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Mite allergens
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Enrique Fernández-Caldas, Leonardo Puerta, Luis Caraballo, Victor Iraola, Richard F. Lockey
As the complex nature of IgE synthesis became more evident, the discovery of “beyond MHC” immune response genes influencing IgE was more frequent. Polymorphisms in Th2 genes, for instance, those in the gene encoding interleukin 4 at the 5q31 locus [257,258] and the signal transducer and activator of transcription 6 (STAT6) [259], have been replicated in different populations. Associations with mite sensitization also have been reported with polymorphisms in the genes encoding interleukin-18 (IL-18) [260,261], leukotriene C4 synthase (LTC4S) [262], nitric oxide synthase 1 (NOS1) [263], interleukin-4 receptor alpha (ILR4A) [257], dendritic cell associated nuclear protein 1 (DCNP1) [264], interferon regulatory factor 1 (IRF-1) [265], CD14 [266,267], Janus kinase 2 (JAK2), GATA binding protein 3 (GATA3), CD40, and interleukin-5 receptor alpha (IL5RA) [268], all of them participating in any of the multiple steps of IgE synthesis. The significant associations with polymorphisms in innate immune genes suggest that genetic effects exert their influences at very early phases of the response. These loci include the complement component 3 (C3) associated with the specific IgE levels to D. pteronyssinus [269], the myeloid differentiation factor 2 (MD2) associated with the specific IgE levels to D. pteronyssinus and Der p 2 [270], and the nucleotide-binding oligomerization domain containing 1 (NOD1) associated with mite sensitization [268].
Current options and investigational drugs for the treatment of eosinophilic esophagitis
Published in Expert Opinion on Investigational Drugs, 2022
Sonsoles Tamarit-Sebastian, Francisco Miguel Ferrer-Soler, Alfredo J Lucendo
Benralizumab is a more promising antibody which, instead of blocking soluble IL-5, is directed against the α chain of the IL-5 receptor (IL5RA), which enhances antibody-dependent cellular cytotoxicity and reduces eosinophils [123]. It has been approved to treat eosinophilic asthma in adolescents and adults, after demonstrating a superior effectiveness when compared to IL-5 blockers [124], and also providing benefit to patients with, among other conditions, hypereosinophilic syndrome [125] and EoE [126]. It is suggested that benralizumab normalizes the function of gastrointestinal eosinophils and improves digestive symptoms, and endoscopic features, as well as additional markers of disease activity. The effects of beralizumab are being investigated in eosinophilic gastritis in an on-going placebo-controlled RCT (NCT03473977) began in 2018. Recently, a phase 3 RCT was started in adolescent and adult patients with active EoE to compare the effectiveness of this drug, over placebo, on EoE histopathology and symptoms along a 24-week course of treatment, followed by a 28-week open-label period (NCT04543409).
Drug treatment strategies for eosinophilic esophagitis in adults
Published in Expert Opinion on Pharmacotherapy, 2022
The IL-5 blockers mepolizumab and reslizumab were tested a decade ago in patients of all ages with EoE: Both drugs were able to reduce blood and esophageal eosinophilia, but all patients maintained a peak eosinophil count over 20 eos/hpf in esophageal mucosal biopsies; as symptoms did not changed significantly, further studies with these drugs in EoE were abandoned. Recently, benralizumab, a new mAb directed against the α chain of the IL-5 receptor (IL5RA), has revitalized interest in this mechanism, and a currently ongoing phase 3 RCT is comparing the effectiveness of benralizumab over placebo to reduce histopathology and symptoms in adolescents and adults with EoE (NCT04543409).
The role of epigenetics in the development of childhood asthma
Published in Expert Review of Clinical Immunology, 2019
Cancan Qi, Cheng-Jian Xu, Gerard H. Koppelman
A subsequent, even larger EWAS meta-analysis by the Pregnancy and Childhood Epigenetics (PACE) consortium identified differential DNA methylation in blood associated with asthma in newborns and children [30]. PACE is a worldwide consortium that investigates the early life environmental impacts on human disease using epigenetics [31]. The PACE asthma study combined a prospective design (newborn blood DNA methylation in relation to subsequent asthma development in childhood) with a cross-sectional design. In the prospective analysis in eight cohorts, nine significant CpGs and 35 regions (FDR<0.05) were identified to be associated with childhood asthma in newborns (668 cases and 2,904 controls), indicating that newborn blood DNA methylation may predict risk of asthma in later life. None of the nine CpGs had been previously associated with asthma nor showed overlap with the findings of the cross-sectional design, and the different CpGs identified in cord blood and in later life may indicate that DNA methylation at birth could reflect intra-uterine exposures and mechanisms that are important in the inception of disease rather than in persistence of asthma. However, these findings need further replication and validation. In the cross-sectional meta-analysis of asthma and whole-blood DNA methylation in children aged 7–17 years (631 cases and 2,231 controls) from nine cohorts, 179 CpGs and 36 regions (FDR<0.05) were associated with childhood asthma. These CpGs were also replicated in purified eosinophils, confirming the findings from the MeDALL study. Several CpGs were annotated to genes previously associated with asthma, for example IL5RA, which is the target for an approved drug for severe asthma patients.