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Casein, the major allergen in cow's milk, presents a significant challenge in providing nutritional support for children with allergies. To address this issue, we investigated a composite enzyme, comprising papain and chymotrypsin, to reduce the allergenicity of casein. Enzymatic hydrolysis induced substantial structural changes in casein, diminishing its affinity for specific IgE and IgG antibodies. Additionally, in a BALB/c mouse model, casein hydrolysate alleviated allergic symptoms, evidenced by lower serum IgE and IgG levels, reduced plasma histamine, and decreased Th2 cytokine release during cell co-culture. Peptidomic analysis revealed a 52.38% and 60% reduction in peptides containing IgE epitopes in casein hydrolyzed by the composite enzyme compared to papain and chymotrypsin, respectively, along with a notable absence of previously reported T cell epitopes. These results demonstrate the potential of enzyme combinations to enhance the efficiency of epitope destruction in allergenic proteins, providing valuable insights into the development of hypoallergenic dairy products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A Coxiella burnetii vaccination program, targeting only doelings, was introduced on a German goat farm to curb bacterial shedding. In 2018, adults were vaccinated with a C. burnetii Phase I vaccine at three-weeks apart following pathogen diagnosis, with a booster administered six months later due to sustained high shedding. From 2018 to 2021, doelings received two vaccine doses without any further boosters. To assess the program's efficacy, vaginal swabs from up to 40 animals per age group were collected during kidding seasons from 2019 to 2022. Bulk tank milk (BTM) samples were gathered monthly from January 2018 to October 2022 to monitor herd-level shedding. Real-time PCR analysis determined genome equivalents in all three sample types. Serum samples were taken before the initial immunization and during the post-kidding season from up to 40 goats per age group annually from 2018 to 2022. Phase-specific ELISAs determined IgG Phase I and Phase II antibodies. Additionally, two serum samples per age group from 2022 were analyzed using a neutralization assay. A few goats continued shedding small quantities during subsequent kidding seasons. Although positive BTM samples decreased, they displayed an undulating trend. Most age groups exhibited robust IgG Phase I responses and lower IgG Phase II levels post immunization. Mean IgG levels remained elevated until the study ended compared to pre-vaccination levels in most age groups. Additionally, neutralizing antibodies were present regardless of IgG response. Overall, double vaccination induced lasting antibody levels, but did not entirely prevent C. burnetii shedding. The resilience of the observed humoral immune activity requires further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cow milk protein allergy (CMPA) is the most common food allergy in infants. Currently, hypoallergenic infant formulas on the market are mainly divided into extensively hydrolyzed whey protein formulas and extensively hydrolyzed casein formulas. There are few extensively hydrolyzed infant formulas (EHFs) with a similar protein composition to breast milk. Therefore, we developed a hypoallergenic infant formula based on extensively hydrolyzed cow milk protein (whey protein-to-casein ratio of 6 : 4) and evaluated its allergenicity in vitro and in vivo . The results showed that the antigenicity of EHF was significantly decreased. The levels of Treg and Th1 cells were increased, while the levels of Th2 cells, IgE and IgG1, plasma histamine and serum mast cell enzymes were significantly decreased. At the same time, the allergic symptoms of the jejunum and lungs of mice were relieved. This study provides a solution for the development of cow milk protein based hypoallergenic infant formulas.

Purpose: Bovine mastitis poses a significant economic burden on the dairy industry worldwide. This pioneering proteomic study conducted a comparative profiling of milk somatic cell (SC) proteins contributing to mammary immune defense during subclinical and clinical mastitis (CM) in Sahiwal (Bos indicus) cows., Experimental Design: Based on California mastitis test (CMT) scores, milk SC counts, differential leukocyte counts (DLCs), and bacteriological culture results, quarter milk SC samples were categorized into healthy (H), subclinical mastitis (SCM), and CM groups. Comparative proteome profiling of milk SCs was done using a label-free liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) proteomic approach., Results: The identified upregulated proteins in mastitis groups such as Vanin 2, Thioredoxin reductase-like selenoprotein T, Ceramidase, Lymphocyte antigen 75, Misshapen-like kinase 1 (MINK1), Thrombospondin 1, Macrophage scavenger receptor 1, Leupaxin, and Lipoamide acyltransferase, involved in immune responses. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed immune functions and pathways like antigen processing, complement cascades, extracellular matrix receptor interaction, efferocytosis, leukocyte migration, chemokine, peroxisome proliferator-activated receptors (PPARs), and transforming growth factor (TGF)-beta signaling., Conclusions and Clinical Relevance: These findings provide essential information on proteomic profiling in milk SCs and contribute valuable insights into immune-related proteins regulated during mastitis in dairy cows. Further, validated proteins (Vanin 2, MINK1, and Thrombospondin 1) offer potential inflammatory biomarkers for early mastitis detection in dairy cows., (© 2024 Wiley‐VCH GmbH.)

Bovine mastitis remains a major problem in the global dairy cattle industry. The acute invasion of udder by pathogens induces innate immune response as the first defence mechanism in subclinical and clinical mastitis. The aim of the study was to determine inflammatory and regulatory cytokines IL-2, IL-4, TGF-β1, IL-17A, beta-defensin 3 and IL-10 and their potential changes in milk of dairy cows with subclinical and clinical mastitis, and to compare the findings with healthy animals. Milk samples from 15 holstein Friesian breed cows were used in the study. Cows were divided into three groups based on their health status (5 healthy, 5 subclinical and 5 clinical animals). All samples were tested using immunohistochemistry to evaluate IL-2, IL-4, IL-10, IL17A, TGF-β1 and β-Def 3 proteins. Expression of all proteins was detected in all milk samples. High expression of IL-2, IL-4, IL17A, TGF-β1 was detected in healthy cows' milk and in milk of cows with subclinical and clinical mastitis. However, expression of IL-10 and β-Def 3 in milk samples of healthy cows was significantly higher compared to the milk of cows with subclinical and clinical mastitis ( p  < .001). IL-10 and β-Def 3 can be considered as informative biomarkers in diagnosis of subclinical and clinical mastitis.

The underlying cause of differences in sensitization between bovine and caprine milk β-lactoglobulin (β-LG) remains unclear. In this study, denatured forms of bovine and caprine milk β-LG were obtained through reductive alkylation and evaluated for allergenicity and digestibility in Balb/c mice. Results indicated weaker sensitization to nondenatured caprine milk β-LG compared to nondenatured bovine milk β-LG, with no significant difference in sensitization observed between denatured β-LG from both sources. The nondenatured β-LG of caprine milk and two types of denatured β-LG were degraded more rapidly than nondenatured bovine milk β-LG in the small intestine of mice. In terms of undenatured proteins, mouse intestinal tissues absorbed more bovine milk β-LG than caprine milk β-LG. Overall, structural disparities in β-LG between bovine and caprine milk resulted in varying digestion rates. Moreover, the slower-degraded bovine milk β-LG and its enzymatic fragments facilitated easier absorption by the intestine, disrupting the Th1/Th2 balance and increasing susceptibility to severe allergic reactions in mice.

Due to the availability, scalability, and low immunogenicity, bovine milk-derived extracellular vesicles (MEVs) are increasingly considered to be a promising carrier of nanomedicines for future therapy. However, considering that extracellular vesicles (EVs) are of biological origin, different sources of EVs, including the host origin and the specific cells that produce the EVs, may have different effects on the structure and function of EVs. Additionally, MEVs play an important role in immune regulation, due to their evolutionary conserved cargo, such as cytokines and miRNAs. Their potential effects on different organs, as well as their accumulation in the human body, should not be overlooked. In this review, we have summarized current impacts and research progress brought about by utilizing MEVs as nano-drug carriers. Nevertheless, we also aim to explore the possible connections between the molecules involved in cellular immunity, cytokines and miRNAs of MEVs produced under different health conditions, and autoimmune diseases.

Asthma susceptibility is linked to dysbiosis in early-life gut microbiota, and the antibody secretory immunoglobulin (Ig)A (SIgA) is a key determinant of gut microbiota composition. SIgA is obtained through breast milk during the critical early-life window. We use a mouse model of SIgA deficiency and the house dust mite (HDM) model of asthma to elucidate the role of maternal SIgA in modulating the early-life gut microbiota and asthma protection. Mice that do not receive maternal SIgA display a transient bloom of segmented filamentous bacteria (SFB) in the small intestine during the early post-weaning period. Mice that do not receive maternal SIgA also display elevated T helper type 17 (Th17) cell activation in the intestine, which persists into adulthood and is associated with more severe inflammation in response to the HDM model of asthma. This study demonstrates a mechanism by which breast-milk-derived SIgA influences immune development and asthma susceptibility by modulating the early-life gut microbiota., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Streptococcus uberis is a member of the pyogenic cluster of Streptococcus commonly associated with intramammary infection and mastitis in dairy cattle. It is a poorly controlled globally endemic pathogen responsible for a significant cause of the disease worldwide. The ruminant mammary gland provides an atypical body niche in which immune cell surveillance occurs on both sides of the epithelial tissue. S. uberis does not cause disease in non-ruminant species and is an asymptomatic commensal in other body niches. S. uberis exploits the unusual niche of the mammary gland to initiate an innate response from bovine mammary macrophage (BMMO) present in the secretion (milk) in which it can resist the host immune responses. As a result - and unexpectedly - the host inflammatory response is a key step in the pathogenesis of S.uberis , without which colonisation is impaired. In contrast to other bacteria pathogenic to the bovine mammary gland, S. uberis does not elicit innate responses from epithelial tissues; initial recognition of infection is via macrophages within milk., Methods: We dissected the role of the bacterial protein SUB1154 in the inflammasome pathway using ex vivo bovine mammary macrophages isolated from milk, recombinant protein expression, and a panel of inhibitors, agonists, and antagonists. We combine this with reverse-transcription quantitative real-time PCR to investigate the mechanisms underlying SUB1154-mediated priming of the immune response., Results: Here, we show that SUB1154 is responsible for priming the NLRP3 inflammasome in macrophages found in the mammary gland. Without SUB1154, IL-1β is not produced, and we were able to restore IL-1β responses to a sub1154 deletion S. uberis mutant using recombinant SUB1154. Surprisingly, only by blocking internalisation, or the cytoplasmic TIR domain of TLR2 were we able to block SUB1154-mediated priming., Discussion: Together, our data unifies several contrasting past studies and provides new mechanistic understanding of potential early interactions between pyogenic streptococci and the host., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hinds, Ward, Archer and Leigh.)

Background: Infants aged <1 year with confirmed food allergies generally need to avoid causative foods completely for a certain period. Low-dose oral food challenges (LD-OFCs) may be an effective strategy for safely introducing small amounts of causative foods to individuals with food allergies. This study clarified the safety of LD-OFCs in infants aged <1 year with food allergies., Methods: We retrospectively analyzed the clinical records of LD-OFCs performed in infants aged <1 year allergic to hen's egg, cow's milk, or wheat between April 2014 and October 2017. Approximately 1/25th-1/20th of the egg white from a heated whole hen's egg, 3 mL heated cow's milk, and 2 g wheat noodles (udon) were used as challenge foods. We examined the LD-OFC results, including the induced symptoms and treatment required for positive LD-OFC results., Results: The LD-Egg, LD-Milk, and LD-Wheat OFC groups comprised 68, 42, and 13 participants, respectively. The positivity rates for the LD-Egg, LD-Milk, and LD-Wheat OFC groups were 7%, 24%, and 0%, respectively. Patients predominantly exhibited skin symptoms, and most were treated with oral antihistamines alone. None of the patients experienced anaphylaxis or required adrenaline injections., Conclusions: Infants aged <1 year with food allergies can safely undergo LD-OFCs by consuming low doses of causative foods. Avoiding the complete elimination of causative foods is an important strategy for managing infants with food allergies when initially introducing causative foods., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Consumption of raw cow's milk has repeatedly been shown to protect from asthma, allergies, and respiratory infections. As raw milk bears potential health hazards, it cannot be recommended for prevention. Therefore, we performed an intervention study with microbially safe but otherwise minimally processed cow's milk. Here we describe feasibility and safety of the trial., Methods: The MARTHA trial (DRKS00014781) was set up as a double-blind randomized intervention in a population residing in Bavaria. Infants from 6 to 36 months of age consumed minimally processed cow's milk (intervention arm) or ultra-heat-treated (UHT) semi-skimmed milk (comparator arm)., Results: At the age of 6 to 12 months, 260 infants were enrolled, with 72% having a family history of atopy. The extensive screening system for milk consumption and symptoms suggestive of adverse events was well accepted with 22,988 completed weekly surveys and an average completion of 82% surveys sent out. The children consumed the study milk on average on 457 days (61% of intervention days). The intervention proved to be safe without any case of milk allergy or milk intolerance under the intervention in both arms. All 6 cases of serious adverse events were unrelated to milk. The most common reason was unscheduled hospitalization of more than 3 days., Conclusions: The intervention with minimally processed milk and the study instruments proved feasible. During the age of 6 to 36 months, there was no increased risk of milk allergy in a population with a substantial proportion of family history of atopy., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Oral immunotherapy (OIT) has emerged as the most popular therapy for food allergy. However, data on the long-term adherence and efficacy of this approach are sparse., Objective: We aimed to assess the long-term adherence rates to OIT protocol and the associated risk of allergic reactions., Methods: Patients who completed milk OIT and reached a maintenance dose of 200 mL of milk were surveyed biannually on their dairy consumption and occurrence of allergic reactions. A survival analysis was performed to evaluate the association between the risk of reaction and the adherence to OIT maintenance protocol., Results: The cohort consisted of 50 patients. Only 56% of the cohort adhered to the protocol, which consisted of ingesting a minimum of 200 mL of milk at least 3 times per week. Adherent patients had a significantly reduced risk of allergic reactions as well as a reduced incidence of anaphylaxis, health care/emergency room visits, and epinephrine/antihistamine administration., Conclusions: The findings demonstrate the importance of consistent maintenance dose consumption in the management of food allergies, with regular milk consumption contributing to the maintenance of unresponsiveness and decreased risk of allergic symptoms., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Cow's milk and egg allergy affect approximately 1.9% and 0.9% of children, respectively. Dietary advancement therapies (DATs), including milk (ML) and egg (EL) ladders, and baked milk (BM-OIT) and baked egg (BE-OIT) oral immunotherapy, are potential therapeutic options for these patients., Objective: To perform systematic review and meta-analysis of the safety and efficacy of DATs in children with IgE-mediated milk or egg allergy., Methods: A systematic literature review was conducted, exploring 22 potential outcomes, with meta-analysis performed where ≥3 studies reported data. The GRADE approach was used to determine the certainty of evidence for each outcome, and the Johanna Briggs Institute tools were used for determining risk of bias., Results: Twenty-nine studies met inclusion criteria among 9946 titles screened. Tolerance occurred in 69% of EL, 58% of ML, 49% of BE-OIT, and 29% of BM-OIT patients. All-severity allergic reactions occurred in 21% of EL, 25% of ML, 20% of BE-OIT, and 61% of BM-OIT patients, with epinephrine use in 3% of EL, 2% of ML, and 9% of BM-OIT patients. At-home reactions occurred in 19% of BE-OIT and 10% of BM-OIT patients. Discontinuation occurred in 14% of EL, 17% of ML, 17% of BE-OIT, and 20% of BM-OIT patients. The mean time to BE egg and BE-OIT tolerance was 13.25 months (4 studies) and 19.1 months (3 studies). Certainty of evidence was very low, and risk of bias high. Study heterogeneity was high, attributable to multiple factors., Conclusions: There is very low certainty of evidence supporting DAT safety and efficacy. We cannot conclude that DAT accelerates tolerance development., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Porcine epidemic diarrhea virus (PEDV) causes severe enteric disease and high mortality in neonatal piglets, leading to significant economic losses in the swine industry. Considering that passive lactogenic immunity is crucial for preventing infection in piglets, necessitating a rapid and accurate tool to measure immunity levels. This study aims to develop a lateral flow immunochromatographic strip (LFICS) to assess IgA and IgG antibodies in colostrum and milk, using PEDV S protein. The performance of LFICS was compared to viral neutralization (VN) and enzyme-linked immunosorbent assay (ELISA) as reference methods, with a visual scoring system applied for field monitoring. Colostrum ( n = 82) and milk ( n = 106) samples were analyzed, showing strong correlation with reference methods and no cross-reactivity with other pig pathogens. The LFICS exhibited high relative sensitivity (Se) and specificity (Sp), with colostrum showing 98.73% Se and 66.67% Sp for IgA, and 96.15% Se and 75.00% Sp for IgG. Milk demonstrated 95.60% Se and 80.00% Sp for IgA, and 84.88% Se and 85.00% Sp for IgG. These findings indicate that the LFICS is a reliable, simple, and rapid method for measuring PEDV-specific IgA and IgG levels, offering valuable support for monitoring herd immunity and evaluating vaccination programs.

The quality and authenticity of milk are of paramount importance. Cow milk is more allergenic and less nutritious than ewe, goat, or donkey milk, which are often adulterated with cow milk due to their seasonal availability and higher prices. In this work, a silicon photonic dipstick sensor accommodating two U-shaped Mach-Zehnder Interferometers (MZIs) was employed for the label-free detection of the adulteration of ewe, goat, and donkey milk with cow milk. One of the two MZIs of the chip was modified with bovine κ-casein, while the other was modified with bovine serum albumin to serve as a blank. All assay steps were performed by immersion of the chip side where the MZIs are positioned into the reagent solutions, leading to a photonic dipstick immunosensor. Thus, the chip was first immersed in a mixture of milk with anti-bovine κ-casein antibody and then in a secondary antibody solution for signal enhancement. A limit of detection of 0.05% v / v cow milk in ewe, goat, or donkey milk was achieved in 12 min using a 50-times diluted sample. This fast, sensitive, and simple assay, without the need for sample pre-processing, microfluidics, or pumps, makes the developed sensor ideal for the detection of milk adulteration at the point of need.

Competing Interests: Disclosures The authors have no conflicts of interest to report.

Background: Anaphylaxis has been increasing in recent years, with common triggers in infants being milk and eggs. Currently, the mainstay of treatment for milk and/or egg allergy is strict avoidance. Recently, new therapies have emerged including stepwise introduction of allergens via a ladder approach. The suitability of infants for the ladders is debated., Objective: This study aims to focus on the use of food ladders in children with anaphylaxis to egg or milk., Methods: Retrospective review of pediatric patients diagnosed with immunoglobulin E-mediated milk and/or egg allergy between 2011 and 2021. Inclusion and exclusion criteria were applied. Anaphylaxis was defined as per the World Allergy Organization-amended criteria 2020. Data analysis utilized SPSS Version 28., Results: We reviewed 1,552 patient charts, and excluded 1,094, leaving a total sample size of 458. Seventy infants had anaphylaxis at diagnosis (milk n = 36; egg n = 34). A range of 77.8% to 85.2% of infants with anaphylaxis successfully completed the ladder, 88.9% to 92.9% without anaphylaxis were successful. Children who successfully completed the ladder did so at similar rates. A range of 20.6% to 50% children presenting with anaphylaxis at diagnosis experienced allergic symptoms during treatment, compared with 17.3% to 40.7% without anaphylaxis. Reactions were mild, mostly cutaneous and not requiring medical attention. Patients experiencing allergic symptoms while on the ladder were less likely to successfully complete treatment., Conclusions: Milk and egg ladders are a safe and effective way of inducing tolerance in infants, including those with a history of anaphylaxis at diagnosis. There are no obvious predictors for who will experience allergic reactions while on the ladder; however, these children are less likely to complete the ladder, so parents should be educated in management of mild allergic reactions at home., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In many parts of the world, goat milk has been part of the human diet for millennia. Allergy to goat's milk, not associated with allergy to cow's milk, is a rare disorder, although some cases have been described. Goat milk proteins have substantial homology with cow's milk proteins and even show cross-reactivity; therefore, they are not advised as an alternative to cow's milk for infants with IgE-mediated cow's milk allergies. However, there are indications that, due to the composition of the goat milk proteins, goat milk proteins show lower allergenicity than cow's milk due to a lower αS1-casein content. For this reason, goat milk might be a better choice over cow's milk as a first source of protein when breastfeeding is not possible or after the breastfeeding period. Additionally, some studies show that goat milk could play a role in specific types of non-IgE-mediated cow milk allergy or even in the prevention of sensitization to cow's milk proteins. This review discusses a possible role of goat milk in non-IgE mediated allergy and the prevention or oral tolerance induction of milk allergy.

The dynamic interplay between intramammary IgG, formation of antigen-IgG complexes and effector immune cell function is essential for immune homeostasis within the bovine mammary gland. We explore how changes in the recognition and binding of anti-LPS IgG to the glycolipid "functional" core in milk from healthy or clinically diagnosed Escherichia coli (E. coli) mastitis cows' controls endotoxin function. In colostrum, we found a varied anti-LPS IgG repertoire and novel soluble LPS/IgG complexes with direct IgG binding to the LPS glycolipid core. These soluble complexes, absent in milk from healthy lactating cows, were evident in cows diagnosed with E. coli mastitis and correlated with endotoxin-driven inflammation. E. coli mastitis milk displayed a proportional reduction in anti-LPS glycolipid core IgG compared to colostrum. Milk IgG extracts showed that only colostrum IgG attenuated LPS induced endotoxin activity. Furthermore, LPS-stimulated reactive oxygen species (ROS) in milk granulocytes was only suppressed by colostrum IgG, while IgG extracts of neither colostrum nor E. coli mastitis milk influenced N-formylmethionine-leucyl-phenylalanine (fMLP)-stimulated ROS in LPS primed granulocytes. Our findings support bovine intramammary IgG diversity in health and in response to E. coli infection generate milk anti-LPS IgG repertoires that coordinate appropriate LPS innate-adaptive immune responses essential for animal health., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors, SH, DF and RK are or were (DF) employees of Koru Diagnostics Ltd, confirm there is no individual personal financial relationship and declare that research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest. AP is a shareholder of Koru Diagnostics Ltd and as CSO was involved in conceptualisation, supervision, investigation and writing of the original draft. No payment or services from a third party was received for any aspect of the submitted work. In addition, selective concepts and data described in this manuscript are part of a patent submission by Koru Diagnostics Ltd, entitled “Method for Detecting Microorganisms and Uses Thereof” in November 2022. Patent Ref: PCT/NC2022/050136, #KDL1007PC. The raw data supporting the conclusions of this study are not readily available as they are proprietary and part of a pending patent submission. However, requests to access specific data should be directed to Koru Diagnostics Ltd info@korudiagnostics.com.

Background: Complete avoidance of milk is the usual management for IgE-mediated cow's milk protein allergy (CMPA). A baked milk ladder is a method of dietary advancement therapy in IgE-mediated CMPA in Ireland, while in Spain, avoidance of milk awaiting natural tolerance acquisition through an oral food challenge (OFC) is employed. The aim of this study was to evaluate the use of dietary advancement therapy using a milk ladder compared with complete avoidance of milk for managing IgE-mediated CMPA., Methods: This is a retrospective chart review of 371 pediatric patients from the population who have been treated for IgE-mediated CMPA between 2011 and 2020, with the milk ladder (Ireland) or complete avoidance followed by an OFC (Spain). The main outcome was the introduction of cow's milk., Results: Milk ladder patients were 3.67 times more likely to succeed in comparison with milk avoidance (p < .001). Anaphylaxis during the treatment period occurred in 34 patients in the milk avoidance groups, while three patients in the milk ladder group experienced anaphylaxis due to accidental exposure to milk (p < .001). Failure to complete treatment was associated with a higher skin prick test in the milk avoidance group and a raised specific IgE in the milk ladder group., Conclusion: This is the first study that compares outcomes of dietary advancement therapy to complete avoidance for CMPA management, demonstrating that cow's milk can be successfully and safely reintroduced using dietary advancement therapy using a milk ladder., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Cow milk allergy is one of the common food allergies. Our previous study showed that the allergenicity of fermented milk is lower than that of unfermented skimmed milk in vitro, and the antigenicity of β-lactoglobulin and α-lactalbumin in fermented milk was decreased by 67.54% and 80.49%, respectively. To confirm its effects in vivo, allergic BALB/C mice model was used to further study the allergenicity of fermented milk. It was found that compared with the skim milk (SM) group, the intragastrically sensitization with fermented milk had no obvious allergic symptoms and the fingers were more stable: lower levels of IgE, IgG, and IgA in serum, lower levels of plasma histamine and mast cell protein-1, and immune balance of Th1/Th2 and Treg/Th17. At the same time, intragastrically sensitization with fermented milk increased the α diversity of intestinal microbiota and changed the microbiota abundance: the relative abundance of norank-f-Muribaculaceae and Staphylococcus significantly decreased, and the abundance of Lachnospiraceae NK4A136 group, Bacteroides, and Turicibacter increased. In addition, fermented milk can also increase the level of short-chain fatty acids in the intestines of mice. It turns out that fermented milk is much less allergenicity than SM. PRACTICAL APPLICATION: Fermentation provides a theoretical foundation for reducing the allergenicity of milk and dairy products, thereby facilitating the production of low-allergenic dairy products suitable for individuals with milk allergies., (© 2024 Institute of Food Technologists.)

Infant formulas based on hydrolysed cow's milk proteins are used when breastfeeding is not feasible in cow's milk allergic infants. Camel milk has been shown to be well-tolerated by the majority of children with cow's milk allergy (CMA) and may be a substitute in management of CMA. Here we aimed to evaluate the impact of processing on immunogenicity, sensitising, antibody-binding and cross-reactive capacity of cow's and camel milk. Cow's and camel milk were processed by means of enzyme hydrolysis or heat treatment. Brown Norway rats were immunised with PBS, non-processed, enzyme hydrolysed or heat-treated cow's or camel milk. In vivo tests were performed for evaluation of clinical signs. Blood and faecal samples were analysed for levels and specificity of antibody responses. Cow's and camel milk showed similar sensitising capacity. Processing decreased the sensitising capacity of cow's milk, yet only enzyme hydrolysis but not heat treatment decreased the sensitising capacity of camel milk. Processing affected the specificity of antibodies raised in the rats, though the effect differed between cow's and camel milk. The study showed a low cross-reactivity between cow's and camel milk, which was decreased with processing, suggesting that processing of camel milk may improve its usefulness in CMA management., Competing Interests: Declaration of competing interest The study was performed during the PhD project of NZM, which was supported by Ausnutria Dairy (China) Co., Ltd, Changsha, Hunan, China. The company, however, did not participate in the study design, data acquisition, data analysis, data interpretation, or the decision where to publish. YG is an employee at Ausnutria Dairy (China) Co., Ltd, Changsha, Hunan, China., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Maternal synbiotic supplementation during pregnancy and lactation can significantly influence the immune system. Prebiotics and probiotics have a positive impact on the immune system by preventing or ameliorating among others intestinal disorders. This study focused on the immunomodulatory effects of B. breve M-16V and short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosachairdes (lcFOS), including systemic and mucosal compartments and milk composition., Methods: Lewis rats were orally administered with the synbiotic or vehicle during pregnancy (21 days) and lactation (21 days). At the weaning day, small intestine (SI), mammary gland (MG), adipose tissue, milk, mesenteric lymph nodes (MLN), salivary gland (SG), feces and cecal content were collected from the mothers., Results: The immunoglobulinome profile showed increased IgG2c in plasma and milk, as well as elevated sIgA in feces at weaning. The supplementation improved lipid metabolism through enhanced brown adipose tissue activity and reinforced the intestinal barrier by increasing the expression of Muc3 , Cldn4 , and Ocln . The higher production of short chain fatty acids in the cecum and increased Bifidobacterium counts suggest a potential positive impact on the gastrointestinal tract., Discussion: These findings indicate that maternal synbiotic supplementation during gestation and lactation improves their immunological status and improved milk composition., Competing Interests: JG is part time employee/scientific advisor of Danone Nutricia Research. RB-S is employee of Danone Nutricia Research, and KK was also at time of the experiment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sáez-Fuertes, Kapravelou, Grases-Pintó, Massot-Cladera, Bernabeu, Knipping, Garssen, Bourdet-Sicard, Castell, Rodríguez-Lagunas, Collado and Pérez-Cano.)

Maternal breast milk plays a key role in providing newborns with passive immunity and stimulating the maturation of an infant's immune system, protecting them from many diseases. It is known that diet can influence the immune system of lactating mothers and the composition of their breast milk. The aim of this study was to establish if a supplementation during the gestation and lactation of Lewis rats with extra virgin olive oil (EVOO), due to the high proportion of antioxidant components in its composition, has an impact on the mother's immune system and on the breast milk's immune composition. For this, 10 mL/kg of either EVOO, refined oil (control oil) or water (REF group) were orally administered once a day to rats during gestation and lactation periods. Immunoglobulin (Ig) concentrations and gene expressions of immune molecules were quantified in several compartments of the mothers. The EVOO group showed higher IgA levels in both the breast milk and the mammary glands than the REF group. In addition, the gene expression of IgA in mammary glands was also boosted by EVOO consumption. Overall, EVOO supplementation during gestation and lactation is safe and does not negatively affect the mother's immune system while improving breast milk immune composition by increasing the presence of IgA, which could be critical for an offspring's immune health.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by gastrointestinal symptom onset within 1-4 hours from trigger food ingestion. In the literature, some authors have previously described the possibility that a patient with FPIES may develop an IgE-mediated allergy to the same trigger food, especially cow's milk (CM). Case Presentation: We reported five cases of CM-FPIES converting to IgE-mediated CM allergy presented at our tertiary pediatric Allergy Unit and performed a review of the literature, aiming to characterize the clinical features of patients who are at risk of developing such conversion. Conclusions: This phenomenon raises the question of whether IgE-mediated and non-IgE-mediated allergies represent a spectrum of the same disease and highlights the need for further investigation to understand the pathophysiological mechanisms of this process.

Among the available diagnostic techniques, antibody detection in bulk tank milk (BTM) represents a useful tool to estimate and monitor Neospora caninum herd prevalence. To evaluate the prevalence of N. caninum and the effect of parasite infection on herd performances, BTM samples collected from 586 dairy herds located in one of the largest dairy production areas in Italy (Lombardy) were analyzed by an indirect ELISA to detect anti-N. caninum specific antibodies. Generalized linear models (GLMs) were developed. A purely spatial analysis scanning for clusters with high or low rates for N. caninum using the Bernoulli model was performed. A maximum entropy approach was used to estimate the probability of distribution of the parasite based on occurrence records together with environmental variables. Overall, 180 herds resulted positive for N. caninum antibodies on bulk tank milk (P = 30.7 %). A higher risk of seropositivity was evidenced in the provinces of Milano, Cremona, Brescia, and Bergamo (P = 32-40 %); a lower risk was evidenced in Lodi, Pavia, and Mantova (P = 13-24 %). A higher risk of seropositivity was revealed for small-medium farms (101-300 animals) (O.R.=2.8) and for older animals with more than 4 years (O.R.=4.4). Regarding the effect of N. caninum infection on herd performances, the number of inseminations for conception was higher (> 3 inseminations), and the period from calving to conception was longer (> 150 days) for positive farms (O.R.=2.0 and O.R.=2.3, respectively); besides, lower head daily milk production (<20 kg and 21-25 kg) and mature equivalent milk yield (<11,000), and somatic cell counts higher than 300,000 cells/ml were observed for N. caninum positive herds (O.R.=0.4, O.R.=0.4 and O.R.=1.9 respectively). The geographical distribution of N. caninum positive farms with the highest level of probability covers the central sector of the Po Plain where a significant cluster for high risk of parasite infection was shown by spatial scan statistic and Maximum entropy ecological niche modelling. A further significant cluster of low risk occurred in the southern. The climatic and environmental variables with the highest training gain when used in isolation resulted altitude, land use/land cover, and other variables related to temperature and precipitation. Neosporosis is widely distributed in Italian dairy herds and an impact of the parasite on herd performances could be hypothesized. Even if the role of N. caninum in alterations of reproductive and productive parameters should be further explored, veterinarians and farmers should be aware of neosporosis, and control plans should be adopted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier B.V.)

Background: Milk oral immunotherapy is the riskiest and most unpredictable form of oral immunotherapy. We aimed to produce a low allergenic product than conventional once baked-cake/muffin, to develop indirect in-house ELISA to check the tolerance status with milk products and evaluate IgE reactivity of patients' sera via western blotting (WB) and indirect in-house ELISA., Method: A low allergenic product named biscotti-twice baked-cake was developed, and the total protein concentration was determined. The protein content was studied by SDS-PAGE and proteomics. Milk-specific IgE (sIgE) binding assays were performed by WB and indirect in-house ELISA by using patients' sera., Results: Casein band intensity was observed to be lower in the biscotti-twice baked-cake than in the once baked-cake (p = .014). Proteomics analysis and αS1-casein measurement showed that the lowest intensity of casein was found in biscotti. The low binding capacity of milk sIgE to biscotti compared with once baked-cake was shown by WB (p = .0012) and by indirect in-house ELISA (p = .0001). In the ROC analysis, the area under the curve (AUC) of the in-house ELISA IgE was comparable with Uni-CAP milk and casein sIgE. The AUC of the in-house ELISA IgE for cake (0.96) and biscotti (1) was slightly better than Uni-CAP milk sIgE (0.94; 0.97) and casein sIgE (0.96; 0.97), respectively., Conclusion: The low allergenicity of the newly developed low allergenic product "biscotti-twice baked-cake" has been demonstrated by in vitro experiments. Biscotti could be a safe treatment option than once baked-cake/muffin in patients who are reactive to once baked-milk products., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Food allergy is widely recognized as a significant health issue, having escalated into a global epidemic, subsequently giving rise to the development of numerous additional complications. Currently, the sole efficient method to curb the progression of allergy is through the implementation of an elimination diet. The increasing number of newly identified allergens makes it harder to completely remove or avoid them effectively. The immunoreactivity of proteins of bacterial origin remains an unexplored topic. Despite the substantial consumption of microbial proteins in our diets, the immunologic mechanisms they might induce require thorough validation. This stands as the primary objective of this study. The primary objective of this study was to evaluate the effects of bacterial proteins on the intestinal barrier and immune system parameters during hypersensitivity induction in both developing and mature organisms. The secondary objective was to evaluate the role of lipids in the immunoreactivity programming of these bacterial proteins. Notably, in this complex, comprehensively designed in vitro, in vivo, and ex vivo trial, the immunoreactivity of various bacterial proteins will be examined. In summary, the proposed study intends to address the knowledge gaps regarding the effects of Lactobacillus microbial proteins on inflammation, apoptosis, autophagy, and intestinal barrier integrity in a single study., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ogrodowczyk, Romaszko. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bovine casein is a major allergen present in cow milk to induce anaphylaxis. In this study, the potential allergenicity of enzymatically hydrolyzed casein (HC) was evaluated based on in vitro and in vivo. The results showed that Alcalase and Protamex treatment (AT, PT) reduced the potential allergenicity of CN, with the greatest reductions of 68.25% and 50.75%, respectively. In addition, in vivo results showed that HC effectively alleviated allergic response symptoms of Balb/c mice; a significant tendency toward decreased serum IgG1 and mast cell tryptase levels was observed, accompanied by a decrease of Th2-associated IL-4, IL-5, and IL-13 and an increase of IFN-γ levels in spleen. Moreover, the inflammation of the lung, jejunum, and ileum was remarkably ameliorated. The findings indicated that HC induced a shift toward Th1 response and maintained the Th1/Th2 immune balance. Importantly, our results provide the basis for the production of hypoallergenic dairy products., (© 2024 Institute of Food Technologists.)

Introduction and Objectives: Food allergy has several negative nutritional consequences and may persist beyond the first year of lives. This study aimed to assess the role of a complete oral amino acid-based supplement in the diet of children on cow's milk protein elimination diet because of food allergy., Materials and Methods: This study included two groups of children aged 1-5 years paired by age and socioeconomic status: (1) study group, on cow's milk protein elimination diet plus an oral amino acid-based supplement, and (2) control group, on cow's milk protein elimination diet. Sociodemographic, clinical, anthropometric, and dietary data were obtained through online interviews. Two 24-h dietary recalls were collected on nonconsecutive days. Both groups comprised mostly boys., Results: The study group presented lower values of body mass index. The frequency of feeding difficulties was similar between groups. The study group had a higher intake of energy, protein, carbohydrates, calcium, iron, zinc, phosphorus, magnesium, copper, selenium, vitamins D, E, B1, B2, B6, and B12, niacin, and folic acid compared to the control group. A higher proportion of children in the study group had adequate intake according to the recommendations made for energy, carbohydrates, iron, phosphorus, selenium, vitamins A, D, E, B1, B2, and B6, and folic acid., Conclusions: The use of a complete oral amino acid-based supplement has a positive effect on the diet quality of preschoolers on cow's milk elimination diet because of food allergy, promoting higher intake of energy, calcium, vitamin D, and other essential nutrients., Competing Interests: Adriana Sanudo, Vanessa Cristina de Castro Rodrigues, and Mauro Batista de Morais received personal fees to develop this study. Thaysa Maués Cezar works the Medical Affairs Division of Danone Nutricia Brazil, and Camila Leonel Mendes de Abreu was working in the Medical Affairs Division of Danone Nutricia Brazil when this study was developed.

Background: The basophil activation test is an emerging clinical tool in the diagnosis of cow's milk allergy (CMA). The aim was to assess the association between the basophil allergen threshold sensitivity to the major milk protein casein (casein-specific CD-sens), the levels of milk- and casein-specific Immunoglobulin E antibodies (IgE-ab), and the severity of allergic reactions at milk challenges., Methods: We enrolled 34 patients aged 5-15 (median 9) years who underwent a double-blind placebo-controlled milk-challenge (DBPCMC) as screening before inclusion in an oral immunotherapy study for CMA. The severity of the allergic reaction at the DBPCMC was graded using Sampson's severity score. Venous blood was drawn before the DBPCMC. Milk- and casein-specific IgE-ab were analyzed. Following in vitro stimulation of basophils with casein, casein-specific CD-sens, was determined., Results: Thirty-three patients completed the DBPCMC. There were strong correlations between casein-specific CD-sens and IgE-ab to milk (r s  = 0.682, p < .001), and between casein-specific CD-sens and IgE-ab to casein (r s  = 0.823, p < .001). There was a correlation between the severity of the allergic reaction and casein-specific CD-sens level (r s  = 0.395, p = .041) and an inverse correlation between casein-specific CD-sens level and the cumulative dose of milk protein to which the patient reacted at the DBPCMC (r s  = -0.418, p = .027). Among the 30 patients with an allergic reaction at the DBPCMC, 67% had positive casein-specific CD-sens, 23% had negative casein-specific CD-sens, and 10% were declared non-responders., Conclusion: Two thirds of those reacting at the DBPMC had positive casein-specific CD-sens, but reactions also occurred despite negative casein-specific CD-sens. The association between casein-specific CD-sens and the severity of the allergic reaction and cumulative dose of milk protein, respectively, was moderate., (© 2024 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Bovine tuberculosis is usually diagnosed using tuberculin skin tests or at post-mortem. Recently, we have developed a serological test for bovine tuberculosis in cattle which shows a high degree of accuracy using serum samples. Here, we have assessed the performance of the test using individual bovine milk samples. The diagnostic specificity estimate using the high sensitivity setting of the test was 99.7% (95% CI: 99.2-99.9). This estimate was not altered significantly by tuberculin boosting. The relative sensitivity estimates of the test using the high sensitivity setting in milk samples from comparative skin test positive animals was 90.8% (95% CI: 87.1-93.6) with boosting. In animals with lesions, the relative sensitivity was 96.0% (95% CI: 89.6-98.7). Analysis of paired serum and milk samples from skin test positive animals showed correlation coefficients ranging from 0.756-0.955 for individual antigens used in the test. Kappa analysis indicated almost perfect agreement between serum and milk results, while McNemar marginal homogeneity analysis showed no statistically significant differences between the two media. The positive and negative likelihood ratio were 347.8 (95% CI: 112.3-1077.5) and 0.092 (95% CI: 0.07-0.13) respectively for boosted samples from skin test positive animals. The results show that the test has high sensitivity and specificity in individual milk samples and thus milk samples could be used for the diagnosis of bovine tuberculosis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:Amanda O’Brien, John Clarke, Alastair Hayton, Keith Cutler, Gordon Harkiss and Neil Watt declare commercial interests in the Enferplex Bovine TB antibody test. Darren Shaw and Andy Adler declare no competing interests., (Copyright: © 2024 O’Brien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Milk is a whitish liquid that is secreted from mammary glands; and considered as the primary source of nutrition for newborns since they are not able to digest solid food. However, it contains primary nutrients, as well as growth and immune factors. Early weaning is a critical issue that face women and their babies in developing countries. To avoid infant malnutrition, they tend to use other milk types instead of baby formula. Therefore, the present study aimed to evaluate the impact of cow, buffalo, goat or camel milk consumption on oxidative stress, inflammation and immune response in male and female Sprague Dawley rats post weaning time. The amino acids, fatty acids, minerals and vitamins in the tested milk types were evaluated. Animals were divided into 5 groups (control, cow, buffalo, goat and camel milk administrated groups) (10 rats/group); each animal was administrated by 3.4 ml/day. Rats were administered with milk for 6 weeks; at the end of the 5th week, five animals of each group were isolated and the remaining five animals were immunized with sheep red blood cells (SRBCs) and kept for another week to mount immune response. The effect of different milk types on rats' immune response towards SRBCs was evaluated through pro-inflammatory cytokines, antioxidants, ESR and CRP measurement; together, with the histopathological examination of spleen samples and hemagglutination assay. Camel milk consumption reduced oxidative stress and inflammation in spleen that resulted from SRBCs immunization; in addition to, B cell stimulation that was apparent from the high level of anti-SRBCs antibodies. Camel milk is recommended for newborn consumption, due to its high-water content, unsaturated fatty acids, and vitamin C, as well as low lactose and fat content., (© 2024. The Author(s).)

The immune system is sensitive to many chemicals. Among dioxin compounds, 2,3,7,8-tetrachlorodizenzo-p-dioxin (TCDD) is the most toxic environmental pollutant. The effects of perinatal maternal exposure to dioxins may persist into childhood. However, there have been no reports to date on the effects of exposure to dioxins during infancy, when the immune organs are developing. Therefore, we investigated the effects of TCDD and antigen exposure during lactation on immune function, especially antibody production capacity, in adult mice. Beginning the day after delivery, lactating mothers were orally administered TCDD or a mixture of TCDD and ovalbumin (OVA) daily for 4 weeks, until the pups were weaned. At 6 weeks of age, progeny mice were orally administered OVA daily for 10 weeks, while non-progeny mice were orally administered OVA or a mixture of TCDD and OVA daily for 10 weeks. Production of serum OVA-specific IgG was examined weekly. The amount of TCDD transferred from the mother to the progeny via breast milk was determined by measuring TCDD in the gastric contents of the progeny. A trend toward increasing IgA titer was observed in TCDD-treated mice, and production of IgE was observed only in progeny whose mothers were treated with TCDD and OVA. The results suggest that exposure to TCDD and OVA in breast milk can affect immune function in newborns.

Milk is an essential source of protein for infants and young children. At the same time, cow's milk is also one of the most common allergenic foods causing food allergies in children. Recently, cow's milk allergy (CMA) has become a common public health issue worldwide. Modern food processing technologies have been developed to reduce the allergenicity of milk proteins and improve the quality of life of patients with CMA. In this review, we summarize the main allergens in cow's milk, and introduce the recent findings on CMA responses. Moreover, the reduced effects and underlying mechanisms of different food processing techniques (such as heating, high pressure, γ-ray irradiation, ultrasound irradiation, hydrolysis, glycosylation, etc.) on the allergenicity of cow's milk proteins, and the application of processed cow's milk in clinical studies, are discussed. In addition, we describe the changes of nutritional value in cow's milk treated by different food processing technologies. This review provides an in-depth understanding of the allergenicity reduction of cow's milk proteins by various food processing techniques.

Introduction: The primary dietary approach for managing cow's milk allergy (CMA) is the elimination diet. We aimed to compare the growth patterns of children with CMA during and after the elimination diet with healthy peers and identify influencing factors., Methods: We compared 74 CMA children with age-matched healthy peers. Anthropometric data were collected during the third month of cow's milk elimination (CME) diet (T1), 3 months after diet cessation (T2), and after ≥3 months of normal diet (T3). Control group measurements coincided. Nutrient intake was assessed by a 3-day record, and patient laboratory results were noted at T3., Results: CMA children had consistently lower weight-for-age (WFA) and height-for-age (HFA) z-scores than controls. WtHt z-score of patients was lower than those of the healthy group at T2. HC z-scores of patients were lower than those of the healthy group at T0, T2, and T3. At T3, the HFA z-score of the CME group demonstrated a negative correlation with the duration of the elimination diet (p = 0.045). Inadequate intake of energy, vitamins A, E, B1, B6, C, folic acid, magnesium, and iron was significantly higher in CMA children (p &lt; 0.05). T3 WFA z-score correlated positively with fiber, vitamin B1, magnesium, and iron intake (p &lt; 0.05). T3 WtHt showed a positive moderate correlation with energy, protein, vitamin E, vitamin B1, vitamin B2, vitamin B6, calcium, magnesium, phosphor, iron intake (p &lt; 0.05)., Conclusions: Post-elimination diet, children with CMA need sustained monitoring and potentially micronutrient supplementation to match healthy peers' growth., (© 2024 S. Karger AG, Basel.)

Objective: Cases of cow's milk allergy (CMA) who reacted to measles or measles, mumps, and rubella (MMR) vaccines containing alpha-lactalbumin have been reported. The purpose of this study was to assess patients with CMA who received measles or MMR vaccines containing alpha-lactalbumin, as well as the characteristics of those who developed reactions to these vaccines. Study Design: Patients followed up in the allergy clinic for CMA and who received measles or MMR vaccines containing alpha-lactalbumin at 9 or 12 months of age were included in the study, and their characteristics were analyzed retrospectively from the hospital registry system. Results: Forty-nine patients were included in the study. Six patients received the measles vaccine, whereas 43 patients received the MMR vaccine containing alpha-lactalbumin. Vaccine skin tests were performed on these 6 patients. One patient had a positive intradermal test, so an alternative vaccine not containing alpha-lactalbumin was administered. The other 5 patients were vaccinated, and no reaction was observed. Anaphylaxis was observed in 3 of 43 patients who received the MMR vaccine containing alpha-lactalbumin. In all of these patients, the first reaction to dairy products was anaphylaxis. In 2 of those patients, cow's milk-specific IgE (spIgE) levels were >100 kU/L, and alpha-lactalbumin-spIgE levels were also high at 97 and 90 kU/L. The third patient's cow's milk-spIgE level was 15.9 kU/L, whereas the alpha-lactalbumin-spIgE level was 0.04 kU/L. Conclusion: Especially in patients with an initial reaction of anaphylaxis to dairy products and high cow's milk-spIgE levels, the risk of reaction is high with the MMR vaccine.

Breast milk immunoglobulin G (IgG) plays an important role in the transfer of passive immunity in early life and in shaping the neonatal immune system through N-glycan-mediated effector functions. Currently, there are no protocols available to analyze breast milk IgG-Fc glycosylation in mouse models. Therefore, we developed and validated a glycoproteomic workflow for the medium-throughput subclass-specific nano-LC-MS analysis of IgG enriched from small milk volumes of lactating mice. With the established methods, the IgG glycopatterns in a mouse model of antibiotic use during pregnancy and increased asthma susceptibility in the offspring were analyzed. Pregnant BALB/c mice were treated with vancomycin during gestation days 8-17 and IgG1F, IgG2, and IgG3-Fc glycosylation was subsequently analyzed in maternal serum, maternal breast milk, and offspring serum on postnatal day 15. The IgG glycosylation profiles of mouse maternal milk and serum revealed no significant differences within the glycoforms quantified across subclasses. However, vancomycin use during pregnancy was associated with changes in IgG-Fc glycosylation in offspring serum, shown by the decreased relative abundance of the IgG1F-G1 and IgG3-G0 glycoforms, together with the increased relative abundance of the IgG3-G2 and S1 glycoforms. The workflow presented will aid in the emerging integrative multi-omics- and glycomics-oriented milk analyses both in rodent models and human cohorts for a better understanding of mother-infant immunological interactions., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow’s milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.

The immune system during pregnancy teeters between maintaining fetal tolerance and providing protection against pathogens. Due to this delicate balance, pregnant women and their offspring often have increased susceptibilities to infection. During the first year of life, infant immunity against infection is mainly mediated via passively transferred maternal antibodies. However, our understanding of the route of transfer of the maternal antibodies for conferring protection to influenza A virus (IAV) infection in offspring is incomplete. Here we have demonstrated that offspring from IAV-infected mice were significantly protected against IAV infection. This remarkable increase in survival is mediated via the elevated maternal serum IgG1. By cross-fostering, we further showed that this enhanced host resistance was only achieved in mice born to and nursed by IAV-infected mothers. Collectively, our data suggest that the prolonged protection of offspring against IAV infection requires maternal IgG1 from both the placenta and breast milk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chronopoulos, Martin and Divangahi.)

Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobin E-mediated food hypersensitivity disorder. However, little is known about the clinical features of FPIES in patients with Down syndrome (DS). Medical records of children with DS diagnosed at our hospital between 2000 and 2019 were retrospectively reviewed. Among the 43 children with DS, five (11.6%) were diagnosed with FPIES; all cases were severe. In the FPIES group, the median age at onset and tolerance was 84 days and 37.5 months, respectively. Causative foods were cow's milk formula and wheat. The surgical history of colostomy was significantly higher in the FPIES group than in the non-FPIES group. A colostomy was performed in two children in the FPIES group, both of whom had the most severe symptoms of FPIES, including severe dehydration and metabolic acidosis. The surgical history of colostomy and postoperative nutrition of formula milk feeding may have led to the onset of FPIES. Therefore, an amino acid-based formula should be considered for children who undergo gastrointestinal surgeries, especially colostomy in neonates or early infants. When an acute gastrointestinal disease is suspected in children with DS, FPIES should be considered. This may prevent unnecessary tests and invasive treatments.

Lipopolysaccharide (LPS) can remain in dairy products after the sterilization of milk powder and may pose a threat to the health of infants and young children. There is a large amount of alkaline phosphatase (ALP) in raw milk, which can remove the phosphate bond of LPS, thus, detoxifying it. ALP is regarded as an indicator of the success of milk sterilization due to its strong heat resistance. ALP can alleviate the toxicity of LPS in enteritis and nephritis models, but the mechanism by which oral-intake of ALP protects liver tissue from LPS stimulation is unclear. In this study, an in vivo acute mouse liver injury model was induced by C. sakazakii LPS (200 μg/kg) and used to verify the protective mechanism of ALP (200 U/kg) on mice livers. The related pathways were also verified by in vitro cell culture. Enzyme linked immunosorbent assays (ELISAs), quantitative reverse transcription PCR (RT-qPCR) and western blotting were used to detect the levels of inflammatory factors at the protein level and RNA level, and to confirm the inflammation of liver tissue caused by LPS. ALP was found to alleviate acute liver injury in vitro by activating miR-146a. We found that ALP could up-regulate the level of miR146a and subsequently alleviates the expression of TLR4, TNF-α, matured IL-1β, and NF-κB in mouse liver tissue and hepatocytes; thus, reducing liver inflammation. Herein, we demonstrated for the first time that oral-intake of ALP protected liver tissue by up-regulating the expression of miR-146a and alleviating inflammatory reactions; thus, providing a research basis for the proper processing of milk. This study also suggests that producers should improve the awareness of the protective effects of bioactive proteins in raw milk., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The breastfeeding period is one of the most important critical windows in our development, since milk, our first food after birth, contains several compounds, such as macronutrients, micronutrients, antibodies, growth factors and hormones that benefit human health. Indeed, nutritional, and environmental alterations during lactation, change the composition of breast milk and induce alterations in the child's development, such as obesity, leading to the metabolic dysfunctions, cardiovascular diseases and neurobehavioral disorders. This review is based on experimental animal models, most of them in rodents, and summarizes the impact of an adequate breast milk supply in view of the developmental origins of health and disease (DOHaD) concept, which has been proposed by researchers in the areas of epidemiology and basic science from around the world. Here, experimental advances in understanding the programming during breastfeeding were compiled with the purpose of generating knowledge about the genesis of chronic noncommunicable diseases and to guide the development of public policies to deal with and prevent the problems arising from this phenomenon. This review article is part of the special issue on "Cross talk between periphery and brain"., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There are increasing global data relating to prevalence of food allergy and food-induced anaphylaxis; however, this is often based on surrogate measures of sensitization rather than objective symptoms at food challenge. In terms of protecting food-allergic consumers from reactions, to our knowledge, there has been no global survey assessing geographic differences in the proportion of anaphylaxis triggered by specific foods., Objective: We sought to identify common triggers for food-induced anaphylaxis and how these vary from country to country., Methods: Systematic review of relevant reports published between January 2010 and November 2020. Results were reported following PRISMA guidelines. Publications were screened and data extracted by 2 independent reviewers, and the risk of bias was assessed., Results: Sixty-five studies (encompassing 41 countries and all 6 regions as defined by the Food and Agriculture Organization of the United Nations) were included. Significant regional variations in the most common triggers of food anaphylaxis were seen; however, in general, there was good agreement between local legislative requirements for allergen disclosure and the most common allergens for each region or nation., Conclusions: Local legislation for allergen disclosure generally reflects those allergens commonly responsible for food anaphylaxis. Cow's milk and crustaceans appear to cause a higher proportion of anaphylaxis compared to peanut in some regions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Milk extracellular vesicles (mEVs) seem to be one of the main maternal messages delivery systems. Extracellular vesicles (EVs) are micro/nano-sized membrane-bound structures enclosing signaling molecules and thus acting as signal mediators between distant cells and/or tissues, exerting biological effects such as immune modulation and pro-regenerative activity. Milk is also a unique, scalable, and reliable source of EVs. Our aim was to characterize the RNA content of cow, donkey, and goat mEVs through transcriptomic analysis of mRNA and small RNA libraries. Over 10,000 transcripts and 2000 small RNAs were expressed in mEVs of each species. Among the most represented transcripts, 110 mRNAs were common between the species with cow acting as the most divergent. The most represented small RNA class was miRNA in all the species, with 10 shared miRNAs having high impact on the immune regulatory function. Functional analysis for the most abundant mRNAs shows epigenetic functions such as histone modification, telomere maintenance, and chromatin remodeling for cow; lipid catabolism, oxidative stress, and vitamin metabolism for donkey; and terms related to chemokine receptor interaction, leukocytes migration, and transcriptional regulation in response to stress for goat. For miRNA targets, shared terms emerged as the main functions for all the species: immunity modulation, protein synthesis, cellular cycle regulation, transmembrane exchanges, and ion channels. Moreover, donkey and goat showed additional terms related to epigenetic modification and DNA maintenance. Our results showed a potential mEVs immune regulatory purpose through their RNA cargo, although in vivo validation studies are necessary.

The determination of the somatic cell count of a milk sample is one of the most common methods to monitor udder health of a dairy cow. However, this procedure does not take into account the fact that cells in milk present a great variety of different cell types. The objective of our study was to establish a high-resolution differential cell count (HRDCC) by means of flow cytometry in blood and milk. We were able to detect ten subpopulations among the three main populations of immune cells and to determine their viability. Additionally, blood samples were analyzed for common laboratory biomarkers, i.e. differential blood counts, haptoglobin levels and several metabolic parameters. In this first feasibility study, we used three different vaccines to stimulate the immune system of five healthy cows each. Samples were collected shortly before, in between and after the vaccinations. Using multivariate statistical methods we saw a diagnostic benefit when HRDCCs were included compared to only the standard laboratory parameters. The impacts of all three vaccinations on the immune system were visible in blood HRDCCs as well as in milk HRDCCs. Cluster of Differentiation 8 + (CD8 + ) T cells, B cells and monocyte/macrophage subpopulations were among the most important and statistically relevant parameters for all treatments in both biofluids. Moreover, in one of the treatment groups intermediate monocytes showed a significant increase after both vaccinations. Although the use of HRDCC in blood or milk was shown to be highly relevant for early systemic diagnostic, to confirm these subpopulations further investigations in cows of different breed, lactation stage or health status are required., (© 2021. The Author(s).)

The function of antibodies, namely the identification and neutralization of pathogens, is mediated by their antigen binding site (Fab). In contrast, the subsequent signal transduction for activation of the immune system is mediated by the fragment crystallizable (Fc) region, which interacts with receptors or other components of the immune system, such as the complement system. This aspect of binding and interaction is more precise, readjusted by covalently attached glycan structures close to the hinge region of immunoglobulins (Ig). This fine-tuning of Ig and its actual state of knowledge is the topic of this review. It describes the function of glycosylation at Ig in general and the associated changes due to corresponding glycan structures. We discuss the functionality of IgG glycosylation during different physiological statuses, like aging, lactation and pathophysiological processes. Further, we point out what is known to date about Ig glycosylation in farm animals and how new achievements in vaccination may contribute to improved animal welfare., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zlatina and Galuska.)