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An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of Fc?R1? and C?.

ABSTRACT: The high affinity immunoglobulin E (IgE) receptor-Fc?R1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to Fc?R1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since Fc?R1 plays a central role in the induction and maintenance of allergic responses, this study aimed to investigate the association of Fc?R1 with the allergic phenotype of C? expression and cytokine and histamine release from peripheral leukocytes. Peripheral leukocytes from 67 allergic and 50 non-allergic subjects were used for genotyping analysis. Peripheral mononuclear cells (PBMCs) were used for C? expression and ELISpot analysis, while polymorphonuclear cells (PMNs) were used for histamine release. The association between genotype polymorphism of the Fc?R1? promoter region (rs2427827 and rs2251746) and allergic features of C? expression and histamine were analyzed, and their effects on leukocytes function were compared with wild type. The genotype polymorphisms of Fc?R1? promoter region with CT and TT in rs2427827 and TC in rs2251746 were significantly higher in allergic patients than in non-allergic controls. Patients with single nucleotide polymorphism (SNP) of Fc?R1? promoter region had high levels of total IgE, mite-specific Der p 2 (Group 2 allergen of Dermatophagoides pteronyssinus)-specific IgE and IgE secretion B cells. The mRNA expression of Fc?R1? was significantly increased after Der p2 stimulation in PBMCs with SNPs of the Fc?R1? promoter region. Despite the increased C? mRNA expression in PBMCs and histamine release from PMNs and the up-regulated mRNA expression of interleukin (IL)-6 and IL-8 secretions after Der p2 stimulation, there was no statistically significant difference between SNPs of the Fc?R1? promoter region and the wild type. SNPs of Fc?R1? promoter region were associated with IgE expression, IgE producing B cells, and increased Der p2-induced Fc?R1? mRNA expression. These SNPs may be used as a disease marker for IgE-mediated allergic inflammation caused by Dermatophagoides pteronyssinus.

SUBMITTER: Liao EC

PROVIDER: S-EPMC4463601 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of FcεR1α and Cε.

Liao En-Chih EC Chang Ching-Yun CY Hsieh Chia-Wei CW Yu Sheng-Jie SJ Yin Sui-Chu SC Tsai Jaw-Ji JJ

International journal of molecular sciences 20150427 5

The high affinity immunoglobulin E (IgE) receptor-FcεR1 is mainly expressed on the surface of effector cells. Cross-linking of IgE Abs bound to FcεR1 by multi-valent antigens can induce the activation of these cells and the secretion of inflammatory mediators. Since FcεR1 plays a central role in the induction and maintenance of allergic responses, this study aimed to investigate the association of FcεR1 with the allergic phenotype of Cε expression and cytokine and histamine release from peripher ...[more]

PMID: 25923080

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Project description:What is already known about this subjectOmalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized.What this study adds(i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy.AimTo determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy.MethodsOmalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change.ResultsThe prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3-5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building.ConclusionsA pharmacokinetic-pharmacodynamic model incorporating omalizumab-IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions.

Dataset Information

An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of Fc?R1? and C?.

Publications

An Exploratory Pilot Study of Genetic Marker for IgE-Mediated Allergic Diseases with Expressions of FcεR1α and Cε.

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