The immunologic functions of the neonatal Fc receptor for IgG.

Careful regulation of the body's immunoglobulin G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. As such, the neonatal Fc receptor (FcRn), as a single receptor, is capable of regulating both of these molecules and has become an important focus of investigation. In addition to these essential protection functions, FcRn possesses a number of other functions that are equally as critical and are increasingly coming to attention. During the very first stages of life, FcRn mediates the passive transfer of IgG from mother to offspring both before and after birth. In the adult, FcRn regulates the persistence of both IgG and albumin in the serum as well as the movement of IgG, and any bound cargo, between different compartments of the body via transcytosis across polarized cells. FcRn is also expressed by hematopoietic cells; consistent with this, FcRn regulates MHC class II presentation and MHC class I cross-presentation by dendritic cells. As such, FcRn plays an important role in immune surveillance throughout adult life. The increasing appreciation for FcRn in both homeostatic and pathological conditions is generating an intense interest in the potential for therapeutic modulation of FcRn binding to IgG and albumin.

Dependence of antibody-mediated presentation of antigen on FcRn.

The neonatal Fc receptor for IgG (FcRn) is a distant member of the MHC class I protein family. It binds IgG and albumin in a pH-dependent manner and protects these from catabolism by diverting them from a degradative fate in lysosomes. In addition, FcRn-mediated IgG transport across epithelial barriers is responsible for the transmission of IgG from mother to infant and can also enhance IgG-mediated antigen uptake across mucosal epithelia. We now show a previously undescribed role for FcRn in mediating the presentation of antigens by dendritic cells when antigens are present as a complex with antibody by uniquely directing multimeric immune complexes, but not monomeric IgG, to lysosomes.

An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice.

BACKGROUND & AIMS: The neonatal Fc receptor for immunoglobulin (Ig)G (FcRn) protects monomeric IgG from catabolism in parenchymal and hematopoietic cells during adult life. In dendritic cells, FcRn also promotes presentation of antigens in association with IgG. Because IgGs with anti-bacterial specificity are a hallmark of inflammatory bowel disease, we sought to determine their significance and relationship to FcRn expression in antigen-presenting cells, focusing on IgGs specific for flagellin. METHODS: Levels of circulating anti-flagellin IgG were induced in wild-type and FcRn(-/-) mice, followed by induction of colitis with dextran sodium sulfate (DSS). Bone marrow chimera models were used to localize the site of FcRn action. RESULTS: Wild-type mice that received anti-flagellin IgG exhibited more severe colitis following administration of DSS, compared with mice that received control IgG. Wild-type mice immunized with flagellin exhibited significantly more severe colitis in response to DSS administration than that observed in similarly treated FcRn(-/-) mice. In chimera studies, FcRn(-/-) mice given wild-type bone marrow and immunized with flagellin exhibited significantly more colitis than wild-type mice given FcRn(-/-) bone marrow and immunized with flagellin. Serum anti-flagellin IgG levels were similar in both sets of chimeric mice, consistent with the equal participation of hematopoietic and nonhematopoeitic cells in FcRn-mediated IgG protection. CONCLUSIONS: Anti-bacterial IgG antibodies are involved in the pathogenesis of colitis; this pathway requires FcRn in antigen presenting cells, the major subset of hematopoietic cells that express FcRn.

Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria.

The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn in the epithelium is shown here to be associated with secretion of IgG into the lumen that allows for defense against an epithelium-associated pathogen (Citrobacter rodentium). This pathway of host resistance to a bacterial pathogen as mediated by FcRn involves retrieval of bacterial antigens from the lumen and initiation of adaptive immune responses in regional lymphoid structures. Epithelial-associated FcRn, through its ability to secrete and absorb IgG, may thus integrate luminal antigen encounters with systemic immune compartments and as such provide essential host defense and immunoregulatory functions at the mucosal surfaces.

{alpha}' Subunit of soybean {beta}-conglycinin forms complex with rice glutelin via a disulphide bond in transgenic rice seeds.

The alpha' and beta subunits of soybean beta-conglycinin were expressed in rice seeds in order to improve the nutritional and physiological properties of rice as a food. The alpha' subunit accumulated in rice seeds at a higher level than the beta subunit, but no detectable difference in mRNA transcription level between subunits was observed. Sequential extraction results indicate that the alpha' subunit formed one or more disulphide bonds with glutelin. Electron microscopic analysis showed that the alpha' subunit and the beta subunit were transported to PB-II together with glutelin. In mature transgenic seeds, the beta subunit accumulated in low electron density regions in the periphery of PB-II, whereas the alpha' subunit accumulated together with glutelin in high-density regions of the periphery. The subcellular localization of mutated alpha' subunits lacking one cysteine residue in the N-terminal mature region (alpha'DeltaCys1) or five cysteine residues in the pro and N-terminal mature regions (alpha'DeltaCys5) were also examined. Low-density regions were formed in PB-II in mature seeds of transgenic rice expressing alpha'DeltaCys 5 and alpha'DeltaCys1. alpha'DeltaCys5 was localized only in the low-density regions, whereas alpha'DeltaCys1 was found in both low- and high-density regions. These results suggest that the alpha' subunit could make a complex via one or more disulphide bonds with glutelin and accumulate together in PB-II of transgenic rice seeds.

Fcgamma receptor regulation of Citrobacter rodentium infection.

Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the colon utilizing attaching and effacing lesions to adhere specifically to the surfaces of intestinal epithelial cells and cause mucosal inflammation. CD4+ T cells, B cells, and immunoglobulin G (IgG), but not secretory IgA or IgM, play a critical role in eradicating this pathogen. Consistent with the importance of IgG in C. rodentium eradication, IgG transport by the neonatal Fc receptor for IgG within the intestinal epithelium also has a critical role in the regulation of C. rodentium infection. It remains to be determined, however, whether Fcgamma receptors (FcgammaRs), the receptors for the Fc portion of IgG, regulate this bacterial infection within mucosal tissues. Therefore, we investigated the roles of FcgammaRs during C. rodentium infection. Fc receptor common gamma chain (FcRgamma)-deficient mice were more susceptible to C. rodentium-induced colitis. This occurred through decreased efficiency of FcR-mediated endocytosis and maturation of dendritic cells and consequently T-cell activation of antigen-specific T cells. Moreover, in the absence of FcgammaRs, phagocytosis by macrophages was significantly diminished. Therefore, activating FcgammaRs play an important role in defending against C. rodentium infection, indicating that the critical role played by IgG in this infection is not mediated by IgG alone but is dependent upon this class of receptors.

Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.

Careful regulation of the body's immunoglobulin-G (IgG) and albumin concentrations is necessitated by the importance of their respective functions. As such, the neonatal Fc receptor (FcRn) which, as a single receptor, is capable of regulating both of these molecules, has become an important focus of investigation. In addition to these essential protection functions, FcRn possesses a host of other functions that are equally as critical. During the very first stages of life, FcRn mediates the passive transfer of IgG from mother to offspring both before and after birth. In the adult, FcRn regulates the persistence of both IgG and albumin in the serum as well as the movement of IgG, and any bound cargo, between different compartments of the body. This shuttling allows for the movement not only of monomeric ligand but also of antigen/antibody complexes from one cell type to another in such a way as to facilitate the efficient initiation of immune responses towards opsonized pathogens. As such, FcRn continues to play the role of an immunological sensor throughout adult life, particularly in regions such as the gut which are exposed to a large number of infectious antigens. Increasing appreciation for the contributions of FcRn to both homeostatic and pathological states is generating an intense interest in the potential for therapeutic modulation of FcRn binding. A greater understanding of FcRn's pleiotropic roles is thus imperative for a variety of therapeutic purposes.

IgG transport across mucosal barriers by neonatal Fc receptor for IgG and mucosal immunity.

Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain significant quantities of IgG. The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. The FcRn can then recycle the IgG/antigen complex back across the intestinal barrier into the lamina propria for processing by dendritic cells and presentation to CD4(+) T cells in regional organized lymphoid structures. FcRn, through its ability to secrete and absorb IgG, thus integrates luminal antigen encounters with systemic immune compartments and, as such, provides essential host defense and immunoregulatory functions at the mucosal surfaces.