Complement is activated by IgG hexamers assembled at the cell surface

Christoph A. Diebolder; Frank J. Beurskens; Rob N. De Jong; Roman I. Koning; Kristin Strumane; Margaret A. Lindorfer; Marleen Voorhorst; Deniz Ugurlar; Sara Rosati; Albert J. R. Heck; Jan G. J. Van De Winkel; Ian A. Wilson; Abraham J. Koster; Ronald P. Taylor; Erica Ollmann Saphire; Dennis R. Burton; Janine Schuurman; Piet Gros; Paul W. H. I. Parren

doi:10.1126/science.1248943

Complement is activated by IgG hexamers assembled at the cell surface

Christoph A. Diebolder, Frank J. Beurskens, Rob N. De Jong, Roman I. Koning, Kristin Strumane, Margaret A. Lindorfer, Marleen Voorhorst, Deniz Ugurlar, Sara Rosati, Albert J. R. Heck, Jan G. J. Van De Winkel, Ian A. Wilson, Abraham J. Koster, Ronald P. Taylor, Erica Ollmann Saphire, Dennis R. Burton, Janine Schuurman, Piet Gros, Paul W. H. I. Parren

Sub Biomolecular Mass Spectrometry and Proteomics

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.

Original language	English
Pages (from-to)	1260-1263
Number of pages	4
Journal	Science
Volume	343
Issue number	6176
DOIs	https://doi.org/10.1126/science.1248943
Publication status	Published - 2014

Keywords

antibody
antigen
complement component C1
immunoglobulin Fc fragment
immunoglobulin G
immunoglobulin G1
immunoglobulin G2
immunoglobulin G3
immunoglobulin G4
article
cell killing
cell surface
complement activation
human
immunotherapy
innate immunity
nonhuman
priority journal
target cell

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.1248943

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diebolder_hexamers_2014
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Diebolder, C. A., Beurskens, F. J., De Jong, R. N., Koning, R. I., Strumane, K., Lindorfer, M. A., Voorhorst, M., Ugurlar, D., Rosati, S., Heck, A. J. R., Van De Winkel, J. G. J., Wilson, I. A., Koster, A. J., Taylor, R. P., Saphire, E. O., Burton, D. R., Schuurman, J., Gros, P., & Parren, P. W. H. I. (2014). Complement is activated by IgG hexamers assembled at the cell surface. Science, 343(6176), 1260-1263. https://doi.org/10.1126/science.1248943

@article{eb30a5b32b744bbeb6ed8801ed38715c,

title = "Complement is activated by IgG hexamers assembled at the cell surface",

abstract = "Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.",

keywords = "antibody, antigen, complement component C1, immunoglobulin Fc fragment, immunoglobulin G, immunoglobulin G1, immunoglobulin G2, immunoglobulin G3, immunoglobulin G4, article, cell killing, cell surface, complement activation, human, immunotherapy, innate immunity, nonhuman, priority journal, target cell",

author = "Diebolder, {Christoph A.} and Beurskens, {Frank J.} and {De Jong}, {Rob N.} and Koning, {Roman I.} and Kristin Strumane and Lindorfer, {Margaret A.} and Marleen Voorhorst and Deniz Ugurlar and Sara Rosati and Heck, {Albert J. R.} and {Van De Winkel}, {Jan G. J.} and Wilson, {Ian A.} and Koster, {Abraham J.} and Taylor, {Ronald P.} and Saphire, {Erica Ollmann} and Burton, {Dennis R.} and Janine Schuurman and Piet Gros and Parren, {Paul W. H. I.}",

year = "2014",

doi = "10.1126/science.1248943",

language = "English",

volume = "343",

pages = "1260--1263",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6176",

}

Diebolder, CA, Beurskens, FJ, De Jong, RN, Koning, RI, Strumane, K, Lindorfer, MA, Voorhorst, M, Ugurlar, D, Rosati, S, Heck, AJR, Van De Winkel, JGJ, Wilson, IA, Koster, AJ, Taylor, RP, Saphire, EO, Burton, DR, Schuurman, J, Gros, P & Parren, PWHI 2014, 'Complement is activated by IgG hexamers assembled at the cell surface', Science, vol. 343, no. 6176, pp. 1260-1263. https://doi.org/10.1126/science.1248943

TY - JOUR

T1 - Complement is activated by IgG hexamers assembled at the cell surface

AU - Diebolder, Christoph A.

AU - Beurskens, Frank J.

AU - De Jong, Rob N.

AU - Koning, Roman I.

AU - Strumane, Kristin

AU - Lindorfer, Margaret A.

AU - Voorhorst, Marleen

AU - Ugurlar, Deniz

AU - Rosati, Sara

AU - Heck, Albert J. R.

AU - Van De Winkel, Jan G. J.

AU - Wilson, Ian A.

AU - Koster, Abraham J.

AU - Taylor, Ronald P.

AU - Saphire, Erica Ollmann

AU - Burton, Dennis R.

AU - Schuurman, Janine

AU - Gros, Piet

AU - Parren, Paul W. H. I.

PY - 2014

Y1 - 2014

N2 - Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.

AB - Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.

KW - antibody

KW - antigen

KW - complement component C1

KW - immunoglobulin Fc fragment

KW - immunoglobulin G

KW - immunoglobulin G1

KW - immunoglobulin G2

KW - immunoglobulin G3

KW - immunoglobulin G4

KW - article

KW - cell killing

KW - cell surface

KW - complement activation

KW - human

KW - immunotherapy

KW - innate immunity

KW - nonhuman

KW - priority journal

KW - target cell

U2 - 10.1126/science.1248943

DO - 10.1126/science.1248943

M3 - Article

C2 - 24626930

SN - 0036-8075

VL - 343

SP - 1260

EP - 1263

JO - Science

JF - Science

IS - 6176

ER -

Complement is activated by IgG hexamers assembled at the cell surface

Abstract

Keywords

UN SDGs

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