Relationships between Levels of Serum IgE, Cell-Bound IgE, and IgE-Receptors on Peripheral Blood Cells in a Pediatric Population

Dehlink, Eleonora; Baker, Alexandra; Yen, Elizabeth H.; Nurko, Samuel; Fiebiger, Edda

doi:10.1371/journal.pone.0012204

Cited by 54 publications

(59 citation statements)

References 31 publications

(43 reference statements)

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“…Some studies have shown that surface FcεRI of human blood BDCA1 + DCs and monocytes correlates positively with serum IgE levels (20,21). However, other studies have shown a lack of correlation between IgE levels in blood and FcεRI levels on BDCA1 + DCs or monocytes among individuals with normal ranges of serum IgE levels (8,22). These findings raise the possibility that FcεRI surface expression in DCs and monocytes may be regulated uniquely from mast cells and basophils, and perhaps independently of IgE.…”

Section: Introductionmentioning

confidence: 98%

Serum IgE clearance is facilitated by human FcεRI internalization

Greer¹,

Wu²,

Putnam³

et al. 2014

J. Clin. Invest.

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The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1-positive (BDCA1 + ) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1 + DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.

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Section: Introductionmentioning

confidence: 98%

Serum IgE clearance is facilitated by human FcεRI internalization

Greer¹,

Wu²,

Putnam³

et al. 2014

J. Clin. Invest.

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“…Consequently, increased receptor expression levels are found in individuals with elevated serum IgE levels. Additionally, elevated serum IgE induces de-novo expression of trimeric FcεRI on monocytes and neutrophils of allergic patients (Kraft and Kinet, 2007; Gould and Sutton, 2008; Dehlink et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

Development and validation of a standardized ELISA for the detection of soluble Fc-epsilon-RI in human serum

Lexmond

Mee

Ruiter

et al. 2011

Journal of Immunological Methods

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The aim of this study was to develop a standardized enzyme-linked immunosorbent assay (ELISA) for detection of human soluble Fc-epsilon-RI (sFcεRI), a serum isoform of the high affinity IgE receptor. A recombinant version of sFcεRI was produced in baculovirus and used as standard. ELISA plates were coated with anti-mouse IgG followed by incubation with the monoclonal capture antibody CRA1. This FcεRI-alpha-specific antibody binds to the stalk region of the protein and does not inhibit IgE-binding. After incubation with standards or serum samples, plates were incubated with chimeric IgE followed by detection with horseradish peroxidase conjugated anti-human IgE. Enzymatic activity was visualized with (3, 3′, 5, 5′)-tetramethylbenzidine. Specificity was demonstrated by omission of capture or detection reagents. Units (U) of detection were established and the dynamic range of the assay was defined as 10 640 U/ml for a 1:5 serum dilution. Parameters of linearity (R2>0.999), matrix interference test (recovery of 70–110%), intra-assay variability (coefficient of variation (CV) <20%) and inter-assay variability (CV <20%) met acceptance criteria for immunoassay validation. Correlation analysis of serum units of sFcεRI measured with the new ELISA and serum IgE levels confirmed earlier published data describing a weak correlation of the two parameters in patients with elevated serum IgE while no correlation in patients with normal serum IgE or the total patient group was found. In summary, we established and validated a standardized ELISA for the detection of sFcεRI. This novel method now allows for comparative analysis of sFcεRI levels in health and disease.

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“…2A), but this was not reflected in the levels of IgE-mediated histamine release in each species, and in concordance with previous findings. 12 One reason for this may be due to the high density of IgE receptors on the cell surface of human basophils, 25 the cells responsible for histamine release in blood. By contrast, the ADCC assay demonstrated, at low IgE concentrations, the capacity of the human antibody to activate cynomolgus monkey effector cells to kill tumor was impaired compared with its effect on human effector cells.…”

Section: Discussionmentioning

confidence: 99%

Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency

Saul¹,

Josephs²,

Cutler

et al. 2014

mAbs

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IntroductionThe cynomolgus monkey is a laboratory primate commonly used as a model for the study of allergic diseases, in particular addressing symptoms, disease mechanisms and treatments for allergic asthma. It has also found use in preclinical toxicology studies of therapeutic agents prior to clinical trials. The choice of cynomolgus monkey as a species for allergic and toxicological evaluations is due to a perceived similarity of primate systems to human biology and to human immunity. However, limited information is available on the biological relevance of these models in relation to IgE immune responses and therapeutics.Antibodies of the IgE class are known to contribute to the body's defense against parasites and toxins, but also to play critical roles in the pathogenesis and potentiation of allergic diseases.1 IgE exerts its biological functions through engagement of its cognate receptors, the low affinity receptor CD23 (K a ~10 Background: Due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. Ige therapeutics in development depend upon engagement with the FcεrI and FcεrII receptors on immune effector cells for their function. only limited knowledge of the primate Ige immune system is available to inform the choice of models for mechanistic and safety evaluations.Methods: The recognition of human Ige by peripheral blood lymphocytes from cynomolgus monkey and man was compared. We used effector cells from each species in ex vivo affinity, dose-response, antibody-receptor dissociation and potency assays.results: We report cross-reactivity of human Ige Fc with cynomolgus monkey cells, and comparable binding kinetics to peripheral blood lymphocytes from both species. In competition and dissociation assays, however, human Ige dissociated faster from cynomolgus monkey compared with human effector cells. Differences in association and dissociation kinetics were reflected in effector cell potency assays of Ige-mediated target cell killing, with higher concentrations of human Ige needed to elicit effector response in the cynomolgus monkey system. additionally, human Ige binding on immune effector cells yielded significantly different cytokine release profiles in each species.Conclusion: These data suggest that human Ige binds with different characteristics to human and cynomolgus monkey Ige effector cells. This is likely to affect the potency of Ige effector functions in these two species, and so has relevance for the selection of biologically-relevant model systems when designing pre-clinical toxicology and functional studies.

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Relationships between Levels of Serum IgE, Cell-Bound IgE, and IgE-Receptors on Peripheral Blood Cells in a Pediatric Population

Cited by 54 publications

References 31 publications

Serum IgE clearance is facilitated by human FcεRI internalization

Serum IgE clearance is facilitated by human FcεRI internalization

Development and validation of a standardized ELISA for the detection of soluble Fc-epsilon-RI in human serum

Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency

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