{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:07:01Z","timestamp":1789549621058,"version":"build-2803163510"},"reference-count":71,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004383","name":"InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences","doi-asserted-by":"publisher","award":["20\/FBW\/2021"],"award-info":[{"award-number":["20\/FBW\/2021"]}],"id":[{"id":"10.13039\/501100004383","id-type":"DOI","asserted-by":"publisher"}]},{"award":["20\/FBW\/2021"],"award-info":[{"award-number":["20\/FBW\/2021"]}],"id":[{"id":"https:\/\/ror.org\/04cnktn59","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Although the impact of \u03b2-casein A1\/A2 variants on human health is well-documented, the immunogenic potential of complex milk protein variants, including \u03ba-casein (variants A, B, and E) and \u03b2-lactoglobulin (variants A and B) polymorphisms, remains poorly understood. This study aimed to evaluate ex vivo the cellular response of casein-sensitized lymphocytes to digests of milk defined for \u03b2-casein, \u03ba-casein and \u03b2-lactoglobulin polymorphisms. Methods: BALB\/c mice were injected intraperitoneally with casein (CAS group) or PBS (control group), and their lymphocytes were subsequently isolated and stimulated with simulated gastrointestinal digests of milk from cows with the genotypes: REF (A1A2\/AB\/AB), HM1 (A1A1\/AA\/AA), HM2 (A2A2\/BB\/BB), HT1 (A1A1\/AE\/AB), and HT2 (A1A1\/BE\/AB). We then analyzed the following: T-cell subpopulations (CD4+CD25+ and CD4+Fosp3+), proliferation, and the secretion (TNF-\u03b1, IL-6, IL-10, IL-17A, IL-4) and gene expression (IL-18, IL-1\u03b2, TGF\u03b21) of key cytokines. Results: Lymphocytes from sensitized mice (CAS) showed generally stronger responses to all treatments compared to non-sensitized PBS cells. Of note is the robust pro-inflammatory response of sensitized lymphocytes to HT1 and HT2 digests, as evidenced by a 9- to 10-fold increase in TNF-\u03b1 and IL-6 secretion compared to the PBS counterparts. This response was uniquely associated with the presence of the \u03ba-casein E variant. Notably, while the population of regulatory lymphocytes (CD4+CD25+ and CD4+Foxp3+) expanded significantly in casein-sensitized lymphocytes in response to all hydrolysates, this expansion was markedly impaired in PBS lymphocytes. Conclusions: Genetic polymorphism of milk proteins, particularly the presence of the \u03ba-casein E variant, significantly modulates the pro-inflammatory potential of milk digests in sensitized lymphocytes. However, while these findings suggest new strategies for reducing milk immunogenicity, further mechanistic research is required to validate the role of the specific composition of protein variants in this phenomenon.<\/jats:p>","DOI":"10.3390\/nu18183021","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"3021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ex Vivo Immune Response of Casein-Sensitized Lymphocytes to Bovine Milk Protein Composite Genotypes: Beyond the \u03b2-Casein A1\/A2 Paradigm"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0109-5710","authenticated-orcid":false,"given":"Lidia Hanna","family":"Markiewicz","sequence":"first","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-5707","authenticated-orcid":false,"given":"Dagmara","family":"Z\u0142otkowska","sequence":"additional","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7350-4072","authenticated-orcid":false,"given":"Anna Maria","family":"Ogrodowczyk","sequence":"additional","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Wasilewska","sequence":"additional","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0116-0909","authenticated-orcid":false,"given":"Joanna","family":"Fotschki","sequence":"additional","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5538-1352","authenticated-orcid":false,"given":"Kamil","family":"Ole\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Animal Genetics, University of Warmia nad Mazury, Oczapowskiego 5, 10-719 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3909-4959","authenticated-orcid":false,"given":"Stanis\u0142aw","family":"Kami\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Animal Genetics, University of Warmia nad Mazury, Oczapowskiego 5, 10-719 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7383-7819","authenticated-orcid":false,"given":"Barbara","family":"Wr\u00f3blewska","sequence":"additional","affiliation":[{"name":"Immunology and Food Microbiology Group, InLife Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tryli\u0144skiego 18, 10-683 Olsztyn, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/WOX.0b013e3181defeb9","article-title":"World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow\u2019s Milk Allergy (DRACMA) Guidelines","volume":"3","author":"Fiocchi","year":"2010","journal-title":"World Allergy Organ. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10703","DOI":"10.3168\/jds.2018-14915","article-title":"Immunoreactive Properties of \u03b1-Casein and \u03ba-Casein: Ex Vivo and in Vivo Studies","volume":"101","author":"Fuc","year":"2018","journal-title":"J. Dairy Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13152","DOI":"10.1111\/1471-0307.13152","article-title":"Genetic Variation in Bovine Milk Proteins: Implications for Functional and Nutritional Properties","volume":"78","author":"Kelly","year":"2025","journal-title":"Int. J. Dairy Technol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Albarella, S., Selvaggi, M., D\u2019anza, E., Cosenza, G., Caira, S., Scaloni, A., Fontana, A., Peretti, V., and Ciotola, F. (2020). Influence of the Casein Composite Genotype on Milk Quality and Coagulation Properties in the Endangered Agerolese Cattle Breed. Animals, 10.","DOI":"10.3390\/ani10050892"},{"key":"ref_5","first-page":"27","article-title":"Association of Kappa Casein Polymorphism with Milk Yield and Milk Protein Genomic Values in Cows Reared in Lithuania","volume":"96","year":"2016","journal-title":"Vet. Zootech."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lavon, Y., Weller, J.I., Zeron, Y., and Ezra, E. (2024). Estimating the Effect of the Kappa Casein Genotype on Milk Coagulation Properties in Israeli Holstein Cows. Animals, 14.","DOI":"10.3390\/ani14010054"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cie\u015bli\u0144ska, A., Fiedorowicz, E., Rozmus, D., Sienkiewicz-Sz\u0142apka, E., Jarmo\u0142owska, B., and Kami\u0144ski, S. (2022). Does a Little Difference Make a Big Difference? Bovine \u03b2-Casein A1 and A2 Variants and Human Health\u2014An Update. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415637"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ramakrishnan, M., Eaton, T.K., Sermet, O.M., and Savaiano, D.A. (2020). Milk Containing A2 \u03b2-Casein Only, as a Single Meal, Causes Fewer Symptoms of Lactose Intolerance than Milk Containing A1 and A2 \u03b2-Caseins in Subjects with Lactose Maldigestion and Intolerance: A Randomized, Double-Blind, Crossover Trial. Nutrients, 12.","DOI":"10.3390\/nu12123855"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/MPG.0000000000002437","article-title":"Effects of Conventional Milk Versus Milk Containing Only A2 \u03b2-Casein on Digestion in Chinese Children: A Randomized Study","volume":"69","author":"Sheng","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1038\/ejcn.2014.127","article-title":"Comparative Effects of A1 versus A2 Beta-Casein on Gastrointestinal Measures: A Blinded Randomised Cross-over Pilot Study","volume":"68","author":"Ho","year":"2014","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12937-017-0275-0","article-title":"Effects of Cow\u2019s Milk Beta-Casein Variants on Symptoms of Milk Intolerance in Chinese Adults: A Multicentre, Randomised Controlled Study","volume":"16","author":"He","year":"2017","journal-title":"Nutr. J."},{"key":"ref_12","first-page":"35","article-title":"Effects of Milk Containing Only A2 Beta Casein versus Milk Containing Both A1 and A2 Beta Casein Proteins on Gastrointestinal Physiology, Symptoms of Discomfort, and Cognitive Behavior of People with Self-Reported Intolerance to Traditional Cows\u2019 Milk","volume":"15","author":"Sun","year":"2016","journal-title":"Nutr. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3168\/jds.2014-8330","article-title":"In Vitro Digestion of Purified \u03b2-Casein Variants A1, A2, B, and I: Effects on Antioxidant and Angiotensin-Converting Enzyme Inhibitory Capacity","volume":"98","author":"Andersen","year":"2015","journal-title":"J. Dairy Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107222","DOI":"10.1016\/j.jff.2026.107222","article-title":"A2 \u03b2-Casein Milk Improves Gastrointestinal Symptoms in Healthy Adults: A 7-Week Randomized, Double-Blind, Crossover Trial","volume":"139","author":"Wang","year":"2026","journal-title":"J. Funct. Foods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"426","DOI":"10.3109\/09637486.2011.634785","article-title":"Milk from Cows of Different \u03b2-Casein Genotypes as a Source of \u03b2-Casomorphin-7","volume":"63","author":"Kostyra","year":"2012","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.peptides.2014.09.020","article-title":"\u03b2-Casomorphin-7 Alters \u03bc-Opioid Receptor and Dipeptidyl Peptidase IV Genes Expression in Children with Atopic Dermatitis","volume":"62","author":"Fiedorowicz","year":"2014","journal-title":"Peptides"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"205","DOI":"10.22358\/jafs\/157531\/2023","article-title":"Long-Term Changes in the Frequency of Beta-Casein, Kappa-Casein and Beta-Lactoglobulin Alleles in Polish Holstein-Friesian Dairy Cattle","volume":"32","author":"Zabolewicz","year":"2023","journal-title":"J. Anim. Feed Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kami\u0144ski, S., and Cie\u015bli\u0144ska, A. (2025). \u03b2-Casein A1 and A2 Genetic Variants and \u03b2-Casomorphin-7 in Raw Milk and Processed Milk Products. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178612"},{"key":"ref_19","first-page":"401","article-title":"Unbalanced Expression of Beta-Casein Variants A1 and A2 in Holstein-Friesian Cows","volume":"42","author":"Brym","year":"2024","journal-title":"Anim. Sci. Pap. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ijfoodmicro.2017.12.024","article-title":"Seasonal Variances in Bacterial Microbiota and Volatile Organic Compounds in Raw Milk","volume":"267","author":"Nalepa","year":"2018","journal-title":"Int. J. Food Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7594","DOI":"10.3168\/jds.2024-24807","article-title":"Assessment of in Vitro Digestibility and Postdigestion Peptide Release of Mare Milk in Relation to Different Management Systems and Lactation Stages","volume":"107","author":"Sousa","year":"2024","journal-title":"J. Dairy Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23990","DOI":"10.1038\/s41598-024-74978-1","article-title":"The Skimmed Milk Proteome of Dairy Cows Is Affected by the Stage of Lactation and by Supplementation with Polyunsaturated Fatty Acids","volume":"14","author":"Veshkini","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.3168\/jds.2015-9655","article-title":"Short Communication: Improved Method for Centrifugal Recovery of Bacteria from Raw Milk Applied to Sensitive Real-Time Quantitative PCR Detection of Salmonella Spp.","volume":"99","author":"Brewster","year":"2016","journal-title":"J. Dairy Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/s41596-018-0119-1","article-title":"INFOGEST Static in Vitro Simulation of Gastrointestinal Food Digestion","volume":"14","author":"Brodkorb","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Markiewicz, L.H., Ogrodowczyk, A.M., Wiczkowski, W., and Wr\u00f3blewska, B. (2021). Phytate and Butyrate Differently Influence the Proliferation, Apoptosis and Survival Pathways in Human Cancer and Healthy Colonocytes. Nutrients, 13.","DOI":"10.3390\/nu13061887"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.foodres.2015.04.001","article-title":"Mare\u2019s and Cow\u2019s Milk: Promote Similar Metabolic Effects and Expression of Innate Markers in Caco-2 Cells?","volume":"72","author":"Fotschki","year":"2015","journal-title":"Food Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Z\u0142otkowska, D., Kuczy\u0144ski, M., Fuc, E., Fotschki, J., and Wr\u00f3blewska, B. (2023). Glycation of Whey Proteins Increases the Ex Vivo Immune Response of Lymphocytes Sensitized to \u03b2-Lactoglobulin. Nutrients, 15.","DOI":"10.3390\/nu15143110"},{"key":"ref_28","unstructured":"Leary, S.L. (2020). AVMA Guidelines for the Euthanasia of Animals: 2020 Edition, American Veterinary Medical Association."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jafc.0c00297","article-title":"Evaluation of Immunoreactivity of Pea (Pisum Sativum) Albumins in BALB\/c and C57BL\/6 Mice","volume":"68","author":"Wasilewska","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Markiewicz, L.H., Ogrodowczyk, A.M., Wiczkowski, W., and Wr\u00f3blewska, B. (2022). Phytate Hydrolysate Differently Modulates the Immune Response of Human Healthy and Cancer Colonocytes to Intestinal Bacteria. Nutrients, 14.","DOI":"10.3390\/nu14204234"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hellgren, L.I., and Nordby, P. (2017). Bioactive Lipids in Dairy Fat. Dairy in Human Health and Disease Across the Lifespan, Elsevier Inc.","DOI":"10.1016\/B978-0-12-809868-4.00017-0"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zlatanova, M., Ne\u0161i\u0107, A., Trbojevi\u0107-Ivi\u0107, J., \u010ceti\u0107, D., and Gavrovi\u0107-Jankulovi\u0107, M. (2024). Targeting NF-\u039aB Signaling: Selected Small Molecules Downregulate Pro-Inflammatory Cytokines in Both Food Allergen and LPS-Induced Inflammation. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115798"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB Signaling in Inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9124","DOI":"10.3168\/jds.2020-18492","article-title":"Frequencies of Milk Protein Variants and Haplotypes Estimated from Genotypes of More than 1 Million Bulls and Cows of 12 French Cattle Breeds","volume":"103","author":"Sanchez","year":"2020","journal-title":"J. Dairy Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fox, P.F., Uniacke-Lowe, T., McSweeney, P.L.H., and O\u2019Mahony, J.A. (2015). Dairy Chemistry and Biochemistry, Springer International Publishing.","DOI":"10.1007\/978-3-319-14892-2"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.idairyj.2014.01.010","article-title":"Particle Size Distribution and Lipid Composition of Skim Milk Lipid Material","volume":"36","author":"Jhanwar","year":"2014","journal-title":"Int. Dairy J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.idairyj.2013.11.008","article-title":"Reciprocal Interacting Effects of Proteins and Lipids during Exvivo Digestion of Bovine Milk","volume":"36","author":"Devle","year":"2014","journal-title":"Int. Dairy J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.3168\/jds.2018-15507","article-title":"Symposium Review: Fat Globules in Milk and Their Structural Modifications during Gastrointestinal Digestion","volume":"102","author":"Singh","year":"2019","journal-title":"J. Dairy Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"146698","DOI":"10.1016\/j.foodchem.2025.146698","article-title":"Milk and Plant Lipids Influence the in Vitro Digestion of Milk Proteins","volume":"496","author":"Miltenburg","year":"2025","journal-title":"Food Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"117264","DOI":"10.1016\/j.foodres.2025.117264","article-title":"Quantitative Peptidomic Profiling of Caprine and Bovine Milk after Simulated Gastrointestinal Digestion: A Multidimensional Analytical Strategy Integrating UHPLC-Q-TOF-MS and QqQ-MS","volume":"221","author":"Zhao","year":"2025","journal-title":"Food Res. Int."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Iwaniak, A., Minkiewicz, P., Mogut, D., Borawska-Dziadkiewicz, J., \u017bulewska, J., and Darewicz, M. (2025). Bovine Milk Protein-Derived Preparations and Their Hydrolysates as Sources of ACE-Inhibitory, DPP-IV-Inhibitory, and Antioxidative Peptides Analyzed Using in Silico and in Vitro Protocols. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094323"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1177\/02601060241307063","article-title":"Interbreed Variation of Dairy Cow Milk in Terms of Specific Proteome and Lipidome for Establishing Criteria of Milk Selection","volume":"31","author":"Devi","year":"2025","journal-title":"Nutr. Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.idairyj.2013.06.012","article-title":"Invitro Gastrointestinal Digestion of Bovine AS1- and AS2-Casein Variants Gives Rise to Different IgE-Binding Epitopes","volume":"34","author":"Lisson","year":"2014","journal-title":"Int. Dairy J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.3168\/jds.2013-6684","article-title":"Genetic Variants of Bovine \u03b2- and \u03ba-Casein Result in Different Immunoglobulin E-Binding Epitopes after in Vitro Gastrointestinal Digestion","volume":"96","author":"Lisson","year":"2013","journal-title":"J. Dairy Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3136\/fstr.26.399","article-title":"Purification and Characterization of Bovine \u03b2-Lactoglobulin Variants a and b (Characterization of Bovine \u03b2-Lactoglobulin Variants)","volume":"26","author":"Fei","year":"2020","journal-title":"Food Sci. Technol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9476","DOI":"10.3168\/jds.2022-22287","article-title":"Identification of Immunoglobulin E Epitopes on Major Allergens from Dairy Products after Digestion and Transportation in Vitro","volume":"105","author":"Yang","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"145829","DOI":"10.1016\/j.foodchem.2025.145829","article-title":"Peptidomics and Molecular Docking Reveal Digestion-Resistant IgE-Binding Epitopes in Bovine \u03b2-Lactoglobulin and \u03b1-Lactalbumin from Simulated Infant Digestion","volume":"493","author":"Yang","year":"2025","journal-title":"Food Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Gai, N., Uniacke-Lowe, T., O\u2019Regan, J., Faulkner, H., and Kelly, A.L. (2021). Effect of Protein Genotypes on Physicochemical Properties and Protein Functionality of Bovine Milk: A Review. Foods, 10.","DOI":"10.3390\/foods10102409"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Carnazza, M., Werner, R., Tiwari, R.K., Geliebter, J., Li, X.M., and Yang, N. (2025). The Etiology of IgE-Mediated Food Allergy: Potential Therapeutics and Challenges. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041563"},{"key":"ref_50","first-page":"298","article-title":"Cow\u2019s Milk Protein Allergy: A Comprehensive Review of Epidemiology, Pathogenesis, Clinical Manifestations, Diagnostics, and Management Strategies","volume":"34","author":"Hao","year":"2025","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Satitsuksanoa, P., Jansen, K., G\u0142obi\u0144ska, A., van de Veen, W., and Akdis, M. (2018). Regulatory Immune Mechanisms in Tolerance to Food Allergy. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02939"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"17098","DOI":"10.1038\/nrdp.2017.98","article-title":"Food Allergy","volume":"4","author":"Renz","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1178334","article-title":"Mechanisms Underlying Lineage Commitment and Plasticity of Helper CD4 + T Cells","volume":"327","author":"Paul","year":"2010","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/1479-5876-12-125","article-title":"Subsets of Regulatory T Cells and Their Roles in Allergy","volume":"12","author":"Zhang","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41392-025-02326-4","article-title":"Regulatory T Cells in Homeostasis and Disease: Molecular Mechanisms and Therapeutic Potential","volume":"10","author":"Wang","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ahmad, S., Azid, N.A., Boer, J.C., Lim, J., Chen, X., Plebanski, M., and Mohamud, R. (2018). The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02572"},{"key":"ref_57","first-page":"e79442","article-title":"Possible Resolution of Food Allergies Following Tocilizumab-Induced Remission of Juvenile Idiopathic Arthritis","volume":"17","author":"Magen","year":"2025","journal-title":"Cureus"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1017\/S0022029914000612","article-title":"Immunoreactivity of Lactic Acid-Treated Mare\u2019s Milk after Simulated Digestion","volume":"82","author":"Fotschki","year":"2015","journal-title":"J. Dairy Res."},{"key":"ref_59","first-page":"375","article-title":"The Allergenicity of a Low Molecular Fraction of Cow Milk Protein Hydrolysates","volume":"62","author":"Farjan","year":"2007","journal-title":"Milchwissenschaft"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"129512","DOI":"10.1016\/j.foodchem.2021.129512","article-title":"The Effect of Lactic Acid Fermentation with Different Bacterial Strains on the Chemical Composition, Immunoreactive Properties, and Sensory Quality of Sweet Buttermilk","volume":"353","author":"Ogrodowczyk","year":"2021","journal-title":"Food Chem."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ambroszkiewicz, J., Gajewska, J., Che\u0142chowska, M., and Rowicka, G. (2021). Assessment of Inflammatory Markers in Children with Cow\u2019s Milk Allergy Treated with a Milk-Free Diet. Nutrients, 13.","DOI":"10.3390\/nu13041057"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Meleti, E., Koureas, M., Manouras, A., Giannouli, P., and Malissiova, E. (2025). Bioactive Peptides from Dairy Products: A Systematic Review of Advances, Mechanisms, Benefits, and Functional Potential. Dairy, 6.","DOI":"10.3390\/dairy6060065"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1248\/bpb.b15-00596","article-title":"Effects of Glycated Whey Protein Concentrate on Pro-Inflammatory Cytokine Expression and Phagocytic Activity in RAW264.7 Macrophages","volume":"39","author":"Chun","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/jn\/nxab350","article-title":"Peptides Derived from In Vitro and In Vivo Digestion of Human Milk Are Immunomodulatory in THP-1 Human Macrophages","volume":"152","author":"Liang","year":"2022","journal-title":"J. Nutr."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Dalaka, E., Stefos, G.C., Politis, I., and Theodorou, G. (2025). Immunomodulatory Properties of Sweet Whey-Derived Peptides in THP-1 Macrophages. Molecules, 30.","DOI":"10.3390\/molecules30061261"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"105973","DOI":"10.1016\/j.idairyj.2024.105973","article-title":"Impact of Genetic \u03ba-Casein Variants (A, B, E) on Chymosin-Induced Milk Coagulation Properties: Application of a New LC\u2013MS-Based Genotyping Method","volume":"155","author":"Guggisberg","year":"2024","journal-title":"Int. Dairy J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.3168\/jds.2021-21172","article-title":"Phosphorylation and Glycosylation Isoforms of Bovine \u03ba-Casein Variant E in Homozygous Swedish Red Cow Milk Detected by Liquid Chromatography-Electrospray Ionization Mass Spectrometry","volume":"105","author":"Sheng","year":"2022","journal-title":"J. Dairy Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"100483","DOI":"10.1016\/j.focha.2023.100483","article-title":"Influence of Genetic Variants and Sialylation of Purified \u03ba-Casein on Peptide Release during in Vitro Digestion","volume":"3","author":"Sheng","year":"2023","journal-title":"Food Chem. Adv."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s12016-026-09146-6","article-title":"Mouse Models of Food Allergies: Where Do They Take Us?","volume":"69","author":"Li","year":"2026","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Alhamwe, B.A., Meulenbroek, L.A.P.M., Veening-Griffioen, D.H., Wehkamp, T.M.D., Alhamdan, F., Miethe, S., Harb, H., Hogenkamp, A., Knippels, L.M.J., and von Strandmann, E.P. (2020). Decreased Histone Acetylation Levels at Th1 and Regulatory Loci after Induction of Food Allergy. Nutrients, 12.","DOI":"10.3390\/nu12103193"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ca\u00f1as, J.A., N\u00fa\u00f1ez, R., Cruz-Amaya, A., G\u00f3mez, F., Torres, M.J., Palomares, F., and Mayorga, C. (2021). Epigenetics in Food Allergy and Immunomodulation. 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