The structural basis of human IgE–Fc receptor interactions

Sayers, Ian; Helm, Birgit A.

doi:10.1046/j.1365-2222.1999.00518.x

Cited by 14 publications

(10 citation statements)

References 87 publications

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“…FcRI binds IgE with a much higher affinity (Ͼ1000-fold) than FcRII (19) and in AA neutrophils IgE primarily binds FcRI (11).…”

Section: Discussionmentioning

confidence: 99%

“…Data from the present study indicate a prosurvival effect of monomeric IgE that does not require receptor crosslinking. This effect is especially interesting because an IgE concentration as low as 100 ng/ml, the lower limit of concentrations found in atopic individuals (19), was capable of significantly inhibiting neutrophil apoptosis. It is worth mentioning that the impact of IgE on neutrophil survival varied among AA individuals to some extent.…”

Section: Figurementioning

confidence: 99%

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IgE Modulates Neutrophil Survival in Asthma: Role of Mitochondrial Pathway

Saffar

Alphonse²,

Shan³

et al. 2007

The Journal of Immunology

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The high-affinity IgE receptor (FcεRI) has recently been reported to be expressed by neutrophils in atopic asthmatic individuals, leading to speculations that IgE could influence biological functions of these cells. In this study, we demonstrate that monomeric human IgE delayed spontaneous apoptosis of primary human neutrophils from atopic asthmatics in vitro. This effect was not dependent on FcεRI cross-linking or autocrine release of soluble mediators; however, it was associated with increased expression of the antiapoptotic myeloid cell leukemia-1 protein, retention of the proapoptotic molecule Bax in the cytoplasm, decreased release of Smac from mitochondria, and reduced caspase-3 activity. Taken together, our results indicate that in vitro IgE can delay programmed cell death of neutrophils from allergic asthmatics and this may possibly contribute to neutrophilic inflammation in atopic asthma.

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“…FcRI binds IgE with a much higher affinity (Ͼ1000-fold) than FcRII (19) and in AA neutrophils IgE primarily binds FcRI (11).…”

Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

IgE Modulates Neutrophil Survival in Asthma: Role of Mitochondrial Pathway

Saffar

Alphonse²,

Shan³

et al. 2007

The Journal of Immunology

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“…Previous observations suggested Lys-352 within the A-B loop may be a key effector residue, with mutation to Gly, the homologous residue in rodent IgE, resulting in a considerable reduction in receptor interaction (50% decrease (versus WT, p ϭ 0.0007), Table I) (11). We interpret the effect of this substitution as identifying Lys-352 as a class-specific effector residue contributing directly to the binding of hIgE to CD23, possibly facilitating docking via an electrostatic interaction.…”

Section: Resultsmentioning

confidence: 88%

“…Using site-specific mutagenesis, the IgE binding region of CD23 has been mapped to two discontinuous segments between residues 165-190 and 224 -256 (10). Although several other ligands for CD23 have been identified (11), the role of the receptor and receptorderived fragments in the regulation of the IgE response has attracted particular interest (12,13). A greater understanding of the IgE-CD23 interaction, based on the identification of complementary binding regions on each molecule, could assist the development of strategies for the manipulation of the allergic response via this regulatory mechanism.…”

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confidence: 99%

The Importance of Lys-352 of Human Immunoglobulin E in FcϵRII/CD23 Recognition

Sayers¹,

Housden²,

Spivey³

et al. 2004

Journal of Biological Chemistry

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The interaction of immunoglobulin E (IgE) with its low affinity receptor (Fc⑀RII/CD23) plays a central role in the initiation and regulation of type I hypersensitivity responses. We have previously identified the importance of amino acid residues in the A-B loop of the C⑀3 domain of human IgE and implicated a region close to the glycosylation site at asparagine 371 as contributing to IgE-CD23 interaction. These residues were now targeted by site-directed mutagenesis. The IgE-CD23 interaction was assessed by semiquantitative flow cytometry. Replacement of the entire C⑀3 A-B loop (residues 341-356) with the homologous rat IgE sequence resulted in complete loss of human CD23 recognition, as did replacement of residues 346 -353, indicating that class-specific effector residue(s) are contained within these eight amino acids. Lysine 352 within the A-B loop was identified as contributing directly to human CD23 interaction. Mutation to the rodent homologue glycine or glutamate resulted in a significant reduction in binding compared with native IgE, whereas conservative substitution with arginine effected a small, but statistically significant, enhancement of CD23 binding. Mutation of the C⑀3 glycosylation site at asparagine 371 to threonine or glutamine did not significantly affect CD23 recognition. Our results yield new insights into the structural basis of the hIgE-CD23 interaction and hold promise for the rational design of drugs that can manipulate IgE-mediated regulation of the allergic response. Antibodies of the immunoglobulin E (IgE)1 isotype have a central role in the initiation and regulation of allergic disorders (1). IgE mediates these functions via the interaction of the Fc region of the molecule with its Fc receptors. The crystal structure of the high affinity receptor (Fc⑀RI, K A ϳ10 10 M Ϫ1 ) complexed to IgE-Fc has been determined, identifying critical residues involved in the interaction (2). Fc⑀RII/CD23 has been identified as a low affinity receptor for human (h) IgE (K A ϳ10 7 M Ϫ1 ) (3). Structurally, CD23 is not a member of the Ig superfamily but a type II transmembrane receptor expressed on a variety of cells of the immune system (4). In the absence of a high resolution structure, a composite molecular model has been proposed based on homology of the lectin head with the rat mannose-binding protein (5, 6). The model predicts that five heptadic repeats of hydrophobic Leu/Ile residues form a trimeric ␣-helical stalk linking the N-terminal extracellular domain to the transmembrane and C-terminal cytoplasmic domain of the receptor (7).Previous studies based on the interaction of hIgE-Fc with a soluble 16-kDa form of the lectin homology domain expressed in NS-O cells identified this region as containing the IgE binding site(s) (8). More recent studies indicate the necessity of the stalk region for IgE interaction (9). Using site-specific mutagenesis, the IgE binding region of CD23 has been mapped to two discontinuous segments between residues 165-190 and 224 -256 (10). Although several other ligands fo...

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“…Binding experiments using chimeric IgE molecules have shown that the FcεRI binding site is predominately located in the Cε3 domain (Nissim et al 1993). Particularly, the N-terminal amino acid residue in the Cε2-3 interface (aa330-335) and the AB loop (aa343-353) in the human Cε3 domain were discussed as the association sites of IgE with the FcεRI (Sutton and Gould 1993;Sayers and Helm 1999). Interestingly, the human P333 and R334 residues, which were suggested to be involved in the maintenance of conformation required for IgE-mediated effector functions (Sayers e t a l .…”

Section: Discussionmentioning

confidence: 99%

Expression of a 4‐(hydroxy‐3‐nitro‐phenyl) acetyl (NP) specific equi‐murine IgE antibody that mediates histamine release in vitro and a type I skin reaction in vivo

Wagner

Siebenkotten

Leibold

et al. 2002

Equine Veterinary Journal

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Summary Due to characteristic clinical signs, immunoglobulins of isotype E (IgE) are believed to be involved in several allergic diseases of the horse. To date, closer investigations have been hampered by the fact that neither purified equine IgE nor anti‐equine IgE monoclonal antibodies were available for IgE isotype determination. As an approach to solve this problem, we constructed a stable cell line (EqE6) that expresses recombinant equi‐murine IgE specific for 4‐(hydroxy‐3‐nitro‐phenyl) acetyl (NP). Biochemical analysis of the purified protein revealed a highly glycosilated IgE monomer of approximately 230,000 Da. The biological ability of the NP‐IgE to mediate histamine release after crosslinking with antigen was demonstrated in vitro using equine blood leucocytes. In vivo, the intradermal application of NP‐IgE followed by antigen crosslinking induced a type I hypersensitivity skin reaction in horses. Both results indicate that the recombinant NP‐IgE contains an intact and functional FceRI binding site and mediates effector functions in equine basophils and cutaneous mast cells. This equi‐murine IgE can be used for the production of IgE‐specific polyclonal and monoclonal antibodies. In addition, the NP specificity allows the antigen‐specific activation of equine Fce‐receptor‐expressing cells, such as mast cells and basophils. This property could be used to investigate IgE‐mediated mechanisms for a better understanding of equine type I allergic diseases.

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The structural basis of human IgE–Fc receptor interactions

Cited by 14 publications

References 87 publications

IgE Modulates Neutrophil Survival in Asthma: Role of Mitochondrial Pathway

IgE Modulates Neutrophil Survival in Asthma: Role of Mitochondrial Pathway

The Importance of Lys-352 of Human Immunoglobulin E in FcϵRII/CD23 Recognition

Expression of a 4‐(hydroxy‐3‐nitro‐phenyl) acetyl (NP) specific equi‐murine IgE antibody that mediates histamine release in vitro and a type I skin reaction in vivo

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