Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.
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4 January 1999
Article|
January 04 1999
Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors
Raphael Clynes,
Raphael Clynes
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Jay S. Maizes,
Jay S. Maizes
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Rodolphe Guinamard,
Rodolphe Guinamard
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Masao Ono,
Masao Ono
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Toshiyuki Takai,
Toshiyuki Takai
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Jeffrey V. Ravetch
Jeffrey V. Ravetch
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
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Raphael Clynes
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Jay S. Maizes
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Rodolphe Guinamard
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Masao Ono
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Toshiyuki Takai
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Jeffrey V. Ravetch
From the *Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the ‡Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan; and §Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Tokyo 101-0062, Japan
Address correspondence to Jeffrey V. Ravetch, Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: 212-327-7321; Fax: 212-327-7318; E-mail: [email protected]
Received:
October 08 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (1): 179–186.
Article history
Received:
October 08 1998
Citation
Raphael Clynes, Jay S. Maizes, Rodolphe Guinamard, Masao Ono, Toshiyuki Takai, Jeffrey V. Ravetch; Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors . J Exp Med 4 January 1999; 189 (1): 179–186. doi: https://doi.org/10.1084/jem.189.1.179
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