Leukocyte Activating Fc Receptors in Immune Lung Injury

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DESCRIPTION (provided by applicant): Leukocytes such as polymorphonuclear leukocytes (PMN) and macrophages, play an important role both in immune complex disease and in host defense. Macrophages and PMN express on their surface Fcgamma receptors (FcgammaR) which 1) interact with IgG containing immune complexes to produce tissue damage, but 2) also function to clear IgG coated bacteria in host defense. In the lung, Fc receptors and, importantly, the individual Fc receptors have been little studied. We will employ transgenic mice and mice deficient in specific FcR in a combined in vitro and in vivo molecular and cell biology approach to elucidate the role of individual Fc receptors in an animal model of immune lung injury. Both human and mouse macrophages express the activating FcgammaRs FcgammaRI and FcgammaRIIIA which interact with a FcR gamma subunit. We have determined that FcgammaRI is unique among FcR not only in the ability to bind monomeric IgG, but also to signal through both its alpha and gamma subunits. Human macrophages and PMN also express the potent activating FcR FcgammaRIIA, which is absent in mice and does not interact with the y chain. We now have available FcgammaRIIA transgenic (TG) mice, which we have determined express FcgammaRIIA on the macrophage surface to a similar extent as humans and have enhanced clearance of IgG coated cells. Our novel mouse strains include: 1) mice individually lacking either FcgammaRI, FcgammaRIIIA or the gamma chain and 2) mice TG for human FcgammaRIIA (as well as FcgammaRIIA crosses) developed with the participation of our laboratory. Our hypothesis, suggested by our data, is that in the lung FcgammaRI plays a predominant role in the release of inflammatory mediators, while FcgammaRIIA plays a predominant role in host defense. Elucidating the role(s) of specific leukocyte FcgammaRs in the lung is potentially important for developing strategies for effective therapy. Another goal is to define the molecular mechanisms involved in specific mediator release induced by individual lung macrophage FcR, specifically FcgammaRI. We have determined that the cytoplasmic domain (CY) of the FcgammaRI alpha chain is required for release of macrophage IL-6. We will examine structure/function relationships of FcgammaRI involved in signaling for IL-6 release. Human FcgammaRI and chimeras of human FcgammaRI, containing transmembrane domains which cannot associate with endogenous murine Fcgamma receptors, will be transfected into a murine macrophage cell line. Our hypothesis is that specific sequences in the FcgammaRI alpha chain CY, but not the gamma chain, are required for IL-6 release.