary immune response to cross-reactive allergens upon ingestion [1].”
Protective immunity and eosinophilia in IgE-deficient SJA/9 mice infected with Nippostrongylus brasiliensis and Trichinella spiralis.
Watanabe, N., Katakura, K., Kobayashi, A., Okumura, K., & Ovary, Z. (1988) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.85.12.4460 · Cited by 71 · see citing works
Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12
Lamhamedi-Cherradi, S.-E., Martin, R., Ito, T., Kheradmand, F., Corry, D. B., Liu, Y., & Moyle, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.6000 · Cited by 70 · cited 1× · see citing works
“Protease allergens from the fungi Alternaria and Aspergillus also directly stimulate DCs to induce Th2-skewing, which may be due to relatively low IL-12 production and increased OX40L expression by these DCs [116, 117].”
Characteristic motifs for families of allergenic proteins
Ivanciuc, O., Garcia, T. I., Torres, M., Schein, C., & Braun, W. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.07.034 · Cited by 68 · cited 1× · see citing works
“16 % of the known pfams—account for 80 % of all described food allergens [5, 6].”
Influence of binding of sodium dodecyl sulfate, all-trans-retinol, palmitate, and 8-anilino-1-naphthalenesulfonate on the heat-induced unfolding and aggregation of beta-lactoglobulin B.
Considine, T., Patel, H., Singh, H., & Creamer, L. K. (2005) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf0481756 · Cited by 65 · cited 1×
“The lipocalin milk allergen, β-lactoglobulin, has been shown to bemore stable when lipidbound [19].”
Basophils are not the key antigen‐presenting cells in allergic patients
Eckl‐Dorna, J., Ellinger, A., Blatt, K., Ghanim, V., Steiner, I., Pavelka, M., Valent, P., Valenta, R., & Niederberger, V. (2012) · Allergy · doi:10.1111/j.1398-9995.2012.02792.x · Cited by 65 · cited 1× · see citing works
“Furthermore, recent studies have reported that human basophils do not act as APCs in the induction of Tcell responses to the major birch pollen allergen, Bet v 1 [128, 129].”
Stability of a set of allergens and non-allergens in simulated gastric fluid
Herman, R. A., Woolhiser, M. R., Ladics, G. S., Korjagin, V. A., Schafer, B. W., Storer, N. P., Green, S. B., & Kan, L. (2007) · International Journal of Food Sciences and Nutrition · doi:10.1080/09637480601149640 · Cited by 62 · see citing works
Increases in schistosome-specific IgE and CD23+ B cells in a cohort of Kenyan children undergoing repeated treatment and reinfection with Schistosoma mansoni
Black, C. L., Muok, E., Mwinzi, P., Carter, J., Karanja, D., Secor, W., & Colley, D. G. (2010) · Journal of Infectious Diseases · doi:10.1086/653828 · Cited by 62 · see citing works
Cellular networks controlling Th2 polarization in allergy and immunity
Kool, M., Hammad, H., & Lambrecht, B. N. (2012) · F1000 Biology Reports · doi:10.3410/b4-6 · Cited by 60 · cited 1× · see citing works
“More recent studies using superior technical approaches have modified these views and have demonstrated that DCs are the dominant APCs in induction of Th2 immunity to helminths and allergens [58, 79, 80].”
The CD28/CTLA-4-B7 Signaling Pathway Is Involved in Both Allergic Sensitization and Tolerance Induction to Orally Administered Peanut Proteins
van Wijk, F., Nierkens, S., de Jong, W., Wehrens, E., Boon, L., van Kooten, P. V., Knippels, L., & Pieters, R. (2007) · Journal of Immunology · doi:10.4049/jimmunol.178.11.6894 · Cited by 57
Human blood basophils do not act as antigen‐presenting cells for the major birch pollen allergen Bet v 1
Kitzmüller, C., Nagl, B., Deifl, S., Walterskirchen, C., Jahn-Schmid, B., Zlabinger, G., & Bohle, B. (2012) · Allergy. European Journal of Allergy and Clinical Immunology · doi:10.1111/j.1398-9995.2011.02764.x · Cited by 56
Naïve T cells sense the cysteine protease allergen papain through protease-activated receptor 2 and propel T helper type 2 immunity
Liang, G., Barker, T. T., Xie, Z., Charles, N., Rivera, J., & Druey, K. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.02.035 · Cited by 56 · cited 1× · see citing works
“Direct activation of T cells through PAR2 by papain induced production of IL-4 and the chemokines CCL17 and CCL22, which are chemoattractants for basophils and Th2 cells [119] (Fig.”
Retagging Identifies Dendritic Cell-specific Intercellular Adhesion Molecule-3 (ICAM3)-grabbing Non-integrin (DC-SIGN) Protein as a Novel Receptor for a Major Allergen from House Dust Mite
Emara, M. M., Royer, P., Mahdavi, J., Shakib, F., & Ghaemmaghami, A. M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.312520 · Cited by 56 · see citing works
Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function
Sala, A., He, J., Laricchia‐Robbio, L., Gorini, S., Iwasaki, A., Braun, M., Yap, G. S., Sher, A., Ozato, K., & Kelsall, B. L. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20080912 · Cited by 55 · see citing works
Selective neoglycosylation increases the structural stability of vicilin, the 7S storage globulin from pea seeds.
Pedrosa, C. M., Felice, F. D. D., Trisciuzzi, C., & Ferreira, S. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.2024 · Cited by 49 · cited 1× · see citing works
“Many food allergens are glycoproteins and protein glycosylation may contribute to protein stability [12], as well as enhance immunogenicity in other ways.”
Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation
Lewkowich, I., Day, S., Ledford, J. R., Zhou, P., Dienger, K., Wills-Karp, M., & Page, K. (2011) · Respiratory Research · doi:10.1186/1465-9921-12-122 · Cited by 48 · see citing works
Mite allergen decreases DC-SIGN expression and modulates human dendritic cell differentiation and function in allergic asthma
Huang, H.-J., Lin, Y.-N., Liu, C.-F., Hui, F.-K., & Wang, J.-Y. (2010) · Mucosal Immunology · doi:10.1038/mi.2011.17 · Cited by 46 · cited 1×
“HDM extract downregulates cell surface DC-SIGN due to endocytosis of the HDM extract–DC-SIGN complex, and inhibits differentiation of monocytes into CD14CD1a DCs [105].”
Der p 1 suppresses indoleamine 2, 3-dioxygenase in dendritic cells from house dust mite-sensitive patients with asthma.
Maneechotesuwan, K., Wamanuttajinda, V., Kasetsinsombat, K., Huabprasert, S., Yaikwawong, M., Barnes, P., & Wongkajornsilp, A. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2008.10.018 · Cited by 46 · see citing works
In silico predictability of allergenicity: from amino acid sequence via 3-D structure to allergenicity.
Aalberse, R., & Stadler, B. (2006) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200500270 · Cited by 37 · cited 1× · see citing works
“Though it seems not to be the case that simple primary or secondary protein structural features are constrained among allergens [2, 4], some protein families do appear to be overrepresented.”
TSLP Promotes Interleukin-3-independent Basophil Haematopoiesis and Type 2 Inflammation
Moran, T., & Vickery, B. (2012) · Pediatrics · doi:10.1542/peds.2012-2183dddd · Cited by 35 · cited 1×
“During helminth infection, basophils may be activated by IL-3, IL-18, IL-33, or TSLP, as well as directly by helminth-derived products such as proteases and glycoproteins, although receptors involved in sensing these products have not yet been found [86, 87].”
Protease-activated receptor 2-dependent fluid secretion from airway submucosal glands by house dust mite extract.
Cho, H.-J., Lee, H. J., Kim, S. C., Kim, K., Kim, Y., Kim, C.-H., Lee, J.-G., Yoon, J.-H., & Choi, J. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.11.024 · Cited by 35 · cited 1×
“Furthermore, expression of PAR2 is increased in submucosal glands of patients with allergic rhinitis or chronic rhinosinusitis, and activation of PAR2 by HDM extract induces glandular secretion of airway surface fluid in these patients, but not in healthy controls [122].”
Adoptive transfer of dendritic cells from allergic mice induces specific immunoglobulin E antibody in naïve recipients in absence of antigen challenge without altering the T helper 1/T helper 2 balance
Chambers, S. J., Bertelli, E., Winterbone, M. S., Regoli, M., Man, A., & Nicoletti, C. (2004) · Immunology · doi:10.1111/j.1365-2567.2004.01846.x · Cited by 34 · see citing works
Antigen coupled with Lewis-x trisaccharides elicits potent immune responses in mice
Hsu, S., Tsai, T., Kawasaki, H., Chen, C.-H., Plunkett, B., Lee, R. T., Lee, Y. C., & Huang, S.-K. (2007) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.01.034 · Cited by 28 · cited 1× · see citing works
“Incubation of DCs with antigencoupled Lewis-x trisaccharides suppressed production of IL12, which is probably important in the mechanism of Th2skewing induced by these glycans [140].”
Schistosoma mansoni infection in IgE-producing and IgE-deficient mice.
Ridi, R. E., Ozaki, T., & Kamiya, H. (1998) · Journal of Parasitology · doi:10.2307/3284552 · Cited by 26
Examining host–microbial interactions through the lens of NOD: From plants to mammals
Robertson, S. J., Rubino, S. J., Geddes, K., & Philpott, D. J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.01.001 · Cited by 23 · cited 1× · see citing works
“NLRs are present in the cytoplasm and are involved in sensing microbe-derived products as well as endogenous danger signals [134].”
Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function
la Sala, A., He, J., Laricchia‐Robbio, L., Gorini, S., Iwasaki, A., Braun, M., Yap, G., Sher, A., Ozato, K., & Kelsall, B. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.2008091262209c · Cited by 22 · cited 1×
“Interestingly, this effect mimics the responses to tick saliva and the Th2-skewing adjuvant CT, which also downregulate IL-12 production in DCs by increasing cAMP [65, 133] (Fig.”
A synonymous variation in protease-activated receptor-2 is associated with atopy in Korean children.
Lee, J. H., Kim, K. W., Gee, H., Lee, J., Lee, K., Park, H.-S., Kim, S.-H., Kim, S. W., Kim, M. N., Kim, K.-E., et al. (2011) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2011.06.036 · Cited by 17 · cited 1× · see citing works
“A single polymorphism of PAR2 is positively associated with PAR2 expression, as well as with atopy, serum IgE levels, and total eosinophil counts [121].”
Faculty Opinions recommendation of Innate immune responses of airway epithelium to house dust mite are mediated through beta-glucan-dependent pathways.
Lambrecht, B. (2012) · doi:10.3410/f.13863979.15301083 · Cited by 15 · cited 1×
“Upregulation of CCL20 was not mediated by the CLR Dectin-1, a known receptor for β-glucans, but was dependent on activation of spleen tyrosine kinase (Syk), indicating that β-glucans in HDM are recognized by and signal through an immunoreceptor tyrosinebased activation motif (ITAM) pathway [107].”
Mechanisms of allergic sensitization to foods: bypassing immune tolerance pathways.
Berin, M. (2012) · Immunology and allergy clinics of North America · doi:10.1016/j.iac.2011.10.001 · Cited by 14 · cited 1×
“Feeding antigens to mice without adjuvant normally gives rise to oral tolerance, but a combination of antigens and CT administered via the oral route results in antigen-specific Th2 responses and allergic sensitization [94].”
Cholera Toxin Impairs the Differentiation of Monocytes into Dendritic Cells, Inducing Professional Antigen-Presenting Myeloid Cells
Veglia, F., Sciaraffia, E., Riccomi, A., Pinto, D., Negri, D. R. M., Magistris, M. T. D., & Vendetti, S. (2010) · Infection and Immunity · doi:10.1128/iai.01181-10 · Cited by 13 · see citing works
Human Dendritic Cells Stimulated with a Novel Peanut Protein Express High Levels of RALDH2 and Induce RA-Sensitive Genes in Naïve T Cells
Ruiter, B., Grishina, G., Jager, S. D. H., Knol, E., Ozias-Akins, P., Sampson, H., & Shreffler, W. (2012) · doi:10.1016/j.jaci.2011.12.043 · Cited by 2 · cited 13×
“Th2 cells produce interleukin (IL)-4, IL-5, and IL-13, and are important in the immune response against extracellular, multicellular pathogens.”
InfluentialSelf-citation
Faculty Opinions recommendation of Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response.
Wynn, T. A. (2009) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.1160902.623327 · cited 13×
“Differentiation of naive T cells is induced by antigenpresenting cells (APCs), most importantly dendritic cells (DCs).”
Influential

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11 of the 155 references couldn’t be matched to a known paper.

Research works printed but not linked: 12

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Sorted by citations

EAACI Molecular Allergology User's Guide
Matricardi, P. M., Kleine‐Tebbe, J., Hoffmann, H. J., Valenta, R., Hilger, C., Hofmaier, S., Aalberse, R. C., Agache, I., Asero, R., Ballmer‐Weber, B., et al. (2016) · Pediatric Allergy and Immunology · doi:10.1111/pai.12563 · Cited by 932 · see citing works
Food Allergies: The Basics
Valenta, R., Hochwallner, H., Linhart, B., & Pahr, S. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.02.006 · Cited by 298 · see citing works
New Perspectives in Food Allergy
Martinis, M. D., Sirufo, M. M., Suppa, M., & Ginaldi, L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041474 · Cited by 252 · see citing works
“FA, therefore, arises in some individuals with atopic predisposition in which tolerance for food antigens is not established or is interrupted, due to an altered functioning of the gut immune system [89,90].”
Background
Skin exposure promotes a Th2-dependent sensitization to peanut allergens
Tordesillas, L., Goswami, R., Benedé, S., Grishina, G. T., Dunkin, D., Järvinen, K. M., Maleki, S. J., Sampson, H. A., & Berin, M. C. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75660 · Cited by 221 · see citing works
“In the case of house dust mite, there are several allergens that have protease activity (Der p 1, Der p 3, Der p 6, Der p 9) and a capacity to bind to lipids (Der p 2) (6, 57, 58).”
Suppression of the immunologic response to peanut during immunotherapy is often transient
Gorelik, M., Narisety, S. D., Guerrerio, A. L., Chichester, K. L., Keet, C. A., Bieneman, A. P., Hamilton, R. G., Wood, R. A., Schroeder, J. T., & Frischmeyer‐Guerrerio, P. A. (2014) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.11.010 · Cited by 118 · see citing works
Scientific Opinion on development needs for the allergenicity and protein safety assessment of food and feed products derived from biotechnology
(GMO), E. P. O. G. M. O., Mullins, E. D., Bresson, J., Dalmay, T., Dewhurst, I. C., Epstein, M. M., Firbank, L. G., Guerche, P., Hejátko, J., Naegeli, H., et al. (2022) · EFSA Journal · doi:10.2903/j.efsa.2022.7044 · Cited by 76 · see citing works
“There is some evidence that some food proteins have innate immune-stimulatory properties due to features such as glycosylation, lipid-binding and enzymatic activity (Ruiter and Shreffler, 2012).”
Background
Egg proteins as allergens and the effects of the food matrix and processing.
Benedé, S., López-Expósito, I., Molina, E., & López-Fandiño, R. (2015) · Food & Function · doi:10.1039/c4fo01104j · Cited by 75 · see citing works
IgG1+ B‐cell immunity predates IgE responses in epicutaneous sensitization to foods
Jiménez‐Saiz, R., Ellenbogen, Y., Koenig, J. F. E., Gordon, M. E., Walker, T. D., Rosace, D., Spill, P., Bruton, K. M., Kong, J., Monteiro, K., et al. (2018) · Allergy · doi:10.1111/all.13481 · Cited by 68 · see citing works
Mouse Models for Food Allergies: Where Do We Stand?
Schülke, S., & Albrecht, M. (2019) · Cells · doi:10.3390/cells8060546 · Cited by 71 · see citing works
“Here, increased sensitizing properties were attributed to allergen molecules with either intrinsic immune activating properties (reviewed in [21]), proteolytic activity [22], or increased stability towards heat and proteases [22–24].”
Background
The Initiation of Th2 Immunity Towards Food Allergens
Ellenbogen, Y., Jiménez‐Saiz, R., Spill, P., Chu, D. K., Waserman, S., & Jordana, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051447 · Cited by 71 · see citing works
Guidelines for the use and interpretation of diagnostic methods in adult food allergy
Macchia, D., Melioli, G., Pravettoni, V., Nucera, E., Piantanida, M., Caminati, M., Campochiaro, C., Yacoub, M., Schiavino, D., Paganelli, R., et al. (2015) · Clinical and Molecular Allergy · doi:10.1186/s12948-015-0033-9 · Cited by 40 · see citing works
“For this reason, LTP exposure through the gastrointestinal tract may induce sensitization in predisposed individuals and may trigger severe reactions in sensitized patients [46].”
Food Components and the Immune System: From Tonic Agents to Allergens
Faria, A. M. C., Gomes-Santos, A. C., Gonçalves, J. L., Moreira, T. G., Medeiros, S. R., Dourado, L. P. A., & Cara, D. C. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00102 · Cited by 63 · see citing works
“This is the case of the milk allergen β-lactoglobulin that has been shown to be more stable when bound to lipids (Ruiter and Shreffler, 2012).”
Background
Use of Animal Models to Investigate Major Allergens Associated with Food Allergy
Gramberg, J. L. V., de Veer, M., O'Hehir, R., Meeusen, E., & Bischof, R. (2013) · Journal of Allergy · doi:10.1155/2013/635695 · Cited by 54
“There is now also recognition of the innate properties of allergens and their role inTh2 polarisation of dendritic cells (DCs) and the process of allergen sensitisation [9, 13].”
China Consensus Document on Allergy Diagnostics
Chen, H., Li, J., Cheng, L., Gao, Z., Lin, X., Zhu, R., Yang, L., Tao, A., Hong, H., Tang, W., et al. (2021) · Allergy Asthma and Immunology Research · doi:10.4168/aair.2021.13.2.177 · Cited by 63 · see citing works
Immunological behavior of in vitro digested egg-white lysozyme.
Jiménez-Saiz, R., Benedé, S., Miralles, B., López-Expósito, I., Molina, E., & López-Fandiño, R. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201300442 · Cited by 40 · see citing works
Identification of IgE-Binding Peptides in Hen Egg Ovalbumin Digested in Vitro with Human and Simulated Gastroduodenal Fluids
Benedé, S., López‐Expósito, I., López‐Fandiño, R., & Molina, E. (2013) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf404226w · Cited by 43 · see citing works
Influence of the Carbohydrate Moieties on the Immunoreactivity and Digestibility of the Egg Allergen Ovomucoid
Benedé, S., López-Fandiño, R., Reche, M., Molina, E., & López-Expósito, I. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080810 · Cited by 33 · see citing works
“In any case, the fact that glycosylation is a common feature to many food allergens has prompted investigations that showed that glycans may enhance immunogenicity through the activation of innate Th2 responses [10].”
Background
Literature review in support of adjuvanticity/immunogenicity assessment of proteins
Parenti, M. D., Santoro, A., Río, A. D., & Franceschi, C. (2019) · EFSA Supporting Publications · doi:10.2903/sp.efsa.2019.en-1551 · Cited by 26 · see citing works
Emerging Role of Alarmins in Food Allergy: An Update on Pathophysiological Insights, Potential Use as Disease Biomarkers, and Therapeutic Implications
Rizzi, A., Presti, E. L., Chini, R., Gammeri, L., Inchingolo, R., Lohmeyer, F. M., Nucera, E., & Gangemi, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12072699 · Cited by 28 · see citing works
“This is possible because alarmins and other innate-stimulatory factors have activated DC during allergen capture [30,31].”
Background
Food Allergy Insights: A Changing Landscape
Martinis, M. D., Sirufo, M. M., Viscido, A., & Ginaldi, L. (2020) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-020-00574-6 · Cited by 26 · see citing works
Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells
Ruiter, B., Smith, N. P., Fleming, E. S., Patil, S. U., Hurlburt, B. K., Maleki, S. J., & Shreffler, W. G. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.11.047 · Cited by 28 · see citing works
Self-citation
Oral tolerance and oral immunotherapy for food allergy: Evidence for common mechanisms?
Kazmi, W., & Berin, M. (2022) · Cellular Immunology · doi:10.1016/j.cellimm.2022.104650 · Cited by 20
Identification and Characterization of β-Lathyrin, an Abundant Glycoprotein of Grass Pea ( Lathyrus sativus L.), as a Potential Allergen.
Xu, Q.-L., Song, B., Liu, F.-J., Song, Y.-Q., Chen, P., Liu, S.-S., & Krishnan, H. (2018) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b02314 · Cited by 19 · see citing works
Natural killer T cells in allergic asthma: implications for the development of novel immunotherapeutical strategies
Gutiérrez-Vera, C., García-Betancourt, R., Palacios, P. A., Müller, M., Montero, D. A., Verdugo, C., Ortiz, F., Simón, F., Kalergis, A. M., González, P. A., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1364774 · Cited by 20 · see citing works
“Since the subject is exposed to a complex mixture of molecules, including the given allergen, naïve CD4 + T cells differentiate into T-helper 2 (T H 2)-lymphocytes (50).”
Background
Cow's milk protein allergy; new knowledge from a multidisciplinary perspective.
Mehaudy, R., Jáuregui, M. B., Vinderola, G., Guzmán, L., Martinez, J., Orsi, M., & Parisi, C. (2022) · Archivos Argentinos de Pediatria · doi:10.5546/aap.2022.eng.200 · Cited by 16 · see citing works
The impact of structural integrity and route of administration on the antibody specificity against three cow’s milk allergens - a study in Brown Norway rats
Madsen, J. L., Kroghsbo, S., Madsen, C., Pozdnyakova, I., Barkholt, V., & Bøgh, K. (2014) · Clinical and Translational Allergy · doi:10.1186/2045-7022-4-25 · Cited by 16 · see citing works
“Another explanation may be that gluten contains some immunomodulatory properties, as accumulating data suggest that food proteins may act as adjuvant and directly activate the innate immune system [35,36].”
Background
Egg white peptide-based immunotherapy enhances vitamin A metabolism and induces RORγt+ regulatory T cells
Lozano‐Ojalvo, D., Martínez‐Blanco, M., Pérez‐Rodríguez, L., Molina, E., Peláez, C., Requena, T., & López‐Fandiño, R. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.11.012 · Cited by 16 · see citing works
A molecular insight of CTLA-4 in food allergy.
Kumar, S., Verma, A., Das, M., & Dwivedi, P. (2013) · Immunology Letters · doi:10.1016/j.imlet.2012.12.003 · Cited by 16
Allergen Ligands in the Initiation of Allergic Sensitization
Thomas, W. (2014) · Current Allergy and Asthma Reports · doi:10.1007/s11882-014-0432-x · Cited by 15
“Large chitin is inert, intermediate-sized stimulates TNF-α via TLR2 and NFκB, while small chitin (2– 10 μm) stimulates cytokine, especially IL-10, via dectin-1 with lesser contributions from TLR-2. Chitin can be an adjuvant for immune responses induced by ovalbumin injections, sensitizing mice for Th2-type pulmonary e…”
BackgroundInfluential
Memory Generation and Re-Activation in Food Allergy
Koenig, J. F. E., Bruton, K. M., Phelps, A., Grydziuszko, E., Jiménez‐Saiz, R., & Jordana, M. (2021) · ImmunoTargets and Therapy · doi:10.2147/itt.s284823 · Cited by 23 · see citing works
The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression
Wansley, D. L., Yin, Y.-Z., & Prussin, C. (2013) · Clinical and Molecular Allergy · doi:10.1186/1476-7961-11-4 · Cited by 14
“To that end, Shreffler and colleagues have characterized a previously undescribed peanut protein that upregulates retinaldehyde dehydrogenase 2 in myeloid dendritic cells [26].”
Background
Egg yolk lipids induce sensitization to egg white proteins in a mouse model without adjuvant and exacerbate Th2 responses to egg white in cells from allergic patients.
Pérez-Rodríguez, L., Lozano-Ojalvo, D., Menchén-Martínez, D., Molina, E., López-Fandiño, R., & Benedé, S. (2023) · Food Research International · doi:10.1016/j.foodres.2023.112669 · Cited by 8
Loss of tolerance to dietary proteins: From mouse models to human model diseases
Levescot, A., & Cerf–Bensussan, N. (2024) · Immunological Reviews · doi:10.1111/imr.13395 · Cited by 8 · see citing works
“39 These particularities may contribute to the frequency and severity of peanut allergy in humans.”
The Immunological Basis of IgE‐Mediated Reactions
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Authors: Ruiter, B., & Shreffler, W. G.
Affiliations: Massachusetts General Hospital (US)
Harvard University (US)
Corresponding author: Ruiter, Bert
ORCID: Ruiter, Bert
Shreffler, Wayne G.
Venue: Seminars in Immunopathology
Publisher: Springer Science and Business Media LLC
Published: 2012-08-12
Volume: 34
Issue: 5
Pages: 617-632
ISSN: 1863-2297 (ISSN-L)
1863-2300
DOI: 10.1007/s00281-012-0334-8
PMC: PMC3459673
OpenAlex: W2007247011
Cited by: 47
References: 155
Citations by year: 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 7 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 1
FWCI: 0.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Seminars in Immunopathology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Allergy and Infectious Diseases (U19AI095261)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
Topics: Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
Keywords: food allergy, allergens, innate immunity, Th2 immune response, glycosylation, lipid binding, proteolytic activity, thymic stromal lymphopoietin, IL-25, IL-33, dendritic cells, basophils, innate lymphoid cells, epithelium, allergic inflammation, parasite immunity, wound healing, cytokines
MeSH terms: Adjuvants, Immunologic, Allergens, Animals, Food Hypersensitivity, Humans, Immunity, Innate, Signal Transduction, Cytokines, Th2 Cells

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Innate immunostimulatory properties of allergens and their relevance to food allergy

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