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Secretory immunoglobulins and their transport
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Charlotte S. Kaetzel, Jiri Mestecky, Jenny M. Woof
Compared with IgA, IgM, and IgG, the levels of IgE are normally very low in mucosal secretions. However, numbers of IgE-producing plasma cells in the lamina propria and levels of IgE in secretions of the respiratory and gastrointestinal tracts are elevated in individuals with allergic diseases such as asthma, allergic rhinitis, and food allergy, and during intestinal parasite infections. The high-affinity receptor for IgE, FcεRI, is expressed by a variety of immune cells and plays an important role in effector functions of IgE (see later). It has recently been appreciated that the low-affinity IgE receptor, FcεRII (CD23), mediates endocytosis and bidirectional transcytosis of IgE and IgE–antigen complexes in several cell types, including enterocytes. CD23-mediated IgE transcytosis may enhance transport of potential allergens across the intestinal epithelial barrier, with important implications for mucosal defense and allergy (see later).
Local mucosal allergic disease
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Ibon Eguiluz-Gracia, Paloma Campo, Carmen Rondón
Nasal inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by tissue eosinophilia and the production of large amounts of IgE. The local IgE in CRSwNP individuals can be produced in a polyclonal or in an allergen-specific manner [58]. Similar to AR, the local production of high-affinity IgE is triggered by the allergen, and the resulting sIgE can sensitize resident mast cells for subsequent activation [59]. On the other hand the generation of polyclonal IgE is induced by Staphylococcus aureus enterotoxins acting as superantigens, with the capacity to nonspecifically stimulate resident T and B cells [24,58]. This activation triggers a rapid εCSR and the release of polyclonal, low-affinity IgE without a proper somatic hypermutation process [60]. Both types of IgE compete for the binding to FcεRI receptors. Given its higher abundance, polyclonal IgE may act as a functional inhibitor of the sIgE-mediated activation of resident cells. This phenomenon explains why the local IgE level does not correlate with the atopic status in CRSwNP patients [61]. Moreover, high levels of FLCs able to mediate allergen-triggered mast cell activation have been described in CRSwNP [49].
Immunoglobulins: Metabolism and biological properties
Published in Gabriel Virella, Medical Immunology, 2019
Two types of Fcε receptors specific for IgE have been defined. One is a low-affinity receptor (FcεRII), present in most types of granulocytes. It mediates ADCC reactions directed against helminths, which typically elicit IgE antibody synthesis (see Chapter 14). The other is a high-affinity Fcε receptor (FcεRI) expressed by basophils and mast cells. The basophil/mast cell–bound IgE functions as a true cell receptor. When an IgE molecule bound to a high-affinity FcεRI membrane receptor interacts with the specific antigen against which it is directed, the cell is activated, and as a consequence, histamine and other mediators are released from the cell. The release of histamine and a variety of other biologically active compounds is the basis of the immediate hypersensitivity reaction.
Drug delivery targets and strategies to address mast cell diseases
Published in Expert Opinion on Drug Delivery, 2023
Clayton H. Rische, Ariel H. Thames, Rebecca A. Krier-Burris, Jeremy A. O’Sullivan, Bruce S. Bochner, Evan A. Scott
Mast cells react to and defend against parasites and likely play diverse roles in host defense and repair. They are mostly known as key effectors of allergy via activation of their FcεRI surface receptors. The basic mechanism of allergy involves sensitization of the host, typically via mucosal surfaces, to a foreign protein antigen. This process involves B cell antibody class switching, during which Immunoglobulin E (IgE) is produced by plasma cells that recognizes epitopes of the target allergen. This IgE circulates throughout the body and attaches to high-affinity IgE receptors (FcεRI), awaiting future exposure to that same antigen. Once exposure occurs, the antigen will crosslink FcεRI receptors on mast cells (and basophils), triggering the rapid release of preformed and newly synthesized substances including histamine, prostaglandin D2, leukotrienes, proteases, heparin, cytokines, and others. The overall result is inflammation that manifests in symptoms such as sneezing, wheezing, hives, itchiness, swelling, and in severe cases anaphylaxis, the latter manifesting in mice as a drop in body temperature. Histology and flow cytometry can identify mast cells and their activation using selective surface markers such as CD117 (KIT), Siglec-6, and FcεRI⍺. Toluidine blue is another common stain used to visualize the granules within mast cells [1]. Commonly used surface markers to assess mast cell degranulation include CD63 and CD107a, as well as measurement of histamine, beta-hexosaminidase and tryptase in cell supernatants or in vivo.
Network pharmacology-based analysis of the mechanism of Saposhnikovia divaricata for the treatment of type I allergy
Published in Pharmaceutical Biology, 2022
Xiangsheng Li, Hui Li, Tingting Wang, Yang Zhao, Yuxin Shao, Yizhao Sun, Yanfen Zhang, Zhongcheng Liu
David database is a biological information database with a great deal of data, which can clearly show the enrichment of target genes through the analysis and integration of biological information about target genes, and is a common tool for bioinformatics analysis (Zhou et al. 2019). GO enrichment analysis and KEGG pathway analysis are commonly analytical methods in network pharmacology, and are the key steps to reveal the mechanism of action between drugs and diseases (Wang et al. 2020). GO analysis can link the gene catalogue obtained from the completely sequenced genome with the system functions at higher levels of cells, species and ecosystems, while KEGG analysis can screen the target proteins, find the signalling pathways involved by drug targets, and explain the potential mechanism of drug treatment of diseases. Through two analysis methods, the molecular function, biological process and influence on disease-related signalling pathway of drug action can be clarified. IgE/FcεRI signalling pathway is the key signalling transduction pathway to trigger TIA (Wang et al. 2020). The results of KEGG enrichment analysis showed that SD may play a role in the treatment of allergic reaction by influencing interleukin-17, Ca2+ signal, PI3K/Akt and MAPK. There were all related to IgE/FcεRI signalling pathway. Therefore, the results indicated that SD may play a role in the treatment of TIA diseases through multi-component and multi-target to regulate of Ca2+ signal, PI3K/Akt signalling pathway and MAPK signalling pathway, because these signal pathways have the potential to be closely related to allergy.
The eIg technology to generate Ig-like bispecific antibodies
Published in mAbs, 2022
Lennart Kühl, Nadine Aschmoneit, Roland E. Kontermann, Oliver Seifert
In this study, we applied the hetEHD2 domains as a solution to the light chain problem. We could demonstrate that fusion of a VH domain to a first hetEHD2 domain and a VL domain to a second hetEHD2 domain results in efficient formation of heterodimeric Fab-like moieties (eFab). These eFabs were then used to generate bispecific Ig-like molecules by combining them with natural Fab arms and an Fc region. Here, various molecular compositions were analyzed, including bivalent bispecific Fab-eFab fusions and Ig-like molecules (eIgs), as well as various trivalent and tetravalent configurations (Fab-eIgs). Proof of concept was obtained for bispecific molecules targeting different surface receptors (dual targeting) and for the retargeting of T cells to tumor cells (T-cell engagement). All molecules were produced in yields and purity comparable to normal IgGs. Furthermore, analysis for binding to FcεRI and FcεRII confirmed lack of interaction with the Fcε receptors, providing evidence that the molecules will not lead to Fcε receptor crosslinking of immune cells. Thus, with our study we established eFabs as robust building blocks to generate bispecific antibodies of varying valency and composition.