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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].
Anisakis
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Mauricio Afonso Vericimo, Gerlinde Teixeira, Israel Figueiredo, Janaina Ribeiro, Maria Augusta Moulin Fantezia, Sergio Carmona São Clemente
To examine the immunological mechanisms underlying the development of allergic airway inflammation, WT and interleukin-4 receptor alpha (IL-4Rα)-deficient mice were sensitized to Anisakis antigens through different routes.123 Live or heat-killed Anisakis larvae were administered intraperitoneally, while Anisakis extract was administered by the intranasal route. Subsequently, all animals were challenged intranasally with an Anisakis extract. Allergen-specific antibodies developed only in intraperitoneally sensitized mice; however, both routes of sensitization induced IL-4Rα-dependent allergic airway responses in WT mice in an IL-4/IL-13-dependent pathway. Unexpectedly, infection with live Anisakis larvae induced airway hyperresponsiveness that was abrogated when IFN-γ was neutralized in vivo. Thus, infection leads to IL-4/IL-13-independent, IFN-γ-dependent airway hyperresponsiveness. Together, these results demonstrate that both infection with larvae and inhalational exposure to Anisakis proteins are potent routes of allergic sensitization, explaining food- and work-related allergies in humans, which can involve either IL-4/IL-13 or IFN-γ. Importantly for diagnosis, detectable Anisakis-specific antibodies may not accompany allergic airway inflammation.
Treatment of generalized granuloma annulare with dupilumab
Published in Journal of Dermatological Treatment, 2023
Xiaoting Song, Zirui Chen, Zuotao Zhao, Aiping Wang
Dupilumab is a monoclonal antibody targeting the Interleukin 4 receptor alpha chain (IL-4Rα) and inhibiting IL-4R signaling. As GA is an inflammatory granulomatous skin disease, macrophage polarization plays an important role in its pathogenesis (2), with an infiltration of M1 macrophages for pro-inflammation at the early stage and polarization to M2 macrophages for promoting tissue regeneration at the late stage. Macrophages could be induced to a M2 phenotype by IL-4 and IL-13. In addition, a retrospective series including 47 pediatric patients with GA (3) and a recent case-control study (4) found a potential association of GA with atopy. A study on the molecular phenotype of GA found significant upregulations in TNF-a and IFN-γ, IL-4, and JAK3, in which IL-4 showed a particularly pronounced increase (15,600-fold) in GA lesional skin versus control skin (1).
Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty
Published in Journal of Asthma, 2022
Satoshi Ano, Norihiro Kikuchi, Masashi Matsuyama, Masayuki Nakajima, Yuzuru Kondo, Michiko Masuda, Hajime Osawa, Yukio Ishii, Nobuyuki Hizawa
Although environmental factors may be associated with changes in difficult-to-treat asthma, recent genome-wide association studies have identified genetic involvement. Some genes are associated with exacerbations of asthma and asthma treatments; for example, glucocorticoid-induced transcript 1 was found to be associated with the response to glucocorticoids (10), and ORM (yeast)-like protein isoform 3 (11), interleukin-33/interleukin 1 receptor-like 1 (12), thymic stromal lymphopoietin (13), and interleukin-4 receptor α genes (14) were associated with severe asthma. Accordingly, specific genes may be biomarkers for severe asthma, and genetic methods for predicting the efficacy of asthma therapies are being explored. Thus, genetic analysis may be important for predicting the efficacy of therapies for severe asthma.
Accurate determination of epitope for antibodies with unknown 3D structures
Published in mAbs, 2021
Shifa Tahir, Thomas Bourquard, Astrid Musnier, Yann Jullian, Yannick Corde, Zakaria Omahdi, Laetitia Mathias, Eric Reiter, Pascale Crépieux, Gilles Bruneau, Anne Poupon
The 3D structure of dupilumab antibody was modeled using MODELER with the aforementioned criteria. Then, by using MAbTope, dupilumab’s epitope was predicted to be located over 4 regions of interleukin 4 receptor α subunit (IL4Rα) extracellular domain, named P1 to P4. Within each of these regions, amino acids having solvent-exposed side-chains were mutated to alanines in the full-length IL4R. We thus designed one mutated IL4Rα construct for each region initially predicted (full-length sequences in Figure S5). In order to avoid affecting IL4Rα’s correct folding, only amino acids with solvent-exposed side-chains were mutated, except those making interactions with other amino acids of the target. We also avoid mutating prolines, as those are usually essential in correct folding. The constructs were named IL4R_WT, IL4R_P1m, IL4R_P2m, IL4R_P3m and IL4R_P4m. The constructs were Flag-tagged at their N-termini in order to monitor antigen expression in cells. Gene synthesis and cloning into pcDNA3.1+ were performed by Twist Bioscience (San Francisco, CA, USA).