Mannoprotein (MP), a major structural molecule in yeast cell walls, has been shown to interact with C-type lectin receptors (CLRs) on antigen-presenting cells (APCs). This study investigated the immunological properties of MP isolated from Saccharomyces cerevisiae. We found that S. cerevisiae MP significantly enhanced the production of the anti-inflammatory cytokine IL-10, but not pro-inflammatory cytokines, in murine dendritic cells via the CLR Dectin-2. Considering therapeutic potential of IL-10 for allergies, we tested the anti-allergic effect of MP in a murine food allergy model. Dietary MP supplementation markedly attenuated the development of allergic symptoms. This suppression was associated with enhanced IL-10 and reduced effector T cell cytokines, IFN-γ, IL-4, IL-5, IL-17A, in lymphoid tissues, alongside decreased IgE levels and intestinal mast cell counts. Gut microbiome analysis revealed increased abundance of Turicibacter and Clostridium sensu stricto 1 in MP-fed mice, although levels of key immunomodulatory metabolites such as short-chain fatty acids and most bile acids remained largely unchanged. These results suggest that S. cerevisiae MP primarily modulates immune responses by promoting IL-10 production through a direct effect on APCs, thereby attenuating Th2-driven food allergy. This study supports the potential of yeast-derived MP as a dietary component with significant immunomodulatory activity.

Currently, there is great interest in the use of pectins for prebiotic treatment of food allergy. Hence, the effects of two different esterified pectins - low methoxyl citrus-derived pectin (CP-DElow) and high methoxyl apple-derived pectin (AP-DEhigh) - were evaluated in peach allergic patients due to sensitization to lipid transfer proteins (LTPs). This study analyzed the systemic immune response, the gut microbiota composition (using 16S rRNA gene sequencing), and microbial-derived metabolome, including short-chain fatty acids (SCFAs) and bile acids (BAs). Prebiotic treatment with both pectins was safe and induced a significant clinical increase in allergen tolerance in more than 50 % of patients. Additionally, CP-DElow and AP-DEhigh groups exhibited a distinctive systemic proteomic profile characterized by a decrease in various inflammatory cytokines compared to Placebo. Regarding microbiota, CP-DElow induced an increase in Bacteroides_H genus and Roseburia intestinalis species, whereas AP-DEhigh was associated with an increase in Bifidobacterium and Succinivibrio genera, and Faecalibacterium prausnitzii species. Reduced concentrations of branched SCFAs were observed after both treatments compared to Placebo. Likewise, fecal levels of microbial-derived secondary BAs were modified by pectin supplementation. Multi-omics integration revealed distinctive signatures in pectin- and placebo-treated patients. This study suggests that pectin treatment is a promising and safe option for LTP allergy.

Recent advancements in genomics and "omic" technologies have ushered in a transformative era referred to as personalized or precision medicine. This innovative approach considers the unique genetic profiles of individuals, along with a range of variability factors, to devise tailored disease treatments and prevention strategies that cater to the distinct needs of each patient. Although the terms personalized medicine and precision medicine are frequently utilized interchangeably, it is essential to delineate the subtle distinctions between them. Personalized medicine concentrates on bespoke treatments and prevention strategies that are meticulously tailored for each individual. Conversely, precision medicine utilizes advanced gene sequencing and comprehensive data analytics to formulate specific treatments and prevention strategies for defined groups of individuals based on genetic, environmental, and lifestyle factors rather than focusing exclusively on individual patients. Therefore, precision medicine constitutes an extension of traditional personalized care, improving the accuracy of diagnosis, prognosis, and therapy estimations for each patient through the application of sophisticated molecular diagnostics and advanced imaging techniques enabled by recent technological innovations. The shift from personalized to precision medicine has gained considerable traction, particularly in the wake of the 2015 US Precision Medicine Initiative, which has further stimulated advancements in this domain. This review will explore multiomics approaches that have facilitated the evaluation of personalized biomarkers associated with allergen immunotherapy, particularly in the treatment of allergic diseases. By leveraging these innovative methodologies, we aspire to cultivate more effective and individualized patient care, ultimately enhancing health outcomes for individuals with allergies.

The US Food and Drug Administration (FDA) hosted a workshop on February 22, 2024, to discuss the status of biomarkers in drug development for allergic asthma and food allergy. The workshop provided a forum for open discussion among regulators, academicians, National Institutes of Health staff and industry to inform stakeholders of the requirements for the FDA to adopt a biomarker as a surrogate end point for a clinical trial, and to inform FDA of the status of various biomarkers in development. The workshop was divided into 3 sessions: (1) FDA and European Union regulators discussing regulatory perspectives on use of biomarkers in drug development programs, (2) investigators discussing biomarkers for pediatric and adult asthma, and (3) investigators discussing biomarkers for food allergy. In this report, we review the information presented at the workshop and summarize the current status of potential biomarkers for these allergic diseases.

Die Europ & auml;ische Akademie f & uuml;r Allergie und klinische Immunologie (EAACI) hat in einem Positionspapier eine aktualisierte Nomenklatur f & uuml;r allergische Erkrankungen erarbeitet, die den Fortschritten des Wissens und der Forschung auf dem Gebiet der Immunologie und Allergologie aufzeigt. Dieser neue Ansatz nutzt Krankheitsendotypen auf der Basis von Biomarkern und immunologischen und metabolischen Pathomechanismen f & uuml;r eine & Uuml;berarbeitung der derzeitigen Krankheitstaxonomie. & Uuml;berempfindlichkeitsreaktionen werden in die Typen I-VII eingeteilt. Die urspr & uuml;nglich von Gell und Coombs klassifizierten Antik & ouml;rper-vermittelten Reaktionen vom Typ I, Typ II und Typ III wurden erweitert und mit ihren Verbindungen zu neu beschriebenen klinischen Zust & auml;nden detailliert definiert (Teil 1 und 2 dieses Beitrags). Zellvermittelte Reaktionen vom Typ IVa (T1), Typ IVb (T2) und Typ IVc (T3) wurden auf der Grundlage der neuen Erkenntnisse & uuml;ber T1-, T2- und T3-Reaktionen weiter klassifiziert (Teil 3). Im vorliegenden Teil 4 werden wir nun epitheliale Barrieredefekte (Typ V), stoffwechselbedingte Immundysregulationen (Typ VI) und direkte zellul & auml;re und entz & uuml;ndliche Reaktionen auf chemische Substanzen (Typ VII) als gewebsbedingte Mechanismen darstellen. The European Academy of Allergy and Clinical Immunology (EAACI) has developed an updated Nomenclature for allergic Diseases in a Position Paper that reflects the Progress of Knowledge and Research in the Field of Immunology and Allergology. This new Approach uses Disease Endotypes based on Biomarkers and Immunological and metabolic Pathomechanisms to revise the current Disease Taxonomy. Hypersensitivity Reactions are divided into Types I-VII. The Antibody-mediated Type I, Type II and Type III Reactions originally classified by Gell and Coombs have been expanded and defined in detail with their Links to newly described clinical Conditions (Parts 1 and 2 of this Article). Cell-mediated Reactions of Type IVa (T1), Type IVb (T2) and Type IVc (T3) were further classified on the Basis of the new Findings on T1, T2 and T3 Reactions (Part 3). In this Part 4 we will now present epithelial Barrier Defects (Type V), metabolic Immune Dysregulation (Type VI) and direct cellular and inflammatory Reactions to chemical Substances (type VII) as tissue-related Mechanisms.

IntroductionRecombinant allergens are an important diagnostic tool for determining the IgE-sensitization profile of patients, assessing the risk of symptom severity and potential clinical cross-reactivity. In this context, the use of different host cells for recombinant expression must be evaluated in terms of IgE reactivity and diagnostic value. Therefore, recombinant Ara h 2, the major peanut allergen, was produced in yeast, structurally characterized and investigated in respect to IgE-binding and allergenic properties.MethodsAra h 2 was produced as recombinant protein using yeast and E. coli expression systems. Purified proteins were assessed using SDS-PAGE (reducing and non-reducing conditions), CD-spectroscopy and IgE-reactivity.ResultsRecombinant Ara h 2wt expressed in yeast resulted in an additional predominant band of approximately 12 kDa upon DTT treatment. In contrast, the molecular mass of rAra h 2 expressed in E. coli (Ara h 2E.coli) remained unaffected by reduction. Analysis of rAra h 2wt confirmed the presence of two Ara h 2-derived peptides, one with the expected N-terminus and the other with an N-terminal glycine residue. In silico analysis revealed the presence of a Kex2 cleavage site (R58R59*G60). To test whether Kex2 cleavage affects an IgE-epitope, mutagenesis of this cleavage site from R58 to E58 (Ara h 2mut) was performed. DTT treatment of rAra h 2mut purified from yeast showed that no cleavage of the protein had occurred. No effect on IgE binding could be observed as all rAra h 2 preparations showed IgE-reactivity. Cross-linking of human serum IgE and monoclonal human Ara h 2-specific IgE antibodies showed comparable mediator release in response to Ara h 2wt and rAra h 2mut. However, utilizing a specific combination of human Ara h 2-specific IgE antibodies revealed slight epitope diversity between wildtype and mutated rAra h 2.DiscussionAn endogenous protease, like Kex2 from the expression system, can affect the structural integrity of the target protein, leading to a slightly altered epitope structure. Even this finding has little or no impact for diagnosis, a suitable expression system and a detailed physico- and immunochemical characterization of recombinant allergens prior to their use as a diagnostic tool are of great importance.

Die Europäische Akademie für Allergie und klinische Immunologie (EAACI) hat in einem Positionspapier eine aktualisierte Nomenklatur für allergische Erkrankungen erarbeitet, die den Fortschritten des Wissens und der Forschung auf dem Gebiet der Immunologie und Allergologie aufzeigt. Dieser neue Ansatz nutzt Krankheitsendotypen auf der Basis von Biomarkern und immunologischen und metabolischen Pathomechanismen für eine Überarbeitung der derzeitigen Krankheitstaxonomie. Überempfindlichkeitsreaktionen werden in die Typen I-VII eingeteilt. Die ursprünglich von Gell und Coombs klassifizierten Antikörper-vermittelten Reaktionen vom Typ I, Typ II und Typ III wurden erweitert und mit ihren Verbindungen zu neu beschriebenen klinischen Zuständen detailliert definiert (Teil 1 und 2 dieses Beitrags). Zellvermittelte Reaktionen vom Typ IVa (T1), Typ IVb (T2) und Typ IVc (T3) wurden auf der Grundlage der neuen Erkenntnisse über T1-, T2- und T3-Reaktionen weiter klassifiziert (Teil 3). Im vorliegenden Teil 4 werden wir nun epitheliale Barrieredefekte (Typ V), stoffwechselbedingte Immundysregulationen (Typ VI) und direkte zelluläre und entzündliche Reaktionen auf chemische Substanzen (Typ VII) als gewebsbedingte Mechanismen darstellen.

The Therapy Allergen Ordinance (TAO) aims to migrate allergen immunotherapy (AIT) products for the treatment of common allergies, which were previously marketed in Germany as named patient products (NPP), into authorized products if their quality, efficacy, and safety are adequately shown. The TAO applies to all NPP containing active ingredients based on the following allergen sources: house dust mites, bee venom, wasp venom, pollen from sweet grasses (excluding maize), birch, alder, or hazel. The last product-specific deadlines granted under the TAO for the submission of clinical data relevant to the marketing authorization process will expire in 2026. The subsequent final assessment of the updated marketing authorization application (MAA) is carried out by the competent authority, the Paul-Ehrlich-Institut. During this period of processing by the competent authority, the products remain marketable until the marketing authorization application has been decided on. Currently (as of 08.08.2025), 40 AIT products are still marketable under the transitional provisions of the TAO (10 preparations for the treatment of allergies to house dust mites, 10 against tree pollen allergies, 16 against grass pollen allergies and 4 mixed preparations containing non-homologous allergen groups). For 8 of these products, the pharmaceutical companies have initiated the withdrawal of MAA as of 01.10.2025 or 31.01.2026, respectively. Prior to the final assessment of the updated MAAs, the competent authority is unable to make any public statements as to whether the individual applications for the remaining 32 products under the transitional provision will be concluded positively with the granting of MA or MA rejection. With the rejection of a MA, the product-specific marketability ends immediately, i.e., there is no additional sell-off period for the TAV products concerned. If a marketing authorization is granted, the marketability of the specific product is sustained.

Since 2006, the responsible regulatory bodies have proposed five health-based guidance values (HBGV) for bisphenol A (BPA) that differ by a factor of 250,000. This range of HBGVs covers a considerable part of the range from highly toxic to relatively non-toxic substances. As such heterogeneity of regulatory opinions is a challenge not only for scientific risk assessment but also for all stakeholders, the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) analyzed the reasons for the current discrepancy and used this example to suggest improvements for the process of HBGV recommendations. A key aspect for deriving a HBGV is the selection of appropriate studies that allow the identification of a point of departure (PoD) for risk assessment. In the case of BPA, the HBGV derived in the 2023 EFSA assessment was based on a study that reported an increase of Th17 cells in mice with a benchmark dose lower bound (BMDL40) of 0.53 µg/kg bw/day. However, this study does not comply with several criteria that are important for scientific risk assessment: (1) the selected end-point, Th17 cell frequency in the spleen of mice, is insufficiently understood with respect to health outcomes. (2) It is unclear, by which mechanism BPA may cause an increase in Th17 cell frequency. (3) It is unknown, if an increase of Th17 cell frequency in rodents is comparably observed in humans. (4) Toxicokinetics were not addressed. (5) Neither the raw data nor the experimental protocols are available. A further particularly important criterion (6) is independent data confirmation which is not available in the present case. Previous studies using other readouts did not observe immune-related adverse effects such as inflammation, even at doses orders of magnitude higher than in the Th17 cell-based study. The SKLM not only provides here key criteria for the use of such studies, but also suggests that the use of such a “checklist” requires a careful and comprehensive scientific judgement of each item. It is concluded that the Th17 cell-based study data do not represent an adequate basis for risk assessment of BPA.

Mass spectrometry (MS) has advanced greatly and many of its applications are ready for utilization within regulatory procedures and could significantly contribute to overcome challenges in standardization of allergen products. It seems sensible to discuss MS within the regulatory framework, before addressing technical questions. While the application to purified proteins is well established from product development to manufacturer's release analytics, its application to complex products such as allergen products is still under development. It needs to be determined where it can complement or replace established methods or where MS offers limited improvement. Despite its technical appeal and versatility, currently MS is mentioned in regulatory guidelines only as one possible measurement method. For example, no specific MS method is given in the European Pharmacopoeia. We discuss applications of MS within the EU regulatory framework. This includes their advantages and disadvantages and their positioning between research, characterization, manufacturer's release analytics and official batch testing. We discuss the qualitative detection of single and multiple allergens as proof of identity, qualitative to semi-quantitative protein profiles for batch to batch consistency testing, and quantification of allergens to state mass units of allergens. MS may also facilitate standardization of allergen products, reference products and reference standards.

Food allergens represent a novel class of active ingredients in Allergen Immunotherapy (AIT). At the given time, only one oral AIT-product for the treatment of peanut allergy has been granted marketing authorization by EMA and FDA. In this article, regulatory aspects of the clinical assessment of food AIT products are summarized, some of which may be useful and potentially transferable to development of other treatment approaches for food allergy. Since this article focuses on immunotherapy, it does not address preclinical studies nor the development, production, characterization and specification of monoclonal antibodies or other symptomatic therapeutic approaches.

BackgroundCelery root is known to cause severe allergic reactions in patients sensitized to mugwort pollen.ObjectiveTo study clinically well-characterized patients with celery allergy by IgE testing with a comprehensive panel of celery allergens to disentangle the molecular basis of the “celery-mugwort-syndrome”.MethodsPatients with suspected food allergy to celery underwent a standardized interview. Main inclusion criteria were a positive food challenge with celery or an unambiguous case history of severe anaphylaxis. IgE to celery allergens (rApi g 1.01, rApi g 1.02, rApi g 2, rApi g 4, nApi g 5, rApi g 6, rApi g 7), and to mugwort allergens (rArt v 1, rArt v 3, rArt v 4) were determined by ImmunoCAP. IgE levels ≥ 0.35kUA/L were regarded positive.ResultsSeventy-nine patients with allergy to celery were included. Thirty patients suffered from mild oral or rhino-conjunctival symptoms and 49 from systemic reactions. Sixty-eight % had IgE to celery extract, 80% to birch pollen and 77% to mugwort pollen. A combination of Api g 1.01, 1.02, 4, 5, and 7 increased diagnostic sensitivity for celery allergy to 92%. The LTPs Api g 2 and Api g 6 were not relevant in our celery allergic population. IgE to Api g 7, detected in 52% of patients, correlated closely (r=0.86) to Art v 1 from mugwort pollen. Eleven out of 12 patients with monosensitization to Api g 7 were IgE negative to celery extract. The odds ratio for developing a severe anaphylactic reaction rather than only mild oral symptoms was about 6 times greater (odds ratio 5.87; 95% CI 1.08-32.0, p=0.0410) for Api g 7 sensitized versus Api g 7 non-sensitized subjects.ConclusionThere is an urgent need for routine diagnostic tests to assess sensitization to Api g 7 not only to increase test sensitivity, but also to identify celery allergic patients at risk of a severe allergic reaction to celery.

Scope Edible insects contain allergens with potential cross‐reactivity to other invertebrates. Here, this study examines IgE‐reactive proteins in a house cricket snack ( Acheta domesticus ) leading to an allergic reaction in a 27‐year old man followed by a similar reaction days later after eating shrimps. Methods and results Prick to prick tests verify the IgE‐mediated allergy to crickets and skin prick testing confirms a type I sensitization to house dust mite without any clinical relevance for the patient, and to shrimp extracts, but is negative for several other foods. Serological testing reveals a sensitization to shrimps, shrimp tropomyosin, and house dust mite tropomyosin. IgE‐immunodetection shows that the cricket allergic patient is sensitized to two proteins of 45 and >97 kDa using aqueous control cricket extract, but to only one protein at around 45 kDa when using the causative, seasoned insect snack extract. Mass spectrometry data and IgE‐inhibition experiments clearly identify this protein belonging to the tropomyosin allergen family. Conclusion This case report suggests that cricket tropomyosin may be an elicitor of allergic reactions even in previously not allergic patients, although it cannot be excluded the patient reacted additionally to other ingredients of the snack.

Current reports increasingly associate dietary "advanced glycation end products" ("AGEs") resulting from the Maillard reaction (glycation) between reducing sugars and amino compounds in foods with pathophysiological consequences, such as chronic inflammation, atherosclerosis, and metabolic syndrome. Heated foods are therefore suggested to pose a potential risk for human health. However, studies in this field are very often based on questionable quantitative data and inadequate structural characterization. To improve the situation, the present perspective suggests quality criteria for future studies and the assessment of the currently available literature.