Whether Fc3RIIb (RIIb) of the mouse yolk sac (YS) protects the conceptus from IgG-mediated allograft rejection, the focus of this application, has evolved from our long term interest in how the human placenta handles maternal IgG antibody. The human placenta transports IgG from maternal to fetal circulation, handily dealing with intrauterine infection and sustaining the newborn with mother's full complement of protective IgG antibody until the infant's its own immune system matures. During the process IgG crosses two placental cell layers and interposed stroma. The first layer, syncytiotrophoblast, expresses the placental transporter, FcRn, a nonclassical MHC1 molecule noncovalently linked with 22 microglobulin. FcRn moves IgG by a pH-dependent mechanism across the cell in endocytic vesicles to the second cell layer, the endothelium, which expresses a different Fc receptor, RIIb2, which might potentially serve as an endothelial transporter but is more widely known to dampen immune complex (IC)-mediated responses. Further, our recent studies in the mouse YS, the mouse organ functionally analogous to the IgG transporting human placenta, indicate that, indeed, RIIb is not an IgG transporter. Most likely, IgG moves passively across the endothelium by nonspecific pinocytosis. What function, then, does RIIb serve? One possibility is that villus endothelial Fc receptors serve to trap and eliminate maternal IgG antibodies provoked by and directed toward foreign (paternal) antigen in the conceptus, antibodies that in the process of transport to the fetus would be complexed with their target conceptus antigens expressed in placental tissue. Recent new data show that RIIb-lacking fetuses tend not to survive pregnancies of histoincompatible parents. Observations from other areas of biology lend suggest a credible mechanism for this process;specifically, RIIb in endothelial and dendritic cells may capture endocytosed immune complexes and move them back, undegraded, to the cell surface, expressing them on the plasma membrane, so that they might then be available to neighboring macrophages. Endothelial cell lysosomes would not be essential and endothelial cells themselves would not be the site of degradation. In human our capacity to evaluate this hypothesis is severely limited. Thus, we move to a mouse model where our immediate goal is to test specific and critical predictions of the idea that RIIb expressed in the mouse YS protects the conceptus from IgG antibody-mediated allograft rejection.
Our specific aims are to test the predictions that 1) YS RIIb is in the immediate IgG transfer pathway from mother to fetus;2) Fetuses lacking YS RIIb, derived from histoincompatible matings, will be less viable than WT littermates;3) Under histoincompatible situations YS RIIb captures IC and expresses them on the cell surface to macrophages for degradation, while in the absence of RIIb the conceptus suffers IC-mediated damage. This project contributes basic elements to our knowledge of fetal, allograft, and Fc receptor biology. It will yield not only a keener understanding of pregnancy and the healthy fetus and newborn, but a greater capacity to deal with their diseases. Quite apart from pregnancy the project extends our understanding of the inhibitory receptor, Fc3RIIb, into areas that may return further insight into immune cell biology.
This project contributes basic elements to our knowledge of fetal, allograft, and Fc receptor biology. It will yield not only a keener understanding of pregnancy and the healthy fetus and newborn, but a greater capacity to deal with their diseases. Quite apart from pregnancy the project extends our understanding of the inhibitory receptor, Fc3RIIb, into areas that may return further insight into immune cell biology.
|Kim, Jonghan; Hayton, William L; Robinson, John M et al. (2007) Kinetics of FcRn-mediated recycling of IgG and albumin in human: pathophysiology and therapeutic implications using a simplified mechanism-based model. Clin Immunol 122:146-55|