It is well‐established that food proteins, such as egg, soya, cow's milk and wheat, are detectable in breastmilk for many hours or days after ingestion. Exposure to these proteins is important to the ...process of developing tolerance but can also sometimes elicit IgE‐mediated and non–IgE‐mediated allergic symptoms in breastfed infants. Non–IgE‐mediated allergy, outside of food protein‐induced allergic proctocolitis and eosinophilic oesophagitis, is not well understood, leading to variations in the diagnosis and management thereof. A primary objective of the European Academy for Allergy and Clinical Immunology is to support breastfeeding in all infants, including those with food allergies. A Task Force was established, to explore the clinical spectrum of non–IgE‐mediated allergies, and part of its objectives was to establish diagnosis and management of non–IgE‐mediated allergies in breastfed infants. Eight questions were formulated using the Patient, Intervention, Comparison, Outcome (PICO) system and Scottish Intercollegiate Guideline Network (SIGN) criteria for data inclusion, and consensus was achieved on practice points through the Delphi method. This publication aims to provide a comprehensive overview on this topic with practice points for healthcare professionals.
Background
We investigated the accuracy of tests used to diagnose food allergy.
Methods
Skin prick tests (SPT), specific‐IgE (sIgE), component‐resolved diagnosis and the atopy patch test (APT) were ...compared with the reference standard of double‐blind placebo‐controlled food challenge. Seven databases were searched and international experts were contacted. Two reviewers independently identified studies, extracted data, and used QUADAS‐2 to assess risk of bias. Where possible, meta‐analysis was undertaken.
Results
Twenty‐four (2831 participants) studies were included. For cows’ milk allergy, the pooled sensitivities were 53% (95% CI 33–72), 88% (95 % CI 76–94), and 87% (95% CI 75–94), and specificities were 88% (95% CI 76–95), 68% (95% CI 56–77), and 48% (95% CI 36–59) for APT, SPT, and sIgE, respectively. For egg, pooled sensitivities were 92% (95% CI 80–97) and 93% (95% CI 82–98), and specificities were 58% (95% CI 49–67) and 49% (40–58%) for skin prick tests and specific–IgE. For wheat, pooled sensitivities were 73% (95% CI 56–85) and 83% (95% CI 69–92), and specificities were 73% (95% CI 48–89) and 43% (95% CI 20–69%) for SPT and sIgE. For soy, pooled sensitivities were 55% (95% CI 33–75) and 83% (95% CI 64–93), and specificities were 68% (95% CI 52–80) and 38% (95% CI 24–54) for SPT and sIgE. For peanut, pooled sensitivities were 95% (95% CI 88–98) and 96% (95% CI 92–98), and specificities were 61% (95% CI 47–74), and 59% (95% CI 45–72) for SPT and sIgE.
Conclusions
The evidence base is limited and weak and is therefore difficult to interpret. Overall, SPT and sIgE appear sensitive although not specific for diagnosing IgE‐mediated food allergy.
The measurement of antigen-specific serum IgE is common in clinical assessments of type I allergies. However, the interaction between antigens and IgE won't invariably trigger mast cell activation. ...We previously developed the IgE crosslinking-induced luciferase expression (EXiLE) method using the RS-ATL8 mast cell line; however, the method may not be sensitive enough in some cases.
In this study, we introduced an NF-AT-regulated luciferase reporter gene into the RBL-2H3 rat mast cell line and expressed a chimeric high-affinity IgE receptor (FcεRI) α chain gene, comprising an extracellular domain from humans and transmembrane/intracellular domains from rats.
We generated multiple clones expressing the chimeric receptor. Based on their responsiveness and proliferation, we selected the HuRa-40 clone. This cell line exhibited significantly elevated human α chain expression compared to RS-ATL8 cells, demonstrating a 10-fold enhancement of antigen-specific reactivity. Reproducibility across different batches and operators was excellent. Moreover, we observed a detectable response inhibition by an anti-allergy drugs (omalizumab and cyclosporin A).
HuRa-40 cells—which carry the human-rat chimeric IgE receptor—comprise a valuable reporter cell line for the EXiLE method. Their versatility extends to various applications and facilitates high-throughput screening of anti-allergy drugs.
Crosslinking of IgE antibodies by multivalent antigens is a key event in allergic reactions. We established a novel cell line (HuRa-40) that expresses human-rat chimeric FcεRIα subunit and luciferase reporter gene. HuRa-40 cells enable highly sensitive measurements of IgE crosslinking-induced luciferase expression (EXiLE), compared with previously used RS-ATL8 cells. This is because HuRa-40 cells express abundant FcεRIα subunits. HuRa-40 cells are also well-suited for high-throughput screening of anti-allergic drugs due to their high reproducibility and wide dynamic range. Display omitted
•A novel human-rat chimeric FcεRI α chain was designed and expressed in rat mast cells.•The HuRa-40 clone abundantly expressed the chimeric receptor, enabling highly sensitive and reproducible EXiLE responses.•HuRa-40 cells are an ideal tool for high-throughput screening of anti-allergy drugs.
IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI ...expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses.
Summary
Background: Our understanding of the pathogenic role of IgE in atopic dermatitis is incomplete. We asked whether blocking free IgE would alter the course of the disease.
Patients and Methods: ...We administered either omalizumab, a humanized monoclonal mouse antibody against IgE, or placebo subcutaneously for 16 weeks to 20 atopic dermatitis patients and measured immunological and clinical disease parameters.
Results: Omalizumab (I) reduced free serum IgE, (II) lowered surface IgE and FcɛRI expression on different peripheral blood mononuclear cells, (III) reduced the saturation of FcɛRI with IgE, (IV) increased the number of free FcɛRI and (V) lowered the number of IgE+, but not of FcɛRI+ cells in skin. The in vivo relevance of these results is evidenced by the increase in the threshold allergen concentration required to give a type I hypersensitivity reaction in the titrated skin test. While not significantly altering the clinical disease parameters, omalizumab treatment led to an improvement of the atopy patch test results in single patients, i.e. an eczematous reaction upon epicutaneous allergen challenge.
Conclusions: The interference with immediate and delayed type skin tests may imply that a therapeutic benefit of omalizumab treatment, if present at all, would be seen in patients with acute rather than chronic forms of the disease.
Background
The value of aeroallergen skin testing is not known in IgE deficient individuals (IgE<2.5 kU/L).
Objective
To investigate the utility of skin prick (SPT), intradermal skin testing (IDST) ...and measuring serum specific IgE (ssIgE) in IgE deficient patients presenting with environmental allergy-like symptoms.
Methods
Individuals with IgE deficiency who had both SPT and IDST performed between 2010 to 2020 were matched (age and gender) to three different groups of non-IgE deficient patients with IgE≥2.5 kU/L (normal IgE 2.5 ≤ IgE<100, high IgE 100≤IgE<1000 and very high IgE levels ≥1000 kU/L) who also had skin testing performed for evaluation of environmental allergy-like symptoms.
Results
Among 34 IgE deficient patients who completed SPT and IDST, 52.9% (18/34) had at least one positive skin test (4 ± 3 positive tests/patient), compared with 91.2% in those with normal, 94.1% with high or 97.1% with very high IgE levels (p < 0.01). In contrast, only one of the IgE deficient patients had detectable ssIgE, while ssIgE levels were significantly higher in all other IgE subgroups. Allergic immunotherapy was prescribed for 22.2% of the IgE-deficient patients with positive skin tests, similar to those with normal (2/31, 6.5%, p = 0.21), high IgE (9/32, 28.1%, p = 0.25) and very high IgE levels (8/33, 23.5%, p = 0.07), with similar efficacy in their symptoms control.
Conclusion
Individuals with IgE deficiency may present with environmental allergy-like symptoms. A combination of SPT and IDST is useful for diagnosing aeroallergen sensitizations in these patients, indicating the presence of skin mast cell-bound IgE in some of these individuals, despite very low serum IgE levels. Further studies are needed to assess the exact significance of positive skin tests and the benefits of immunotherapy in this group.
Persisting adaptive humoral immunity relies on two key cell types: memory B lymphocytes and long-lived plasma cells. Independently from the specific Ig class they produce, those cells can on one side ...maintain immunity but on the other side account for dysimmune conditions or hypersensitivity. Stringent control is thus required for both their generation and their survival. Among Ig classes, IgE carries the most powerful pro-inflammatory properties, even at minimal concentration. IgE responses and memory, although protecting against parasites and certain venoms, can inversely mediate devastating effects. The long-term memory of anaphylactic responses against allergens thus stands as the black side of IgE responses, accounting for chronic conditions punctuated with dramatic acute adverse events, some eventually lethal. To manage both their value and their danger, the immune system has evolved with multiple and drastic safeguards around IgE responses, notably ensuring a “B-cell self control” which could now be exploited and reinforced by new specific therapeutic strategies.
La persistance de l’immunité humorale adaptative repose particulièrement sur 2 acteurs clés : les lymphocytes B mémoires et les plasmocytes à longue durée de vie. Indépendamment de la classe d’immunoglobuline produite, ces cellules peuvent maintenir tant la protection contre des pathogènes que des manifestations d’hypersensibilité ou d’immunopathologie. Elles requièrent donc une régulation stricte de leur génération comme de leur survie. Parmi toutes les classes d’immunoglobuline produites, l’IgE constitue l’anticorps aux propriétés les plus puissantes, pouvant déclencher des réactions inflammatoires majeures même à doses infimes. Les réponses et la mémoire de classe IgE, au rôle protecteur contre les parasites et certains venins ou toxines, sont conservées par l’évolution chez la quasi-totalité des mammifères. Cependant, les réponses anaphylactiques aux venins peuvent à l’inverse être dramatiques et la mémoire à long terme des sensibilisations et des réactions anaphylactiques contre les allergènes constitue le côté obscur des IgE, responsable de pathologies chroniques ponctuées d’évènements aigus parfois fatals. Face à leur utilité mêlée de dangerosité, l’évolution du système immunitaire a entouré les réponses IgE des cellules B de multiples et stricts garde-fous, un self-control naturel en renfort duquel s’ouvrent aujourd’hui de nouvelles voies thérapeutiques.
Background
Omalizumab is an effective and well‐tolerated treatment for chronic spontaneous urticaria (CSU). Markers and predictors of response are largely unknown, but needed to optimize omalizumab ...treatment. Omalizumab targets IgE, and IgE levels may be linked to the effects of treatment. We evaluated whether response rates to treatment with omalizumab in patients with CSU are linked to their baseline IgE levels, their IgE levels after omalizumab treatment, and the ratio of on treatment IgE and baseline IgE levels.
Methods
Chronic spontaneous urticaria (CSU) patients (n = 113) were treated with omalizumab 300 mg/4 weeks for 12 weeks, when their treatment responses, that is, no, partial, or complete response, were assessed by use of the urticaria activity score, physician and patient visual analog scale, and treatment effectiveness score. Total IgE levels were measured before treatment (bIgE) with omalizumab and 4 weeks thereafter (w4IgE).
Results
Nonresponders to omalizumab had significantly lower bIgE levels (17.9, 17.0‐55.0 IU/mL) than partial responders (82.0, 46.2‐126.5 IU/mL, P = .008) and complete responders (73.7, 19.45‐153.8 IU/mL, P = .032). Nonresponders also had lower w4IgE levels and lower ratios of w4IgE/bIgE levels than partial and complete responders (P < .001). Nonresponse to omalizumab was best predicted by patients' w4IgE/bIgE ratios, significantly better than by bIgE levels (P = .016).
Conclusions
In CSU, total IgE levels and their change predict the response to treatment with omalizumab. The assessment of pre‐ and post‐treatment IgE levels and their ratio may help to improve the management of CSU in patients who require omalizumab treatment.
EAACI Molecular Allergology User's Guide Matricardi, P. M.; Kleine-Tebbe, J.; Hoffmann, H. J. ...
Pediatric allergy and immunology,
20/May , Letnik:
27, Številka:
S23
Journal Article
Recenzirano
Odprti dostop
The availability of allergen molecules (‘components’) from several protein families has advanced our understanding of immunoglobulin E (IgE)‐mediated responses and enabled ‘component‐resolved ...diagnosis’ (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low‐abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross‐reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE‐mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross‐reactive panallergens from plant (lipid transfer proteins, polcalcins, PR‐10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE‐mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.
Background
Allergic rhinoconjunctivitis is a public health problem. Allergen Immunotherapy is an effective and safe treatment, that modifies the natural course of allergic disease and induces ...long‐term tolerance.
Objective
To correlate basophil and antibody biomarkers of subcutaneous immunotherapy to clinical outcomes and cellular changes in target tissue.
Methods
Adults suffering from allergic rhinoconjunctivitis due to grass pollen allergy were randomized to receive subcutaneous immunotherapy (n = 18) or to an open control group (n = 6). Patients reported daily symptom and medication scores and weekly rhinitis related quality of life scores during four pollen seasons. Biomarkers were measured every 3 months for three years treatment and every 6 months in the follow‐up year. Nasal and cutaneous allergen challenge tests were performed annually. Leukocyte subsets were assessed in nasal mucosa biopsies at baseline and after treatment.
Results
Subcutaneous immunotherapy led to a 447‐fold decrease in basophil sensitivity during the first treatment year. This remained 100‐fold lower than baseline during the 3 year‐treatment period and 10‐fold lower during the follow‐up year (n = 18, P = .03). Decrease in basophil sensitivity after three weeks of treatment predicted long‐term improvement in seasonal combined symptom and medication scores (ῥ=−0.69, P = .0027) during three years of treatment. AUC of IgE‐blocking factor correlated to nasal allergen challenge (ῥ = 0.63, P = .0012) and SPT (ῥ = 0.45, P = .03). Plasma cell numbers in the nasal mucosa increased during treatment (P = .02).
Conclusion
Decrease in basophil sensitivity after three weeks of subcutaneous allergen immunotherapy predicted the clinical outcome of this treatment.
Grass SCIT leads to a 447‐fold decrease in basophil sensitivity during the first treatment year. AUC of IgE‐blocking factor correlates to nasal challenge and SPT. Decrease in basophil sensitivity during the first three weeks predicts the long‐term clinical improvement during subcutaneous immunotherapy and may represent the biomarker of choice for recommending continued SCIT treatment.
Abbreviations: AUC, area under the curve; SCIT, subcutaneous immunotherapy; SPT, skin prick test
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