Jeffrey V. Ravetch, MD, PhD
Theresa and Eugene M. Lang Professor

Immunology is focussed on dissecting 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 which initiate B cell activation upon antigenic challenge, the controls which maintain tolerance both centrally and in the periphery and the mechanisms which 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 which form in these diseases and trigger tissue damage. This complex problem has been simplified by focussing on the mechanisms by which immune complexes influence both the afferent and efferent immune responses through their interaction with a family 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. 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 appropriate immune responses.

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We have demonstrated that inhibitory Fc receptors for IgG are responsible for maintaining peripheral tolerance; animal deficient in these molecules develop spontaneous autoimmunity and autoimmune disease. This loss of tolerance to nuclear antigens is strain-specific, establishing the critical role of epistasis in autoimmunity. These recessive, strain-specific modifiers are unlinked to the MHC, and have been mapped to mouse chromosomes 9, 12 and 17. This robust genetic system is the best animal model yet described for the identification of genetic modifiers for autoimmunity. The identification of these strain-specific modifiers has been extended to determine their role in modifying other susceptibility loci such as lpr, yaa and Sle 1 as a prelude to determining their linkage to human autoimmune diseases.

Conversely, deficiency of activation Fc receptors result in a protective phenotype, uncoupling autoimmunity from autoimmune disease. Mice susceptible to spontaneous or induced autoimmune disease are protected when the activation FcR is deleted from the appropriate genetic background. Loss of activation receptors does not alter the development of autoantibody and immune complex deposition. Rather, these potentially pathogenic complexes are unable to trigger effector cell responses and are thus benign. The precise cellular pathways engaged by activation receptors by autoantibodies are under investigation through the generation of cell-type specific targeted gene disruptions of the relevant activation receptors and through the identification of the downstream effector molecules responsible for the observed pathology.

Modulation of activation and inhibitory receptors, then, is a central mechanism for mediating antibody coupling to effector cells. The regulatory circuits involved in this coordinate regulation are a focus of study in the laboratory to determine the signals that shift the balance from inhibition to activation. We have demonstrated that the potency of a cytotoxic anti-tumor antibody, for example, can be dramatically increased by removing the inhibitory pathway in vivo. This represents the first demonstration of ADCC in vivo, establishing a physiological role for this in vitro reaction. Current studies are aimed at manipulating the inhibitory response to enhance or limit the cytotoxicity of antibodies in vivo to gain insight into the role of these pathways in protective immunity and for their potential therapeutic development.

In a related area of study, we also seek to determine the pathways by which the coupling of innate and adaptive mechanisms are coordinated to initiate an immune response. Two such pathways are 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 engage these pathways selectively we are determining the role of each in activating or tolerizing presenting cells in vivo. However, for many pathogenic microorganisms, T independent responses are a dominant feature of the adaptive response. We have been investigating the cellular and biochemical components mediating these responses through the analysis of mice deficient in a cell type critical to this response, the marginal zone B cell. Mice rendered deficient in these cells have revealed a mechanism by which selected antigens are able to localize to MZB cells and override B cell threshold to trigger cellular activation in the absence of T cell help. Further dissection of these mechanisms will reveal the interplay between innate and adaptive mechanism in initiating antibody responses.