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Pyzik, Michal

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Pyzik

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Michal

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Pyzik, Michal

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    Publication
    The Role of FcRn in Antigen Presentation
    (Frontiers Media S.A., 2014) Baker, Kristi; Rath, Timo; Pyzik, Michal; Blumberg, Richard
    Immunoglobulins are unique molecules capable of simultaneously recognizing a diverse array of antigens and themselves being recognized by a broad array of receptors. The abundance specifically of the IgG subclass and the variety of signaling receptors to which it binds render this an important immunomodulatory molecule. In addition to the classical Fcγ receptors that bind IgG at the cell surface, the neonatal Fc receptor (FcRn) is a lifelong resident of the endolysosomal system of most hematopoietic cells where it determines the intracellular fate of both IgG and IgG-containing immune complexes (IgG IC). Cross-linking of FcRn by multivalent IgG IC within antigen presenting cells such as dendritic cells initiates specific mechanisms that result in trafficking of the antigen-bearing IgG IC into compartments from which the antigen can successfully be processed into peptide epitopes compatible with loading onto both major histocompatibility complex class I and II molecules. In turn, this enables the synchronous activation of both CD4+ and CD8+ T cell responses against the cognate antigen, thereby bridging the gap between the humoral and cellular branches of the adaptive immune response. Critically, FcRn-driven T cell priming is efficient at very low doses of antigen due to the exquisite sensitivity of the IgG-mediated antigen delivery system through which it operates. FcRn-mediated antigen presentation has important consequences in tissue compartments replete with IgG and serves not only to determine homeostatic immune activation at a variety of sites but also to induce inflammatory responses upon exposure to antigens perceived as foreign. Therapeutically targeting the pathway by which FcRn enables T cell activation in response to IgG IC is thus a highly attractive prospect not only for the treatment of diseases that are driven by immune complexes but also for manipulating local immune responses against defined antigens such as those present during infections and cancer.
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    Regulation of Immune Responses by the Neonatal Fc Receptor and Its Therapeutic Implications
    (Frontiers Media S.A., 2015) Rath, Timo; Baker, Kristi; Pyzik, Michal; Blumberg, Richard
    As a single receptor, the neonatal Fc receptor (FcRn) is critically involved in regulating albumin and IgG serum concentrations by protecting these two ligands from degradation. In addition to these essential homeostatic functions, FcRn possesses important functions in regulating immune responses that are equally as critical and are increasingly coming to attention. During the first stages of life, FcRn mediates the passive transfer of IgG across the maternal placenta or neonatal intestinal walls of mammals, thereby conferring passive immunity to the offspring before and after birth. In fact, FcRn is one of the very few molecules that are known to move from luminal to serosal membranes of polarized cells that form epithelial barriers of the lung and intestines. Together with FcRn’s recently explored critical role in eliciting MHC II presentation and MHC class I cross-presentation of IgG-complexed antigen, this renders FcRn capable of exerting broad and potent functions in regulating immune responses and immunosurveillance at mucosal sites. Further, it is now clear that FcRn dependent mucosal absorption of therapeutic molecules is a clinically feasible and potent novel route of non-invasive drug delivery, and the interaction between FcRn and IgG has also been utilized for the acquisition of humoral immunity at mucosal sites. In this review, we begin by briefly summarizing the basic knowledge on FcRn expression and IgG binding, then describe more recent discoveries pertaining to the mechanisms by which FcRn orchestrates IgG related mucosal immune responses and immunosurveillance at host–environment interfaces within the adult organism. Finally, we outline how the knowledge of actions of FcRn at mucosal boundaries can be capitalized for the development and engineering of powerful mucosal vaccination strategies and novel routes for the non-invasive delivery of Fc-based therapeutics.
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    Neonatal Fc receptors for IgG drive CD8+ T cell-mediated anti-cancer immunosurveillance at tolerogenic mucosal sites
    (Landes Bioscience, 2014) Baker, Kristi; Rath, Timo; Pyzik, Michal; Blumberg, Richard
    Mucosal boundaries, which are immunologically tolerogenic, and is further enhanced by undergo malignant transformation at high rates. We have identified the expression of neonatal Fc receptor for IgG (FcRn) by dendritic cells as a critical mediator of mucosal anti-cancer immunosurveillance. This discovery extends our understanding of neonatal Fc receptors, defines a role for tumor-reactive IgGs, and identifies an avenue for the development of novel anti-cancer therapeutics.