The immunoglobulin-like modules Cε3 and α2 are the minimal units necessary for human IgE-FcεRI interaction

Vangelista, Luca; Laffer, Sylvia; Turek, Robert; Grönlund, Hans; Sperr, Wolfgang R.; Valent, Peter; Pastore, Annalisa; Valenta, Rudolf

doi:10.1172/jci6551

Cited by 29 publications

(21 citation statements)

References 43 publications

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“…The significance of each of the domains in Fc⑀RI binding has been extensively investigated (21)(22)(23)(24). It is commonly accepted that the principal determinants are located in the C⑀3 domain of IgE (22,23). However, there is no agreement on the involvement of the adjoining C⑀2 and C⑀4 regions in the high affinity interaction.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-Inducing Human-Origin Fcε-Bak Chimeric Proteins for Targeted Elimination of Mast Cells and Basophils: A New Approach for Allergy Treatment

Belostotsky

Lorberboum-Galski

2001

The Journal of Immunology

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During the past few years, many chimeric proteins have been developed to specifically target and kill cells expressing specific surface molecules. Generally these molecules carry a bacterial or plant toxin to destroy the unwanted cells. The major obstacle regarding these molecules in their clinical application is the immunogenicity and nonspecific toxicity associated with bacterial or plant toxins. We lately reported a new approach for construction of chimeric proteins: we successfully replaced bacterial or plant toxins with human apoptosis-inducing proteins. The resulting chimeras were shown to specifically induce apoptosis in the target cells. Taking advantage of the human apoptosis inducing proteins Bak and Bax as novel killing components, we have now constructed new chimeric proteins targeted against the human FcεRI, expressed mainly on mast cells and basophils. These cells are the main effectors of the allergic response. Treatment of the target cells with the new chimeric proteins, termed Fcε-Bak/Bax, had a dramatic effect on cell survival, causing apoptosis. The effect was specific to cells expressing the FcεRI of both human and, very unexpectedly, also of mouse origin. Moreover, interaction of the chimeric proteins with the mast cells did not cause degranulation. Fcε-Bak/Bax are new chimeric proteins of human origin and, as such, are expected to be both less immunogenic and less toxic and, thus, may be specific and efficient reagents for the treatment of allergic diseases.

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Section: Discussionmentioning

confidence: 99%

Apoptosis-Inducing Human-Origin Fcε-Bak Chimeric Proteins for Targeted Elimination of Mast Cells and Basophils: A New Approach for Allergy Treatment

Belostotsky

Lorberboum-Galski

2001

The Journal of Immunology

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“…Domain exchange studies (19 -21), together with phage display and soluble expression of single Fc⑀RI␣ domains (22)(23)(24), had demonstrated the essential requirement of the ␣2 domain for IgE binding, and indeed the crystal structure has shown that the regions of Fc⑀RI␣ that contact the C⑀3 domains of IgE lie solely within ␣2. However, it was also clear from these earlier studies that ␣1 was required for optimal Ab binding.…”

mentioning

confidence: 99%

Mutagenesis Within Human FcεRIα Differentially Affects Human and Murine IgE Binding

Mackay

Hulett

Cook

et al. 2002

The Journal of Immunology

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Soluble fragments of the α-chain of FcεRI, the high-affinity receptor for IgE, compete with membrane-bound receptors for IgE and may thus provide a means to combat allergic responses. Mutagenesis within FcεRIα is used in this study, in conjunction with the crystal structure of the FcεRIα/IgE complex, to define the relative importance of specific residues within human FcεRIα for IgE binding. We have also compared the effects of these mutants on binding to both human and mouse IgE, with a view to evaluating the mouse as an appropriate model for the analysis of future agents designed to mimic the human FcεRIα and attenuate allergic disease. Three residues within the C-C′ region of the FcεRI α2 domain and two residues within the α2 proximal loops of the α1 domain were selected for mutagenesis and tested in binding assays with human and mouse IgE. All three α2 mutations (K117D, W130A, and Y131A) reduced the affinity of human IgE binding to different extents, but K117D had a far more pronounced effect on mouse IgE binding, and although Y131A had little effect, W130A modestly enhanced binding to mouse IgE. The mutations in α1 (R15A and F17A) diminished binding to both human and mouse IgE, with these effects most likely caused by disruption of the α1/α2 interface. Our results demonstrate that the effects of mutations in human FcεRIα on mouse IgE binding, and hence the inhibitory properties of human receptor-based peptides assayed in rodent models of allergy, may not necessarily reflect their activity in a human IgE-based system.

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“…18,40,[43][44][45][46] It is very easy and fast to generate recombinant viruses expressing H or L bearing specific mutations and to determine the impact of these mutations on the specificity or activity of a given antibody. 21,22,41 This strategy has been successfully used to analyze the catalytic activity of the 6D9 monoclonal antibody and the specificity of the PAC1 antibody that binds to the integrin αII b β3 on activated platelets.…”

Section: Biological Activities Of Recombinant Antibodies Produced In mentioning

confidence: 99%

“…Several immunoglobulin isotypes from many different species, including murine IgG, 2,3,[21][22][23][24][25] chimeric IgG, [26][27][28][29][30] human IgG, [31][32][33][34][35][36][37][38][39] IgA, [40][41][42] IgM 41 and IgE, [43][44][45] as well as pig Igs 30,45 have been successfully expressed in insect cells. These molecules are all correctly processed (signal peptide cleaved), glycosylated and assembled (H2L2) with a production rate varying from 0.75 to 100 mg/l, depending on the antibody ( …”

Section: Introductionmentioning

confidence: 99%

Lepidopteran cells, an alternative for the production of recombinant antibodies?

Cérutti

Golay

2012

mAbs

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The immunoglobulin-like modules Cε3 and α2 are the minimal units necessary for human IgE-FcεRI interaction

Cited by 29 publications

References 43 publications

Apoptosis-Inducing Human-Origin Fcε-Bak Chimeric Proteins for Targeted Elimination of Mast Cells and Basophils: A New Approach for Allergy Treatment

Apoptosis-Inducing Human-Origin Fcε-Bak Chimeric Proteins for Targeted Elimination of Mast Cells and Basophils: A New Approach for Allergy Treatment

Mutagenesis Within Human FcεRIα Differentially Affects Human and Murine IgE Binding

Lepidopteran cells, an alternative for the production of recombinant antibodies?

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