Mechanism of allergic cross-reactions—I. Multispecific binding of ligands to a mouse monoclonal anti-DNP IgE antibody

Várga, J.; Kalchschmid, Gertrud; Klein, Georg; Fritsch, Peter

doi:10.1016/0161-5890(91)90133-5

Cited by 40 publications

(33 citation statements)

References 12 publications

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“…Of course, one cannot entirely rule out the possibility that the true PAL-E antibody may recognize more than one antigen (12,13), perhaps in different settings. Indeed, cross-reaction of monoclonal antibodies with multiple antigens has long been shown (35,36). Be that as it may, the common biochemical, morphologic, and functional features between PAL-E and NRP-1 support the interpretation of our experimental findings.…”

Section: Discussionsupporting

confidence: 79%

The Original Pathologische Anatomie Leiden-Endothelium Monoclonal Antibody Recognizes a Vascular Endothelial Growth Factor–Binding Site within Neuropilin-1

et al. 2007

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For two decades, the antigen recognized by the Pathologische Anatomie Leiden-Endothelium (PAL-E) monoclonal antibody, a standard vascular endothelial cell marker, has remained elusive. Here, we used a combinatorial phage display-based approach (''epitope mapping'') to select peptides binding to the original PAL-E antibody. We found that a subset of the selected panel of peptides had motifs with strong homology to an exposed site within the b1 domain of human neuropilin-1 (NRP-1). We confirmed peptide binding by ELISA and by surface plasmon resonance. We also showed that the PAL-E antigen colocalizes with NRP-1 staining in endothelial cells. Crystal structure of the b1 domain in NRP-1 suggests that the PAL-E binding site overlaps with a vascular endothelial growth factor (VEGF) binding site. Taken together, these results indicate that NRP-1 is an endothelial cell antigen recognized by the true PAL-E antibody. The consistent biochemical, morphologic, and functional features between the PAL-E antigen and NRP-1 support our interpretation. Given that NRP-1 is a VEGF receptor, these results explain the attributes of the PAL-E antibody as a marker of vascular permeability and angiogenesis. [Cancer Res 2007;67(20):9623-9]

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Section: Discussionsupporting

confidence: 79%

The Original Pathologische Anatomie Leiden-Endothelium Monoclonal Antibody Recognizes a Vascular Endothelial Growth Factor–Binding Site within Neuropilin-1

et al. 2007

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“…In the IgE antibody SPE7, both cross-reactivity and exquisite specificity exist side by side. In addition to binding the immunizing hapten (DNP), SPE7 isomer Ab 2 binds to a number of other synthetic ligands, including furazolidone and three-ring quinones (11). Interestingly, although SPE7 accommodates these quite different compounds, it is able to discriminate between highly related derivatives (12).…”

mentioning

confidence: 99%

Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition

James

Tawfik²

2005

Proc. Natl. Acad. Sci. U.S.A.

114

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Induced fit is a predominant phenomenon in protein-ligand interactions, yet it is invariably attributed without establishing the existence, let alone the structure, of the initial, low-affinity encounter complex. We determined the crystal structure of the encounter complex on the pathway of ligand binding by IgE antibody SPE7. We show that this complex is formed by a wide range of ligands that initially bind with identical affinity. Nonspecific ligands rapidly dissociate, whereupon the antibody isomerizes to a nonbinding isomer. Specific ligand complexes, however, slowly isomerize to give a high-affinity complex. This isomerization involves backbone and side-chain rearrangements of up to 14 Å and the formation of specific hydrogen bonds. The postbinding conformational switch, combined with the prebinding isomerization to an energetically favorable nonbinding isomer, results in a ''kinetic discrimination'' mechanism that mediates selective binding, by a factor of >10 3 , between highly related ligands that initially bind with the same affinity. This model may apply to proteins that bind multiple ligands in a specific manner or other proteins that, although capable of binding many ligands, are activated by only a few.conformational diversity ͉ induced fit ͉ multispecificity ͉ promiscuity

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“…The affinity o f anti-DNP antibodies was determined by an ELISA inhibition assay, a modification of the assay described above, which was developed by reference to the radioimmunoassay of Varga [15], Near-saturation concentrations of the two anti-DNP antibodies were…”

Section: Elisa Assaysmentioning

confidence: 99%

Antigen Valency as a Determinant of the Responsiveness of IgE-Sensitised Rat Basophil Leukemia Cells

Collins¹,

Thelian²,

Basil³

1995

Int Arch Allergy Immunol

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Rat basophil leukemia (RBL) cells were sensitised with varying proportions of monoclonal IgE anti-ovalbumin (OVA) and anti-DNP antibodies, and serotonin release was measured after challenge with aggregated OVA or dinitrophenylated human serum albumin (DNP-HSA). Highly aggregated OVA was shown to provoke the degranulation of RBL cells that had been sensitised with an IgE preparation containing 2% IgE anti-OVA antibodies. Highly substituted DNP₃₂-HSA induced degranulation of RBL cells sensitised with just 0.5% antigen-specific IgE. When cells were sensitised with high percentages of specific IgE, maximum degranulation was seen at concentrations of 2 μg/ml (aggregated OVA) and 50 ng/ml (DNP-HSA), while moderate degranulation was still seen at antigen concentrations as low as 50 and 2 ng/ml, respectively. Low-molecular weight aggregates of OVA and low-valency DNP₄-HSA only stimulated degranulation when high percentages of RBL Fcε receptor were occupied by antigen-specific IgE. The sensitising abilities of two anti-DNP monoclonal antibodies of differing affinities were compared. When challenged with low-valency antigen, only cells sensitised with the higher-affinity monoclonal antibody exhibited moderate levels of degranulation. Degranulation required exposure to high antigen challenge doses (5 μg/ml). Cells sensitised with either monoclonal antibody responded strongly when challenged with a wide range of concentrations (1–250 ng/ml) of high-valency DNP₃₂-HSA, although greater sensitivity was always seen with the higher-affinity antibody. These results suggest that antigen valency is a critical parameter for mast cell function, and that low-affinity antibody may be capable of sensitising mast cells to high-valency antigen.

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Mechanism of allergic cross-reactions—I. Multispecific binding of ligands to a mouse monoclonal anti-DNP IgE antibody

Cited by 40 publications

References 12 publications

The Original Pathologische Anatomie Leiden-Endothelium Monoclonal Antibody Recognizes a Vascular Endothelial Growth Factor–Binding Site within Neuropilin-1

The Original Pathologische Anatomie Leiden-Endothelium Monoclonal Antibody Recognizes a Vascular Endothelial Growth Factor–Binding Site within Neuropilin-1

Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition

Antigen Valency as a Determinant of the Responsiveness of IgE-Sensitised Rat Basophil Leukemia Cells

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