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Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding
Falk Nimmerjahn, and
Jeffrey V. Ravetch*
Abstract:
Subclasses of immunoglobulin G (IgG) display substantial differencesin their ability to mediate effector responses, contributingto variable activity of antibodies against microbes and tumors.We demonstrate that the mechanism underlying this long-standingobservation of subclass dominance in function is provided bythe differential affinities of IgG subclasses for specific activatingIgG Fc receptors compared with their affinities for the inhibitoryIgG Fc receptor. The significant differences in the ratios ofactivating-to-inhibitory receptor binding predicted the in vivoactivity. We suggest that these highly predictable functionsassigned by Fc binding will be an important consideration inthe design of therapeutic antibodies and vaccines.
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
* To whom correspondence should be addressed. E-mail: ravetch{at}rockefeller.edu
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Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations.
M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius (2008)
J. Immunol.
180, 4338-4345
|Abstract »|Full Text »|PDF »
B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in Fc{gamma}R Effector Functions.
Y. Xiu, C. P. Wong, J.-D. Bouaziz, Y. Hamaguchi, Y. Wang, S. M. Pop, R. M. Tisch, and T. F. Tedder (2008)
J. Immunol.
180, 2863-2875
|Abstract »|Full Text »|PDF »
Differential Contribution of Three Activating IgG Fc Receptors (Fc{gamma}RI, Fc{gamma}RIII, and Fc{gamma}RIV) to IgG2a- and IgG2b-Induced Autoimmune Hemolytic Anemia in Mice.
L. Baudino, F. Nimmerjahn, S. Azeredo da Silveira, E. Martinez-Soria, T. Saito, M. Carroll, J. V. Ravetch, J. S. Verbeek, and S. Izui (2008)
J. Immunol.
180, 1948-1953
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Suppression of Lethal Plasmodium yoelii Malaria following Protective Immunization Requires Antibody-, IL-4-, and IFN-{gamma}-Dependent Responses Induced by Vaccination and/or Challenge Infection.
Autoimmunity Stimulated by Adoptively Transferred Dendritic Cells Is Initiated by Both {alpha}beta and {gamma}{delta} T Cells but Does Not Require MyD88 Signaling.
D. A. Martin, K. Zhang, J. Kenkel, G. Hughes, E. Clark, A. Davidson, and K. B. Elkon (2007)
J. Immunol.
179, 5819-5828
|Abstract »|Full Text »|PDF »
Rectification of Age-Associated Deficiency in Cytotoxic T Cell Response to Influenza A Virus by Immunization with Immune Complexes.
B. Zheng, Y. Zhang, H. He, E. Marinova, K. Switzer, D. Wansley, I. Mbawuike, and S. Han (2007)
J. Immunol.
179, 6153-6159
|Abstract »|Full Text »|PDF »
Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus.
F. Wermeling, Y. Chen, T. Pikkarainen, A. Scheynius, O. Winqvist, S. Izui, J. V. Ravetch, K. Tryggvason, and M. C.I. Karlsson (2007)
J. Exp. Med.
204, 2259-2265
|Abstract »|Full Text »|PDF »
Fc Optimization of Therapeutic Antibodies Enhances Their Ability to Kill Tumor Cells In vitro and Controls Tumor Expansion In vivo via Low-Affinity Activating Fc{gamma} Receptors.
J. B. Stavenhagen, S. Gorlatov, N. Tuaillon, C. T. Rankin, H. Li, S. Burke, L. Huang, S. Johnson, E. Bonvini, and S. Koenig (2007)
Cancer Res.
67, 8882-8890
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A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects.
S. E. Strome, E. A. Sausville, and D. Mann (2007)
Oncologist
12, 1084-1095
|Abstract »|Full Text »|PDF »
Signaling through Fc{gamma}RIII is required for optimal T helper type (Th)2 responses and Th2-mediated airway inflammation.
H. S. Bandukwala, B. S. Clay, J. Tong, P. D. Mody, J. L. Cannon, R. A. Shilling, J. S. Verbeek, J. V. Weinstock, J. Solway, and A. I. Sperling (2007)
J. Exp. Med.
204, 1875-1889
|Abstract »|Full Text »|PDF »
Immunomodulatory Dendritic Cells Inhibit Th1 Responses and Arthritis via Different Mechanisms.
L. M. van Duivenvoorde, W. G. H. Han, A. M. Bakker, P. Louis-Plence, L.-M. Charbonnier, F. Apparailly, E. I. H. van der Voort, C. Jorgensen, T. W. J. Huizinga, and R. E. M. Toes (2007)
J. Immunol.
179, 1506-1515
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Activating Fc{gamma} Receptors Participate in the Development of Autoimmune Diabetes in NOD Mice.
Y. Inoue, T. Kaifu, A. Sugahara-Tobinai, A. Nakamura, J.-I. Miyazaki, and T. Takai (2007)
J. Immunol.
179, 764-774
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Agalactosylated IgG antibodies depend on cellular Fc receptors for in vivo activity.
F. Nimmerjahn, R. M. Anthony, and J. V. Ravetch (2007)
PNAS
104, 8433-8437
|Abstract »|Full Text »|PDF »
Mouse models of IgG- and IgM-mediated hemolysis.
D. A. Schirmer, S.-C. Song, J. P. Baliff, S. O. Harbers, R. A. Clynes, A. Krop-Watorek, G. R. Halverson, M. Czerwinski, and S. L. Spitalnik (2007)
Blood
109, 3099-3107
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A Novel Antibody-Dependent Cellular Cytotoxicity Mechanism Involved in Defense against Malaria Requires Costimulation of Monocytes Fc{gamma}RII and Fc{gamma}RIII.
A. Jafarshad, M. H. Dziegiel, R. Lundquist, L. K. Nielsen, S. Singh, and P. L. Druilhe (2007)
J. Immunol.
178, 3099-3106
|Abstract »|Full Text »|PDF »
The antiinflammatory activity of IgG: the intravenous IgG paradox.
