Browsing by Subject "Receptors, Fc"
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Item Immune-complex vasculitis: the result of paradoxical deficits in complement and IgG-Fc receptor functions(1988-12-08) Smiley, J. DonaldItem Targeting the Neonatal Fc Receptor, FcRn, to Treat Autoimmunity and Elucidation of Sites of FcRn Function(2016-10-13) Challa, Dilip Kumar; Eberhart, Robert C.; Ward, E. Sally; Greenberg, Benjamin M.; Satterthwaite, Anne B.; Stüve, OlafThe neonatal Fc receptor, FcRn, is expressed in many different cell types and serves several functions, some of which are cell type-specific. A function common to most cell types that express this receptor is salvage of IgG from cellular degradation which is responsible for the long in vivo half-life of IgG. This property of IgG is responsible for its indispensable role in humoral immunity and also contributes to the successful use of IgGs as therapeutics. In autoimmunity, however, autoantibodies are generated that can contribute to pathology. FcRn-mediated salvage is also responsible for the long half-life of autoreactive IgGs. Therefore, this study employed an engineered antibody (Abdeg, a novel FcRn inhibitor) that lowers endogenous IgG levels by competing for binding to FcRn, to directly assess the effect of decreased antibody levels in an autoantibody-dependent murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Essentially, Abdeg delivery reduced the accumulation of autoantibodies in the target organs and ameliorated the disease. Autoreactive CD4+ T cells are also known to play an important role in the pathogenesis of autoimmune diseases. Thus, with the goal of inducing antigen-specific T cell tolerance, the current study employed immunoglobulin Fc engineering to develop a novel platform for the delivery of peptide epitopes as Fc-peptide fusions with different dynamic properties. Using very low doses of these engineered antigens to avoid anaphylactic shock, the study demonstrates that the longevity of the peptide antigen is the primary determinant of tolerance induction in a murine EAE model that is driven by autoreactive CD4+ T cells. Long-lived Fc-antigen fusions are effective tolerogens in both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Further, to identify the FcRn-expressing cell types that mediate the effects of Abdegs and Fc-antigen fusions on autoantibodies and autoreactive T cells, respectively, cre-loxp technology was used to generate multiple cell type-specific FcRn knockout mice. This study indicates that macrophages are the primary sites among hematopoietic cells where IgG homeostasis occurs. Collectively, these studies have led to an improved understanding of FcRn function at both the level of its sites of functional activity and targeting this receptor for therapy.Item Using Advanced Fluorescence Microscopy to Analyze Intracellular Trafficking of FcRn In Live Cells(2013-01-17) Gan, Zhuo; Ward, E. Sally; Ober, Raimund J.The MHC class I-related Fc receptor (FcRn) regulates the in vivo half-life of immunoglobulin G (IgG) and transports IgG across cell barriers. The intracellular trafficking of FcRn is central to its diverse functions. FcRn, like all receptors, is transferred to lysosomes for constitutive degradation to maintain a balance between synthesis and breakdown. Using live cell imaging, a novel lysosomal delivery pathway for FcRn has been observed. Unlike signaling receptors that enter the intraluminal vesicles in late endosomes, FcRn remains on the limiting membrane of late endosomes and is delivered to lysosomes through a selective, primarily tubule-mediated process. Following transfer, FcRn is rapidly internalized into the lysosomal lumen. By contrast, LAMP1 remains on the limiting membrane of lysosomes. Rab5 can persist on late endosomes, which can not only fuse with lysosomes, but can also give rise to tubulovesicular carriers that enter the recycling pathway. Thus, late endosomes are functionally plastic. These observations have relevance to understanding lysosomal delivery pathways. A combination of MUltifocal plane Microscopy (MUM) and localized photoactivation ('LP-MUM') has been developed to investigate the intracellular recycling pathway of FcRn. LP-MUM has been used to activate photoactivatable GFP (PAGFP) tagged proteins in individual sorting endosomes within cells, followed by imaging in two focal planes simultaneously. This approach has enabled the tracking of small, motile and dense transport carriers (TCs) that deliver FcRn to different destinations within the cell. The Rab GTPases, SNX4 and APPL1 play important roles in various steps of receptor trafficking pathways, and their associations with TCs has also been investigated. Four distinct itineraries taken by TCs at various stages of FcRn recycling have been characterized. In addition, the effectors associated with TCs on different pathways have been identified. APPL1+ TCs can transfer FcRn from the plasma membrane to pre-existing sorting endosomes. Interendosomal TCs migrate between sorting endosomes and are Rab4+/SNX4+ but Rab11-/APPL1-. Post-endosomal TCs that deliver FcRn to the plasma membrane are Rab11+ but Rab4-/SNX4-/APPL1-. Unexpectedly, a novel class of 'looping' TCs that leave a sorting endosome and return to the same endosome after several minutes has also been observed. The 'looping' TCs are Rab11+/Rab4+/SNX4+. The analyses of these TCs should have general relevance to other receptors and cargo on the recycling pathway.