Dimerization kinetics of the IgE-class antibodies by divalent haptens. II. The interactions between intact IgE and haptens

Schweitzer‐Stenner, Reinhard; Licht, A.; Pecht, Israel

doi:10.1016/s0006-3495(92)81610-7

Cited by 13 publications

(8 citation statements)

References 18 publications

(19 reference statements)

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“…2.12 b, bottom pathway) [104,[150][151][152][153][154][155][156]. In solution, these aggregates were shown to be stable on relatively long time-scales (for analysis by HPLC and ultracentrifugation) [104,[155][156][157].…”

Section: Fig 212mentioning

confidence: 99%

Multivalency in Ligand Design

Krishnamurthy

Estroff

Whitesides

2006

Methods and Principles in Medicinal Chemistry

142

186

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Section: Fig 212mentioning

confidence: 99%

Multivalency in Ligand Design

Krishnamurthy

Estroff

Whitesides

2006

Methods and Principles in Medicinal Chemistry

142

186

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“…Evidence suggests that these ligands are poor initiators of cell signaling because they aggregate receptors predominantly in the form of stable cyclic dimers. 12 Modeling suggests that cyclic dimers, in which two ligand molecules connect two IgE -FcεRI complexes to form a closed ring, prevent chain elongation, limit the size of ligand-induced aggregates, and may generate an inhibitory signal. 13 In contrast to divalent antigens, trivalent antigens are predicted to form larger, highly branched aggregates ( Figure 1B) leading to strong responses by IgE -FcεRI presenting cells ( Figure 1C).…”

Section: Nih Public Accessmentioning

confidence: 99%

Trivalent Antigens for Degranulation of Mast Cells

et al. 2007

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Degranulation of basophils and mast cells, releasing histamine, plays a central role in allergic reactions. Degranulation is a response to cell surface receptor aggregation caused by association of receptors with antibodies bound to multivalent antigens. Tools used in studying this process have included small-molecule divalent antigens, but they suffer from weak signaling due to small aggregate size. We have prepared trivalent antigens that allow formation of larger aggregates and potent responses from mast cells.Aggregation of cell surface receptors is a common mechanism involved in signal transduction across cell membranes. 1 This mechanism is used, for example, by receptors that are intrinsic protein tyrosine kinases (i. e., autophosphorylation of aggregated receptors), 2,3 such as the epidermal growth factor receptor, the platelet derived growth factor receptor, and the high affinity receptor for IgE (Fcε RI), which plays a central role in allergic reactions. 4,5 Early steps in the initiation of signaling by this class of receptors are similar: multivalent interactions with a ligand lead to aggregation of receptors and enhanced phosphorylation of tyrosines, which can be recognized by cytoplasmic regulatory molecules.FcεRI receptors are found on the surface of mast cells, basophils, and rat basophilic leukemia (RBL) cells, and these receptors bind the Fc (invariant) region of the divalent antibody IgE. When multiple IgE molecules bind a polyvalent antigen and in turn associate with FcεRI on a cell surface, aggregates of these receptors are generated (Figure 1). Formation of aggregates can in some cases trigger calcium release and degranulation (export of histamine).* paul_savage@byu.edu . Supporting Information Available:Experimental details for the degranulation experiments; a synthetic scheme for 8a and 8b; synthetic details for the preparation of the di-and tri-valent antigens (6a, 6b, 7a, 7b, 8a and 8b); and 1 H NMR spectra for 6a, 6b, 7a, 7b, 8a and 8b. For example, it has been observed that aggregation caused by IgE dimers are less effective than those caused by larger IgE oligomers at stimulating cellular responses 6 and that cellular responses are inhibited when an optimal degree of aggregation is exceeded. 9 The factors that cause an aggregate to be a robust signaling unit, an inhibitor of signal transduction, or a nonsignaling unit remain to be fully elucidated. NIH Public AccessThe importance of influences of ligand-induced receptor aggregates on cellular signals has prompted significant effort in developing means for quantitative analysis of the interactions between multivalent ligands and cell surface receptors. 10 An attractive approach to studing IgE -FcεRI aggregation involves the use of synthetic symmetric divalent ligands, which are the simplest type of ligand capable of aggregating receptors. The interaction of divalent IgE antibodies with a divalent ligand can result in an IgE -FcεRI aggregate spectrum that contains only linear chains and rings of various sizes (including one to on...

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“…This notion, however, was challenged by experiments using divalent DNP haptens of different lengths and flexibility as cross-linking reagents for cell-bound, hapten-specific IgE antibodies. All of these ligands 0006-2960/94/0433-8813$04.50/0 © 1994 American Chemical Society were found to be capable of cross-linking IgEs into dimers in solution and on the surface of mast cells (Schweitzer-Stenner et al, 1987, 1992bPosner et al, 1991). The corresponding Fc(RI aggregates, however, differ in terms of their triggering efficiency.…”

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confidence: 99%

Kinetics of Fc.epsilon.RI Dimer Formation by Specific Monoclonal Antibodies on Mast Cells

Schweitzer‐Stenner

Ortega²,

Pecht³

1994

Biochemistry

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Clustering of the type I receptor for Fc epsilon domains constitutes the signal initiation leading to mast cell secretory response. In order to characterize the relationship between the lifetime of clustered Fc epsilon receptors and the cellular response we have studied the rates of association and dissociation of monoclonal, IgG class antibodies (mAbs) specific for the alpha-subunit of type 1 receptor for IgE (Fc epsilon RI) (designated as F4, J17, and H10) to and from this receptor on live rat mucosa-type mast cells (line RBL-2H3) were measured at three different temperatures (25, 15, and 4 degrees C). These antibodies dimerize the Fc epsilon RI on these cells and induce their secretion, thus providing clear evidence that Fc epsilon receptor dimers are sufficient for the stimulus [Ortega et al. (1988), EMBO J. 7, 4101]. Marked differences in the response to the different mAbs have been explained in terms of possible orientational constraints imposed by them on the Fc epsilon receptor dimers. Interaction kinetics between the Fab fragments of these mAbs and the Fc epsilon RI have previously been measured and found to be best fitted by a two-reaction-step model involving a conformational transition from a low-affinity (l) to a high-affinity (h) state of the receptor-ligand complex [Ortega et al. (1991) Biochemistry 30, 3473]. Analysis of the interaction kinetics between the corresponding intact mAbs and the Fc epsilon RI therefore requires consideration of this 1-->h transition for both complexes involved, namely, the monomeric Fc epsilon RI-mAb and the dimeric Fc epsilon RI-mAb-Fc epsilon RI complexes. This was done by assuming the involvement of the following Fc epsilon RI dimer species: all 1- or h-state dimers Dll and Dhh and a hybrid Dlh with one receptor in the l state and the other in the h state. A self-consistent set of rate constants was derived by fitting the experimental results to this model. At 25 degrees C the all-h-state dimers Dhh turned out to be preferentially stabilized, probably by interaction with other cellular components. Different dimer formation rates were observed for each of the three mAbs, indicating that the dimer distribution among different states is determined by the individual epitope-binding site combination and also by the geometry of the respective complexes.(ABSTRACT TRUNCATED AT 400 WORDS)

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Dimerization kinetics of the IgE-class antibodies by divalent haptens. II. The interactions between intact IgE and haptens

Cited by 13 publications

References 18 publications

Multivalency in Ligand Design

Multivalency in Ligand Design

Trivalent Antigens for Degranulation of Mast Cells

Kinetics of Fc.epsilon.RI Dimer Formation by Specific Monoclonal Antibodies on Mast Cells

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