PIPE-cloned human IgE and IgG4 antibodies: New tools for investigating cow's milk allergy and tolerance.
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ABSTRACT:
SUBMITTER: Pranger CL
PROVIDER: S-EPMC8247298 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe dynamics and balance of allergen-specific IgE, IgG4, and IgA binding might contribute to the development of tolerance in patients with cow's milk allergy (CMA). Profiling of antibody binding to cow's milk (CM) protein epitopes might help in predicting the natural history of allergy.ObjectiveWe sought to investigate differences in IgE, IgG4, and IgA binding to CM epitopes over time between patients with early recovery or with persisting CMA.MethodsWe studied serum samples at the time of diagnosis (mean age, 7 months), 1 year later, and at follow-up (mean age, 8.6 years) from 11 patients with persisting IgE-mediated CMA at age 8 to 9 years and 12 patients who recovered by age 3 years. We measured the binding of IgE, IgG4, and IgA antibodies to sequential epitopes derived from 5 major CM proteins with a peptide microarray-based immunoassay. We analyzed the data with a novel image-processing method together with machine learning prediction.ResultsIgE epitope-binding patterns were stable over time in patients with persisting CMA, whereas binding decreased in patients who recovered early. Binding patterns of IgE and IgG4 overlapped. Among patients who recovered early, the signal of IgG4 binding increased and that of IgE decreased over time. IgE and IgG4 binding to a panel of alpha(s1)-, alpha(s2)-, beta-, and kappa-casein regions predicted outcome with significant accuracy.ConclusionsAttaining tolerance to CM is associated with decreased epitope binding by IgE and a concurrent increase in corresponding epitope binding by IgG4.
| S-EPMC3289532 | biostudies-literature
Project description:BackgroundOral immunotherapy (OIT) with cow's milk (CM) has been reported to induce a number of specific antibody responses, but these remain to be fully characterized. Our objective was to explore whether IgE and IgG4 epitope binding profiles could predict the risk of side effects during CM OIT.MethodsThe study population consisted of 32 children (6-17 yr of age) with CM allergy: 26 children who successfully completed OIT and six children who discontinued therapy due to adverse reactions. We investigated sera drawn before and after OIT. We analyzed specific IgE and IgG4 binding to CM protein-derived peptides with a microarray-based immunoassay. Antibody binding affinity was analyzed with a competition assay where CM proteins in solution competed with peptides printed on the microarray.ResultsIgE binding to CM peptides decreased and IgG4 binding increased following the OIT in children who attained desensitization. Compared with children who successfully completed OIT, those who discontinued OIT due to adverse reactions developed increased quantities and affinity of epitope-specific IgE antibodies and a broader diversity of IgE and IgG4 binding, but less overlap in IgE and IgG4 binding to CM peptides.ConclusionsDetailed analysis of IgE and IgG4 binding to CM peptides may help in predicting whether CM OIT will be tolerated successfully. It may thus improve the safety of the therapy.
| S-EPMC3997594 | biostudies-literature
Project description:Food allergy (FA) and, in particular, IgE-mediated cow's milk allergy is associated with compositional and functional changes of gut microbiota. In this study, we compared the gut microbiota of cow's milk allergic (CMA) infants with that of cow's milk sensitized (CMS) infants and Healthy controls. The effect of the intake of a mixture of Bifidobacterium longum subsp. longum BB536, Bifidobacterium breve M-16V and Bifidobacterium longum subsp. infantis M-63 on gut microbiota modulation of CMA infants and probiotic persistence was also investigated. Gut microbiota of CMA infants resulted to be characterized by a dysbiotic status with a prevalence of some bacteria as Haemophilus, Klebsiella, Prevotella, Actinobacillus and Streptococcus. Among the three strains administered, B.longum subsp. infantis colonized the gastrointestinal tract and persisted in the gut microbiota of infants with CMA for 60 days. This colonization was associated with perturbations of the gut microbiota, specifically with the increase of Akkermansia and Ruminococcus. Multi-strain probiotic formulations can be studied for their persistence in the intestine by monitoring specific bacterial probes persistence and exploiting microbiota profiling modulation before the evaluation of their therapeutic effects.
| S-EPMC7915344 | biostudies-literature
Project description:BackgroundOral food challenge (OFC) is useful for diagnosing food allergies and assessing tolerance, but severe reactions may occur during the procedure.ObjectiveTo characterize the frequency and severity of reactions during cow's milk (CM) OFCs.MethodsA cross-sectional study was conducted to analyze the outcome of cow's milk oral food challenges (CMOFCs) performed to confirm IgE-mediated CM allergy or to assess food tolerance. CM was given first as baked milk (BM), followed by whole CM if there was no prior reaction to BM. An OFC was considered positive if IgE-mediated symptoms developed up to 2 h after ingestion. Symptoms were described and variables including age at OFC, prior anaphylaxis, other atopic diseases, and skin test results were compared according to the OFC outcomes.ResultsA total of 266 CMOFCs were performed, including 159 patients with a median age of 6.3 years old. One hundred thirty-six tests were positive and 62 resulted in anaphylaxis. Thirty-nine anaphylactic reactions were observed up to 30 min after the first dose. Severe anaphylaxis (cardiovascular and/or neurological involvement) was reported in 5 tests. A second dose of epinephrine was required in 3 tests, and 1 presented a biphasic response. Younger patients had a higher risk of anaphylaxis during baked milk oral food challenge (BMOFC) (p = 0.009). The frequency of anaphylaxis was higher in patients submitted to BM (p = 0.009).ConclusionsAnaphylaxis is a known complication of CMOFCs even when there is no prior anaphylaxis or when conducted with baked products. This study reinforces the importance of conducting OFC in appropriate settings with a well-trained team.
| S-EPMC10209878 | biostudies-literature
Project description:Amino acid-based formulas (Aaf) are increasingly used in children with cow's milk allergy (CMA). To be labeled hypoallergenic these formulas must demonstrate in clinical studies that they don't provoke reactions in 90% of subjects with confirmed CMA with 95% confidence when given in prospective randomized, double-blind, placebo-controlled challenge (DBPCFC) trials. The majority of available safety data on Aaf derived from patients with IgE-mediated CMA. Considering substantial differences in the immunologic mechanism and clinical presentation of non-IgE-mediated CMA it's important to investigate the hypoallergenicity of these formulas also in these patients. We prospectively assessed the tolerance to a new commercially available Aaf in children affected by IgE- or non-IgE-mediated CMA.Consecutive patients affected by IgE- or non-IgE-mediated CMA, aged ? 4 years, were enrolled. DBPCFC was carried out with increasing doses of the new Aaf (Sineall, Humana, Milan, Italy), using validated Aaf as placebo. Faecal concentrations of calprotectin (FC) and eosinophilic cationic protein (ECP) were monitored.Sixty patients (44 male, 73.3%, median age 37, 95%CI 34.5-39.6 months, IgE-mediated CMA 29, 48.3%) were enrolled. At the diagnosis clinical symptoms were gastrointestinal (46.6%), cutaneous (36.6%), respiratory (23.3%), and systemic (10.0%). After DBPCFC with the new Aaf, no patient presented early or delayed clinical reactions. Faecal concentration of calprotectin and of ECP remained stable after the exposure to the new Aaf.The new Aaf is well tolerated in children with IgE- or non-IgE-mediated CMA, and it could be used as a safe dietotherapy regimen for children with this condition.The trial was registered in the ClinicalTrials.gov Protocol Registration System (ID number: NCT01622426).
| S-EPMC3583738 | biostudies-literature
Project description:BackgroundAmino acid-based formula (AAF) is a relevant dietary strategy for paediatric patients affected by cow's milk allergy (CMA). The present study was designed to evaluate the hypoallergenicity of a new AAF in children with immunoglobulin (Ig)E-mediated CMA.MethodsAccording to the criteria provided by the American Academy of Pediatrics Subcommittee on Nutrition and Allergic Diseases, we designed a prospective trial in CMA children (aged 1-36 months) aimed to demonstrate the hypoallergenicity of the new AAF in 90% of subjects with 95% confidence during the double-blind, placebo-controlled challenge (DBPCFC). A skin prick test (SPT) with the new AAF was also performed.ResultsTwenty-nine children [all Caucasian, 55.2% male, mean age (±SD) 16.9 ± 5.7 months] were enrolled. The SPT and the DBPCFC with the new AAF were negative in all study subjects.ConclusionsThe study results support the hypoallergenicity of the new AAF. This formula could be considered an additional dietary option for non-breastfed children affected by CMA.Trial registrationThe trial was registered in the ClinicalTrials.gov Protocol Registration System (ID number: NCT03909113 ).
| S-EPMC8254988 | biostudies-literature
Project description:Cow's milk allergy (CMA) is one of the earliest and most common food allergy and can be elicited by both IgE- or non-IgE-mediated mechanism. We previously described dysbiosis in children with IgE-mediated CMA and the effect of dietary treatment with extensively hydrolyzed casein formula (EHCF) alone or in combination with the probiotic Lactobacillus rhamnosus GG (LGG). On the contrary, the gut microbiota in non-IgE-mediated CMA remains uncharacterized. In this study we evaluated gut microbiota composition and fecal butyrate levels in children affected by non-IgE-mediated CMA. We found a gut microbiota dysbiosis in non-IgE-mediated CMA, driven by an enrichment of Bacteroides and Alistipes. Comparing these results with those previously obtained in children with IgE-mediated CMA, we demonstrated overlapping signatures in the gut microbiota dysbiosis of non-IgE-mediated and IgE-mediated CMA children, characterized by a progressive increase in Bacteroides from healthy to IgE-mediated CMA patients. EHCF containg LGG was more strongly associated with an effect on dysbiosis and on butyrate production if compared to what observed in children treated with EHCF alone. If longitudinal cohort studies in children with CMA will confirm these results, gut microbiota dysbiosis could be a relevant target for innovative therapeutic strategies in children with non-IgE-mediated CMA.
| S-EPMC6104073 | biostudies-literature
Project description:Introduction Cow's milk protein allergy (CMPA) is the most commonly encountered food allergy in the world, usually seen in infants under the age of 2 years. This study aims to determine the factors including COVID-19 affecting formula compliance of CMPA patients. Methods This study is a prospective, observational study based on 10 different Paediatric Allergy-Immunology clinics in Turkey. Patients aged between 6 months and 2 years, who were followed up with IgE-mediated CMPA treatment or newly diagnosed and using breast milk and/or formula were included in the study. The sociodemographic characteristics of the patients, their symptoms, the treatments they received, and the effects of the COVID-19 pandemic on adherence to formula were evaluated with a questionnaire administered to the parents. Results The compliance rate for formula-based treatment was 30.8% (IQR: 28.3, SD: 21.86). The number of patients with a single and multiple food allergy was 127 (51.6%) and 71 (28.9%), respectively. Breastfeeding duration, daily amount of prescribed formula and addition of sweetener to the formula were found to reduce compliance (p = 0.010, p = 0.003, and p = 0.004, respectively). However, it was determined that the patient's height, weight, age at diagnosis, and age of formula onset did not have a significant effect on compliance. Conclusion It was found that the duration of breastfeeding, the increase in the daily amount of formula requirement, and the addition of sweeteners had adverse effects on formula compliance. There was no significant correlation between the formula adherence of CMPA patients and the pandemic.
| S-EPMC10198129 | biostudies-literature
Project description:BackgroundEpigenetic changes in DNA methylation could regulate the expression of several allergy-related genes. We investigated whether tolerance acquisition in children with immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) is characterized by a specific DNA methylation profile of Th2 (IL-4, IL-5) and Th1 (IL-10, IFN-γ)-associated cytokine genes.ResultsDNA methylation of CpGs in the promoting regions of genes from peripheral blood mononuclear cells and serum level of IL-4, IL-5, IL-10 and INF-γ were assessed in children with active IgE-mediated CMA (group 1), in children who acquired tolerance to cow's milk proteins (group 2) and in healthy children (group 3). Forty children (24 boys, aged 3 to 18 months) were enrolled: 10 in group 1, 20 in group 2, and 10 in the control group. The DNA methylation profiles clearly separated active CMA patients from healthy controls. We observed an opposite pattern comparing subjects with active IgE-mediated CMA with healthy controls and group 2 children who outgrew CMA. The IL-4 and IL-5 DNA methylation was significantly lower, and IL-10 and INF-γ DNA methylation was higher in active IgE-mediated CMA patients. Gene promoter DNA methylation rates of all cytokines and respective serum levels were strongly correlated. Formula selection significantly influenced cytokine DNA methylation profiles in group 2.ConclusionsTolerance acquisition in children with IgE-mediated CMA is characterized by a distinct Th1 and Th2 cytokine gene DNA methylation pattern. These results suggest that DNA methylation may be a target for CMA prevention and treatment.
| S-EPMC4391731 | biostudies-literature
Project description:Among the four immunoglobulin G (IgG) subclasses, IgG4 is the least represented in serum of a healthy human and it is considered an "odd" antibody. The IgG4 antibody has unique structural features that affect its biological function. These include the ability to undergo antigen-binding fragment (Fab)-arm exchange, to create fragment crystallizable (Fc) - Fc binding with other IgG4 and other IgG subclass antibodies, have a unique affinity profile for Fc gamma receptors (Fc?Rs) and no binding to complement component C1q. Altogether, these characteristics support anti-inflammatory roles of IgG4 leading to immune tolerance. Under conditions of chronic antigenic stimulation and Th2-type inflammation, both tissue and serum IgG4 levels are increased. This review seeks to highlight how in allergen immunotherapy IgG4 can confer a protective role as a "blocking" antibody and safeguard from subsequent allergen exposure, while IgG4 can confer immunomodulatory functions to support malignancy. While Th2 conditions drive polarization of macrophages to the M2a subtype, chronic antigen stimulation drives B cell class switching to IgG4 to further support phenotypical macrophage changes towards an M2b-like state. M2b-like macrophages can secrete chemokine (C-C motif) ligand 1 (CCL1) and interleukin-10 (IL-10) to support regulatory cell recruitment and to further shape a tolerogenic microenvironment. Thereby, IgG4 have a Janus-faced role, favorable in allergy but detrimental in cancer.
| S-EPMC7404042 | biostudies-literature