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Dr. Ravetch dissects the cellular and molecular mechanisms that govern the generation of antibody specificity and the translation of that specificity into cellular responses. By identifying the genetic components that cause immune system cells to respond to specific antibodies, Dr. Ravetch hopes to gain a better understanding of how a functioning immune system protects organisms from invaders, and how a dysfunctional immune system attacks the body’s own tissues.

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 trigger tissue damage. They simplify this 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, and play a central role in appropriate immune responses.

Dr. Ravetch has shown that inhibitory Fc receptors for immunoglobulin G (IgG) are responsible for maintaining peripheral tolerance; animals without inhibitory Fc receptors develop spontaneous autoimmunity and autoimmune disease. Conversely, mice susceptible to autoimmune disease fail to develop it if they have deficient activation of Fc receptors. But loss of activation receptors does not alter the development of autoantibody 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. Recent work from the Ravetch lab showed that a sugar attached to IgG antibodies confers their protective ability; they are now working on a synthetic therapy rich in these sugar-linked antibodies.

Another focus in the Ravetch lab is the regulation of shifts from inhibition to activation. He has demonstrated that removing the inhibitory pathway in vivo, for example, can dramatically increase the potency of a cytotoxic antitumor antibody. This was the first demonstration of antibody-dependent cell cytotoxicity in vivo. Current studies aim at manipulating the inhibitory response to enhance or limit the cytotoxicity of antibodies in vivo to better understand the role of these pathways and their therapeutic potential.

The lab is also working to determine the pathways through which the coupling of innate and adaptive mechanisms are coordinated. 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.

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 discovered how immunoglobulin receptors mediate antibody-triggered inflammation and determined the mechanism by which intravenous immunoglobulin causes immunosuppression. He also played a key role in establishing Fc receptor pathways as an essential part of the immune response and in describing the mechanisms of antibody-mediated effector responses.