Ozlem Cavkaytar

Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β

The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.

Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis

To inform the development of the European Academy of Allergy and Clinical Immunologys (EAACI) Guidelines on Allergen Immunotherapy (AIT) for allergic asthma, we assessed the evidence on the effectiveness, cost‐effectiveness and safety of AIT.

Modulation of immune responses by immunotherapy in allergic diseases.

Allergen immunotherapy (AIT) has been used for 100 years and until now different immunoregulatory pathways have been shown to take place in its mechanisms of action. It is characterized by administration of the causative allergen and is shown to be clinically efficient even after discontinuation of therapy particularly in allergic respiratory diseases, bee venom allergy, and food allergy. Generation of antigen/allergen-specific peripheral tolerance is the key mechanism during immunotherapy. It is mediated by development of T and B regulatory cells, IgG4 isotype allergen-specific antibodies and the involvement of multiple suppressor factors, which lead to decreased tissue inflammation, early and late phase responses. Describing novel regulatory mechanisms in the process of immune tolerance induction will help to identify treatment modalities not only for allergic disorders, but also for autoimmune diseases, organ transplantation, chronic infections, and cancer.

Serum basal tryptase may be a good marker for predicting the risk of anaphylaxis in children with food allergy.

A relationship between serum basal tryptase (sBT) levels, anaphylactic reactions, and clonal mast cell diseases was shown recently in adults with venom allergy, but the relationship between sBT levels and IgE‐mediated food allergy and anaphylaxis is not known. In this study, children with food allergy (FA; n = 167) were analyzed in two groups according to the presence (FA+/A+; n = 79) or absence of anaphylaxis (FA+/A−; n = 88) and were compared with a control group (n = 113). Median sBT values in FA+/A+, FA+/A−, and control groups were 4.0 ng/ml (2.8–5.8), 3.6 (2.3–4.5), and 3.3 (2.4–4.4), respectively (P = 0.022). sBT measurements higher than the cutoff values of 5.7 and 14.5 were associated with 50% and 90% predicted probabilities, respectively, of moderate to severe anaphylaxis. Children with tree nuts/peanut allergies had significantly higher levels of sBT than children with milk and egg allergy (P = 0.022). Results suggest that sBT levels may predict moderate to severe anaphylaxis in children with food allergy, which may follow a particular pattern according to the food allergy phenotype.

Different Phenotypes of Non-Steroidal Anti-Inflammatory Drug Hypersensitivity during Childhood

Background: Although non-steroidal anti-inflammatory drug hypersensitivity (NSAID-H) has been widely studied in adults, there is still a lack of data regarding the features and phenotypes of NSAID-H in children. Our aim was to define risk factors and different phenotypes according to clinical patterns. Methods: Patients with a history of reaction to any NSAIDs referred between January 2012 and October 2014 were included. After completing a European Network for Drug Allergy (ENDA) questionnaire, initial skin and/or oral provocation tests (OPTs) were performed for the offending drug. Additional OPTs were done with aspirin in case of NSAID-H to determine cross-reactivity. NSAID-hypersensitive patients were defined as being either a selective responder (SR) or cross-intolerant (CI) and further categorized according to either the ENDA/GA2LEN classification or an alternative scheme by Caimmi et al. [Int Arch Allergy Immunol 2012;159:306-312]. Results: Among 121 patients [58.7% male, average age 7.8 years (4.7-10.8)] with 161 NSAID-related reactions, 110 patients with 148 reactions were assessed. NSAID-H was diagnosed in 30 (27%) patients with 37 (25%) reactions. Multivariate regression analysis revealed that an immediate-type reaction and respiratory symptoms during the reaction increased the risk of a reproducible NSAID-related reaction (OR 3.508, 95% CI 1.42-8.7, p = 0.007; OR 3.951, 95% CI 1.33-11.77, p = 0.014, respectively). Additional OPTs revealed 13 SRs and 14 CIs. A family history of allergic disease was more frequent in CIs compared to SRs (57.1 vs. 15.4%, p = 0.031). Reactions belonging to CIs were more frequently characterized by angioedema compared to those of SRs (81.3 vs. 46.2%, p = 0.019). SRs and CIs were further classified as single NSAID-induced urticaria/angioedema and/or anaphylaxis (n = 13), NSAID-induced urticaria/angioedema (n = 7), NSAID-exacerbated cutaneous disease (n = 2) and NSAID-exacerbated respiratory disease (n = 1). Four CIs could not be categorized according to either classification system. One SR could not be categorized according to ENDA/GA2LEN. Conclusion: During childhood, NSAID-H exhibits different phenotypes and the majority of them can be categorized with current classification systems; however, classifications based on adult data may not exactly fit NSAID-H in paediatric patients.

Allergen immunotherapy for allergic asthma: Protocol for a systematic review

AbstractBackgroundThe European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for Allergic Asthma. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of allergic asthma. MethodsWe will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. DiscussionThe findings from this review will be used to inform the development of recommendations for EAACI’s Guidelines on AIT.

Challenge-proven aspirin hypersensitivity in children with chronic spontaneous urticaria.

Nonsteroidal anti‐inflammatory drug (NSAID) exacerbated cutaneous disease is defined as the exacerbation of wheals and/or angioedema in patients with a history of chronic spontaneous urticaria (CSU). The objective of this study was to define ‘aspirin‐hypersensitive’ children and adolescents in a clearly defined group of patients with CSU and to describe their clinical features.

Cor a 14, Hazelnut-Specific IgE, and SPT as a Reliable Tool in Hazelnut Allergy Diagnosis in Eastern Mediterranean Children

BACKGROUND Improving the diagnostic efficacy of laboratory tests might reduce the need for oral food challenges and facilitate our daily practice. OBJECTIVE We aimed to determine cutoff values and probability curves, as well as to investigate the role of component-resolved diagnosis in predicting clinical reactivity in children with hazelnut allergy and to evaluate the association with pollen sensitivity. METHODS A total of 56 children with hazelnut allergy who underwent double-blind placebo-controlled food challenge and 8 children who experienced anaphylaxis after accidental hazelnut intake were included. Serum IgE levels to hazelnut extract, Cor a 1, Cor a 8, Cor a 9, Cor a 14, and Bet v 1 were measured with the ImmunoCAP system. Skin prick tests (SPT) with hazelnut, other implicated foods, and aeroallergens were performed. RESULTS The optimal cutoff levels for hazelnut sIgE and SPT wheal diameter that predicted clinical reactivity with the highest sensitivity and specificity were 3.15 kU/L and 7.5 mm, respectively. Among the components, only Cor a 14 discriminated between reactive and nonreactive children. The area under curve (AUC) at the optimal cutoff point of 0.63 kU/L for Cor a 14 (0.936) was higher than the AUC of hazelnut sIgE (0.818) and SPT wheal diameter (0.803). For the first time, a 95% probability for clinical reactivity was estimated for SPT wheal diameter, IgE to hazelnut extract, and to Cor a 14 at 12 mm, 10.2 kU/L, and 1.0 kU/L, respectively. CONCLUSION Cor a 14 was found to be a useful and reliable tool for predicting clinical reactivity in children with hazelnut allergy in the Eastern Mediterranean area.

Low indoleamine 2,3-dioxygenase activity in persistent food allergy in children.

Indoleamine 2,3‐dioxygenase (IDO), which degrades tryptophan (Trp) to kynurenine (Kyn), has been demonstrated to contribute to modulation of allergic responses. However, the role of IDO in food allergy has not yet been elucidated.

Egg yolk: An unusual trigger of food protein-induced enterocolitis syndrome

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