Jeffrey Victor Ravetch, MD, PhD
Honorary member, elected 2007
We study the cellular and molecular mechanisms governing the generation of antibody specificity and the translation of that specificity into cellular responses. Our work seeks to identify the genetic components that initiate B-cell activation upon antigenic challenge, the controls that maintain tolerance both centrally and in the periphery and the mechanisms that govern the coupling of antibody specificity to effector cell response. Our entry point into this system has been through the analysis of systemic autoimmunity in murine models of disease through the investigation of the genesis and fate of the pathological antigen-antibody complexes that form in these diseases and trigger tissue damage. This complex problem has been simplified by focusing on the mechanisms by which immune complexes influence both the afferent and efferent immune responses through their interaction with a family of low-affinity surface receptors, the Fc receptors. These receptors are expressed as pairs of activation and inhibitory molecules, providing a threshold mechanism for cellular triggering and for terminating the activation response. Each function is critical for maintaining tolerance and modulating effector cell activation. Perturbations of these pathways have revealed the central role these receptors play in immune responses. Ongoing studies aim at defining the mechanisms balancing activation and inhibitory responses. Regulation of gene expression, receptor assembly, localization and signaling influence the responsiveness of a target cell to immune complex activation. Dissection of these pathways is underway through genetic and biochemical approaches.