Fc receptors for IgG (Fc?R) are essential for mediating the effector properties of IgGs in vivo, as well as regulating the afferent response through the engagement of immune complexes with B cells and dendritic cells. Perturbations in expression and signaling of these receptors can contribute to the loss of tolerance and immunopathology observed in autoimmune diseases such as lupus and rheumatoid arthritis. While previous studies utilizing gene disruptions have revealed the overall function of these receptors, a detailed analysis of the contribution of individual cellular populations with their specific FcR expression and binding properties is, as yet, lacking. 1) We will address the functional contribution of specific receptors on discrete lymphoid and myeloid cells using conditionally floxed alleles of murine Fc?Rs B6 ES cells. RIIB deletion in B cell subsets and dendritic cells will determine their respective contributions to the regulation by immune complexes of autoreactive B cells in the periphery. The contribution of macrophage/neutrophils, mast cells and NK cells to IgG mediated cytotoxicity and immune complex triggered inflammation will be characterized in strains conditionally deleted for Fc?Rs on these effector cells. 2) Extrapolation of these results to the human system will be addressed by the generation of fully humanized FcR mouse lines, in which all endogenous murine FcR expression is ablated and human FcR expression is obtained in a cellular pattern appropriate for the human FcRs. These lines will be characterized in models of human IgG mediated cytotoxicity and immune complex inflammation for specific IgG subclasses and modified human Fcs.
TO HUMAN DISEASE: The studies outlined in this proposal will provide a rational basis for the re-engineering of therapeutic IgG antibodies for the treatment of neoplastic and inflammatory diseases and for their evaluation in vivo in an animal model that recapitulates the human system.
|Li, Fubin; Smith, Patrick; Ravetch, Jeffrey V (2014) Inhibitory FcÎ³ receptor is required for the maintenance of tolerance through distinct mechanisms. J Immunol 192:3021-8|
|Kubagawa, H; Chen, C C; Ho, L H et al. (1999) Biochemical nature and cellular distribution of the paired immunoglobulin-like receptors, PIR-A and PIR-B. J Exp Med 189:309-18|
|Heiken, H; Schulz, R J; Ravetch, J V et al. (1996) T lymphocyte development in the absence of Fc epsilon receptor I gamma subunit: analysis of thymic-dependent and independent alpha beta and gamma delta pathways. Eur J Immunol 26:1935-43|
|Sylvestre, D L; Ravetch, J V (1994) Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265:1095-8|