Ligand inhibition studies on the role of Fc receptors in antibody-dependent cell-mediated cytotoxicity

Sármay, Gabriella; Benczúr, M.; Petrányi, G; Klein, Eva; Kahn, M F; Stanworth, D.R.; Gergely, J.

doi:10.1016/0161-5890(84)90088-9

Cited by 27 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies mapped the binding site on human and murine IgG for Fc␥R primarily to the lower hinge region composed of IgG residues 233-239 (Eu numbering, see Ref. 18) (8, 14 -17, 19 -22 (23,24), or found few specific residues outside the lower hinge, e.g. Asn 297 and Glu 318 for murine IgG2b interacting with murine Fc␥RII (25).…”

mentioning

confidence: 99%

High Resolution Mapping of the Binding Site on Human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and Design of IgG1 Variants with Improved Binding to the FcγR

Shields

Namenuk

Hong³

et al. 2001

Journal of Biological Chemistry

1,068

915

View full text Add to dashboard Cite

Immunoglobulin G (IgG) Fc receptors play a critical role in linking IgG antibody-mediated immune responses with cellular effector functions. A high resolution map of the binding site on human IgG1 for human Fc␥RI, Fc␥RIIA, Fc␥RIIB, Fc␥RIIIA, and FcRn receptors has been determined. A common set of IgG1 residues is involved in binding to all Fc␥R; Fc␥RII and Fc␥RIII also utilize residues outside this common set. In addition to residues which, when altered, abrogated binding to one or more of the receptors, several residues were found that improved binding only to specific receptors or simultaneously improved binding to one type of receptor and reduced binding to another type. Select IgG1 variants with improved binding to Fc␥RIIIA exhibited up to 100% enhancement in antibody-dependent cell cytotoxicity using human effector cells; these variants included changes at residues not found at the binding interface in the IgG/Fc␥RIIIA co-crystal structure (Sondermann, P., Huber, R., Oosthuizen, V., and Jacob, U. (2000) Nature 406, 267-273). These engineered antibodies may have important implications for improving antibody therapeutic efficacy.

show abstract

mentioning

confidence: 99%

High Resolution Mapping of the Binding Site on Human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and Design of IgG1 Variants with Improved Binding to the FcγR

Shields

Namenuk

Hong³

et al. 2001

Journal of Biological Chemistry

1,068

915

View full text Add to dashboard Cite

show abstract

“…This sequence showed the lowest binding ability both to recombinant Fc + RIIb and to cell surfaceexpressed Fc + R and, as a consequence, the smallest functional activity. This part was suggested as an interacting site by earlier studies [7,27] and also by the recent 3D structure [6]. The above-mentioned mutation mapping also pointed to the importance of residues in this segment for binding to Fc + R [14].…”

Section: Discussionmentioning

confidence: 78%

“…Hence, monomeric IgG present in the circulation does not trigger responses mediated by Fc + RI, Fc + RII or Fc + RIII [4]. Tryptophan residues in the first domain of all Fc + R play an important role in forming a hydrogen bridge with the ligand [6], and both the lower hinge and several residues in the CH2 domain of IgG were shown to participate in the interaction [6][7][8][9][10][11][12][13][14]. Glycosylation of IgG may also influence binding to certain Fc + R isoforms [15,16].…”

Section: Introductionmentioning

confidence: 99%

Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides

et al. 2004

View full text Add to dashboard Cite

Receptors specific for the Fc part of IgG (Fc + R) are expressed by several cell types and play diverse roles in immune responses. Impaired function of the activating and inhibitory Fc + R may result in autoimmunity. Thus, the modulation of IgG-Fc + R interaction can be a target for the development of treatments for some autoimmune and inflammatory diseases. This study addresses the localization and functional characterization of linear sequences in human IgG1 which bind to Fc + RII. Peptides with overlapping sequences derived from the CH2 domain of human IgG1 between P 234 and S 298 were synthesized and used in binding and functional experiments. Binding of the peptides to Fc + R was assayed in vitro and ex vivo, and peptides found to interact were functionally tested. The shortest effective peptide was T 256-P 271 complexed by avidin exhibited functional activity; they induced Fc + RIIb-mediated inhibition of the BCR-triggered Ca 2+ response of human Burkitt lymphoma cells, and inflammatory cytokine production (TNF- § and IL-6) by the human monocyte cell line MonoMac. In conclusion, our results suggest that the selected peptides functionally represent the Fc + RII-binding part of IgG1.

show abstract

“…This latter effect is not necessarily mediated by FcR, but rather by the peptides which supposedly act as short-range immune regulatory hormones [29]. Synthetic peptides representative of sequences 289-301 in the CH2 and 407-416 in the CH3 domain were previously shown to inhibit FcR-mediated ADCC [14,301. In the present study we have examined the effect of the same peptides on different stages of lymphocyte activation.…”

Section: Discussionmentioning

confidence: 98%

“…We have shown earlier that synthetic peptides comprizing sequences within the C H 2 (274-301) or CH3 (407-416) domain of IgG1 inhibit ADCC, one of the FcR-mediated functions [14]. The amino acid sequences of these peptides partly overlap with two of the predicted antigenic epitopes of Fc [15].…”

Section: Introductionmentioning

confidence: 97%

The effect of synthetic peptides corresponding to Fc sequences in human IgG 1 on various steps in the B cell activation pathway

et al. 1988

View full text Add to dashboard Cite

The influence of synthetic peptides comprising sequences in the exposed positions of the Fc region of human IgG 1 was tested on B lymphocyte activation. CH 2 domain peptides having an inhibitory effect on antibody-dependent cellular cytotoxicity, as well as the whole Fc fragment, induced the appearance of the early signs of activation on resting B lymphocytes such as increase in cell volume and HLA-DR antigen expression or leukocyte migration inhibitory factor production. The peptides did not induce proliferation of resting B cells even when B cell growth factor (BCGF)-containing supernatants were added. Exposure to Fc fragment, however, induced a weak proliferation which was significantly enhanced by BCGF. On the other hand, both the Fc fragment and the CH 2 or CH 3 domain peptides enhanced the IgM synthesis of human blood mononuclear cells when a suboptimal dose of pokeweed mitogen was present. This effect was lost when Fc fragment or the peptides were added on the third day of culture. These results suggest that the early steps of B cell activation can be induced by Fc fragment and by small molecular weight Fc peptides, which are potential ligands of Fc receptors. The Fc fragment activates B cells to the state where they respond to BCGF, but the peptides do not possess this activity. Furthermore, both Fc fragment and Fc peptides are able to enhance the IgM synthesis, when accessory cells and the appropriate differentiating factors are present.

show abstract

Ligand inhibition studies on the role of Fc receptors in antibody-dependent cell-mediated cytotoxicity

Cited by 27 publications

References 21 publications

High Resolution Mapping of the Binding Site on Human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and Design of IgG1 Variants with Improved Binding to the FcγR

High Resolution Mapping of the Binding Site on Human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and Design of IgG1 Variants with Improved Binding to the FcγR

Functional mapping of the FcγRII binding site on human IgG1 by synthetic peptides

The effect of synthetic peptides corresponding to Fc sequences in human IgG 1 on various steps in the B cell activation pathway

Contact Info

Product

Resources

About