The Ravetch laboratory analyzes systemic autoimmunity in mouse models of certain diseases by investigating the genesis and fate of the pathological antigen-antibody complexes that form and trigger tissue damage. They simplify this complex problem by examining the mechanisms through which immune complexes influence both the afferent and efferent immune responses by interacting with a family of low-affinity surface receptors, the Fc receptors. These receptors are expressed as pairs of activation and inhibitory molecules, providing a mechanism for establishing thresholds for cellular triggering and for terminating the activation response. Disruptions of these pathways have revealed the central role these receptors play in appropriate immune responses.

Dr. Ravetch has shown that inhibitory Fc receptors (or FcRs) for Immunoglobulin G (IgG) are responsible for maintaining peripheral tolerance; animals without inhibitory FcRs develop spontaneous autoimmunity and autoimmune disease. Conversely, a deficiency of activation FcRs results in a protective effect, in which mice susceptible to autoimmune disease fail to develop it. But loss of activation receptors does not alter the development of auto-antibody and immune complex deposition. Rather, Dr. Ravetch has found that these potentially pathogenic complexes are unable to trigger effector cell responses and are therefore benign. His lab is now investigating the precise cellular pathways engaged by activation receptors via auto-antibodies by generating cell-type specific targeted gene disruptions of the relevant activation receptors and by identifying the downstream effector molecules responsible for the observed pathology. Recent work from the Ravetch lab showed that a sugar attached to IgG antibodies confers their protective ability; they are now working on creating a synthetic therapy that is rich in these sugar-linked antibodies.

Another focus in the Ravetch lab is the regulatory circuits involved in coordinating the regulation of activation and inhibitory receptors, in order to determine the signals that shift the balance from inhibition to activation. He has demonstrated that removing the inhibitory pathway in vivo, for example, can dramatically increase the potency of a cytotoxic anti-tumor antibody. This represents the first demonstration of antibody-dependent cell cytotoxicity in vivo, establishing a physiological role for the in vitro reaction. Current studies are now aimed at manipulating the inhibitory response to enhance or limit the cytotoxicity of antibodies in vivo to better understand the role these pathways play in protective immunity and their therapeutic potential.

Researchers in Dr. Ravetch’s lab are also working to determine the pathways by which the coupling of innate and adaptive mechanisms is coordinated to initiate an immune response. Two such pathways are currently under investigation: the feedback by immune complexes on antigen presentation, and the targeting of selected antigens to restricted follicular locations to initiate T cell independent responses. Using a series of mice deficient in specific Fc receptors and immune complexes designed to selectively engage these pathways, they are determining the role of each in activating or tolerizing presenting cells in vivo.

Prior work by Dr. Ravetch led to the cloning and mapping of the first malarial parasite chromosome, and more recently to the cloning of the first Fc receptor genes. He was responsible for discovering how immunoglobulin receptors mediate antibody-triggered inflammation, and determining the mechanism by which intravenous immunoglobulin causes immunosuppression. He also played a key role in establishing FcR pathways as an essential part of the immune response, and contributed significantly to understanding the mechanisms of antibody-mediated effector responses.

CAREER

Dr. Ravetch graduated from Yale University in 1973 and received his Ph.D. from Rockefeller University in 1978, where he studied under Norton Zinder and Peter Model. He received his M.D. from Cornell University Medical College in 1979, and completed his postdoctoral research at the National Institutes of Health in the Laboratory of Molecular Genetics. In 1982, Dr. Ravetch joined the faculty of Cornell University Medical College and Memorial Sloan-Kettering Cancer Center and in 1984 also became a guest investigator in the Rockefeller Laboratory of Cellular Physiology and Immunology. He was appointed professor at Rockefeller in 1996, and named Theresa and Eugene M. Lang Professor in 1997.

Dr. Ravetch received the American Association of Immunologists-Huang Foundation Meritorious Career Award in 2005, the Lee J. Howley Jr. Award in 2004 and the Burroughs Wellcome Fund Award in Molecular Parasitology in 1986. He is a member of the National Academy of Sciences.