Manufacturing and Standardizing Allergen Extracts in Europe
Richard F. Lockey, Dennis K. Ledford in Allergens and Allergen Immunotherapy, 2014
Specific allergy treatment, that is, specific immunotherapy or specific allergy vaccination, has been performed for more than a century, since it was first described by Noon in 1911 [1]. The discovery in 1966 of the immunoglobulin E (IgE) molecule [2], and the central role of IgE in allergy, has facilitated a better understanding of the immunological mechanisms of allergic disease and has led to the improvement of diagnostic tools and consolidation of the concept of diagnosis and treatment of specific allergies. Scientific methods were introduced to standardize allergen extracts in the 1970s and 1980s [3] and this, in combination with gradual improvement of the clinical procedures, established specific allergy treatment as a scientifically based, reproducible, and safe treatment for allergic diseases.
Effects
Frank A. Barile in Barile’s Clinical Toxicology, 2019
Type I antibody-mediated reactions occur as three phases. The initial phase, the sensitization phase, is triggered by contact with a previously unrecognized antigen. This reaction entails binding of the antigen to immunoglobulin E (IgE) present on the surface of mast cells and basophils. A second phase, the activation phase, follows after an additional dermal or mucosal challenge with the same antigen. This phase is characterized by degranulation of mast cells and basophils with a subsequent release of histamine and other soluble mediators. The third stage, the effector phase, is characterized by accumulation of preformed and newly synthesized chemical mediators that precipitate local and systemic effects. Degranulation of neutrophils and eosinophils completes the late-phase cellular response.
Molecular Mechanisms Controlling Immunoglobulin E Responses
Thomas F. Kresina in Immune Modulating Agents, 2020
In summary, IgE production is the end result of highly coordinated and specific immune responses beginning with exposure to allergens in a genetically predisposed individual. Activated Th2 cells secrete IL-4 and IL-13 that bind to their cell surface receptor on the resting IgM+ B cells. After tyrosine phosphorylation of the receptor complex, Stat 6 is activated, rendering it competent for translocation into the nucleus and binding to specific DNA sequences found in the promoter region, thereby stimulating germline ∈ transcription. After T cell-B cell contact involving CD40L and CD40, a deletional recombination event occurs, resulting in mRNA that encodes for the IgE heavy-chain polypeptide (Figure 4). Immunoglobulin E binds to FceRI on mast cells and basophils, allowing cross-linking of FC∈RI/IgE complex by antigens and release of a variety of inflammatory mediators that cause allergic symptoms. What remains unclear at this point is precisely how this pathway is modified during human allergic disease or after exposure to certain antigens and what dictates an individual’s genetic predisposition to a heightened IgE production. The 5q31-q33 chromosome locus containing genes encoding for IL-4, IL-5, IL-13 has been associated with clinical atopy, bronchial hyperresponsiveness, and elevated IgE levels [85,87], but delineating how interactions between environmental and genetic influences modify complex immune responses remains a great challenge.
Efficacy and safety of omalizumab in children with moderate-to-severe asthma: a meta-analysis
Published in Journal of Asthma, 2021
Zhuo Fu, Yongsheng Xu, Chunquan Cai
Immunoglobulin E (IgE) is an immune mediator in asthma which contributes to some clinical manifestations, including mast cell activation, airway remodeling, and irreversible change in pulmonary function. Omalizumab is a recombinant, humanized, monoclonal antibody that can suppress free IgE levels and cure IgE-mediated diseases (5). Omalizumab, in combination with inhaled steroid treatment, has been reported to be effective in adults with moderate-to-severe persistent asthma (6–9). However, few data on omalizumab treatment in childhood asthma are available. Several studies have been performed to date evaluating the efficacy and safety of omalizumab in pediatric asthma, but the smaller number of patients leads to uncertainty about the effects of omalizumab (10–13). Therefore, we conducted this meta-analysis to assess the efficacy and safety of omalizumab in children with moderate-to-severe asthma.
Dynamic Aspects of the Immunoglobulin Structure
Published in Immunological Investigations, 2019
Immunoglobulin E is an important participant in allergic reactions. The Fcε fragment reacts with the FcεRI receptor on mast cells, and with CD23 on B cells. The Fcε is composed of dimers from the Cε2, Cε3, and Cε4 domains, and is, by nature, flexible (Wurzburg and Jardetzky, 2009). According to crystallographic studies (Drinkwater et al., 2014), the Cε2 domains fold back on the Cε3 and Cε4 domains. The Cε3 domains react with the both cell receptors and thus play a central role in IgE’s biological activity. Isolated Cε3 have a ”molten globule” structure, retaining their flexibility within the IgE molecule (Borthakur et al., 2011; Harwood and McDonnell, 2007; Henry et al., 2000; Price et al., 2005), but is well-structured, following formation of complexes with the FcεRI receptor. The detailed structure of Fcε and its domains was elucidated at the highest resolutions by means of X-ray crystallography and by differential scanning fluorimetric analysis (Doré et al., 2017). It was found that the Cε3 domain displays intrinsic flexibility and quaternary structural variation especially in regions distant from Cε4. The reaction with the cell receptors or corresponding antibodies stabilizes the Cε3 structure. The high-mannose carbohydrate unit of Cε3 is well-ordered and makes contact with Cε4, which is not essential for cell receptor binding.
Recent developments in the use of biologics targeting IL-5, IL-4, or IL-13 in severe refractory asthma
Published in Expert Review of Respiratory Medicine, 2018
Asthma can be divided into ‘asthma phenotypes’ that take demographic, clinical, and/or pathophysiological characteristics into account. A further evolving process involves further division into disease entities termed ‘asthma endotypes’ based on the underlying specific pathophysiological mechanisms that represent key targets for the development of new asthma treatment. For example, T helper 2 (TH2)-high asthma is seen in around 50% of patients who typically have eosinophilic inflammation mediated by cytokines including IL-4, IL-5, and IL-13. Elevated levels of immunoglobulin E (IgE) may also be present. The elucidation of these complex patterns of inflammation has informed the development of antibody-based biological therapies that target the type 2 cytokines IL-4, IL-5, and IL-13 [3]. It is increasingly accepted that significant clinical effects with these anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account that in turn rely on straightforward discriminatory biomarkers to aid the targeting of those most likely to benefit from treatment with these expensive interventions [4,5].
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