HUMAN BLOOD MONOCYTE RECEPTOR EXPRESSION AND MODULATION

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Monocyte/macrophage Fcgamma receptors are important in host defense and in the pathophysiology of several hematologic diseases. Enhancement of their activity facilitates the ability of these cells to eliminate microorganisms. Inhibition of their activity improves the clinical status of patients with autoimmune hemolytic anemia and thrombocytopenia. There is substantial heterogeneity among the Fcgamma receptors and three distinct monocyte/macrophage Fcgamma receptor proteins, FcgammaRI (CD64), FcgammaRII (CD32) and FcgammaRII (CD16), have been defined in man. Considerable data from our laboratory and that of others have helped to elucidate the number of these receptors on monocytes/macrophages, their affinity for IgG ligand and their modulation in vitro and in vivo. However, the significance of each monocyte/macrophage Fcgamma receptor and the function each subserves are virtually unknown. Our goals in this research proposal are to delineate the interrelationships between the different monocyte/macrophage Fcgamma receptors in an attempt to understand why these cells have more than one Fcgamma receptor. We will give particular attention to the potential role of FcgammaRI, the receptor which binds monomeric IgG. Specifically, we will explore the following questions: 1) The relationship of the monocyte Fcgamma receptors to one another. We will establish whether monocyte FcgammaRI is topographically related to FcgammaRII or FcgammaRIII and will examine the effect of perturbation of FcgammaRI on FcgammaRII and the role of FcgammaRI in the de novo expression of cultured monocyte FcgammaRIII. Our hypothesis is that occupancy or cross-linking of FcgammaRI affects these processes. 2) The role of each Fcgamma receptor in important monocyte functions. The effect of activation of each Fcgamma receptor on changes in intracellular Ca++, superoxide generation and lysosomal enzyme release will be studied. Our hypothesis is that activation of each Fcgamma receptors leads to quantitatively or qualitatively different functional programs. Transfection studies will examine the hypothesis that the cytoplasmic domain is critical to the signal transduction of FcgammaRI. 3). The relationship of monocyte FcgammaRI to the function of FcgammaRII and FcgammaRIII. The hypothesis to be tested is that perturbation of FcgammaRI modulates the functional programs mediated by activation of FcgammaRII and FcgammaRIII. 4) We will also define the effect of one mediator which modulates Fcgamma receptor activity, Hageman factor, on monocyte FcgammaRI. 5) Finally, we will examine the regulation of the Fcgamma receptors in an established experimental model which enables us to focus on the differential modulation of these receptors in vivo.