The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/179/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 1, January 4, 1999 179-186

Articles

Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors

Raphael Clynes*, Jay S. Maizes*, Rodolphe Guinamard*, Masao Ono{ddagger},§, Toshiyuki Takai{ddagger},§, and Jeffrey V. Ravetch*

From the * Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the {ddagger} 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

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 Fc{gamma}RIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of Fc{gamma}RII 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, Fc{gamma}RII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from Fc{gamma}RII–/– stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that Fc{gamma}RII 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 FcR{gamma}–/– mice are completely protected from inflammatory injury. An inhibitory role for Fc{gamma}RII on macrophages is demonstrated by analysis of Fc{gamma}RII–/– macrophages which show greater phagocytic and calcium flux responses upon Fc{gamma}RIII 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 Fc{gamma}R expression. Exploiting the Fc{gamma}RII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

Key Words: Fc receptor • complement • immune complex • chemokine • cytokine

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: ravetch{at}rockvax.rockefeller.edu

Abbreviations used: BAL, bronchoalveolar lavage; HSA, human serum albumin; IC, immune complex; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; MIP, macrophage-inflammatory protein; MPO, myeloperoxidase.


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