Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes

Paul A. Ramsland, William Farrugia, Tessa M. Bradford, Caroline Tan Sardjono, Sandra E Esparon, Halina M. Trist, Maree S. Powell, Peck Szee Tan, Angela C. Cendron, Bruce D. Wines, Andrew M. Scott, P. Mark Hogarth

Research output: Contribution to journalArticleResearchpeer-review

101 Citations (Scopus)

Abstract

The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. FcγRIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of FcγRIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of FcγRIIa (FcγRIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence FcγRIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for FcγRIIa (IV.3), FcγRIIb (X63-21), and a pan FcγRII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of FcγRIIa and FcγRIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of FcγRIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.

Original languageEnglish
Pages (from-to)3208-3217
Number of pages10
JournalJournal of Immunology
Volume187
Issue number6
DOIs
Publication statusPublished - 15 Sep 2011

Cite this

Ramsland, Paul A. ; Farrugia, William ; Bradford, Tessa M. ; Sardjono, Caroline Tan ; Esparon, Sandra E ; Trist, Halina M. ; Powell, Maree S. ; Tan, Peck Szee ; Cendron, Angela C. ; Wines, Bruce D. ; Scott, Andrew M. ; Hogarth, P. Mark. / Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes. In: Journal of Immunology. 2011 ; Vol. 187, No. 6. pp. 3208-3217.
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title = "Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes",
abstract = "The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. FcγRIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of FcγRIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of FcγRIIa (FcγRIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence FcγRIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for FcγRIIa (IV.3), FcγRIIb (X63-21), and a pan FcγRII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of FcγRIIa and FcγRIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of FcγRIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.",
author = "Ramsland, {Paul A.} and William Farrugia and Bradford, {Tessa M.} and Sardjono, {Caroline Tan} and Esparon, {Sandra E} and Trist, {Halina M.} and Powell, {Maree S.} and Tan, {Peck Szee} and Cendron, {Angela C.} and Wines, {Bruce D.} and Scott, {Andrew M.} and Hogarth, {P. Mark}",
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doi = "10.4049/jimmunol.1101467",
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Ramsland, PA, Farrugia, W, Bradford, TM, Sardjono, CT, Esparon, SE, Trist, HM, Powell, MS, Tan, PS, Cendron, AC, Wines, BD, Scott, AM & Hogarth, PM 2011, 'Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes', Journal of Immunology, vol. 187, no. 6, pp. 3208-3217. https://doi.org/10.4049/jimmunol.1101467

Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes. / Ramsland, Paul A.; Farrugia, William; Bradford, Tessa M.; Sardjono, Caroline Tan; Esparon, Sandra E; Trist, Halina M.; Powell, Maree S.; Tan, Peck Szee; Cendron, Angela C.; Wines, Bruce D.; Scott, Andrew M.; Hogarth, P. Mark.

In: Journal of Immunology, Vol. 187, No. 6, 15.09.2011, p. 3208-3217.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structural basis for FcγRIIa recognition of human IgG and formation of inflammatory signaling complexes

AU - Ramsland, Paul A.

AU - Farrugia, William

AU - Bradford, Tessa M.

AU - Sardjono, Caroline Tan

AU - Esparon, Sandra E

AU - Trist, Halina M.

AU - Powell, Maree S.

AU - Tan, Peck Szee

AU - Cendron, Angela C.

AU - Wines, Bruce D.

AU - Scott, Andrew M.

AU - Hogarth, P. Mark

PY - 2011/9/15

Y1 - 2011/9/15

N2 - The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. FcγRIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of FcγRIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of FcγRIIa (FcγRIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence FcγRIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for FcγRIIa (IV.3), FcγRIIb (X63-21), and a pan FcγRII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of FcγRIIa and FcγRIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of FcγRIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.

AB - The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. FcγRIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of FcγRIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of FcγRIIa (FcγRIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence FcγRIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for FcγRIIa (IV.3), FcγRIIb (X63-21), and a pan FcγRII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of FcγRIIa and FcγRIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of FcγRIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.

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U2 - 10.4049/jimmunol.1101467

DO - 10.4049/jimmunol.1101467

M3 - Article

VL - 187

SP - 3208

EP - 3217

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

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