Fc receptors and their interactions with immunoglobulins

Division of Biology, Howard Hughes Medical Institute, California Institute of Technology, Pasadena 91125, USA.
Annual Review of Cell and Developmental Biology (Impact Factor: 16.66). 02/1996; 12(1):181-220. DOI: 10.1146/annurev.cellbio.12.1.181
Source: PubMed


Receptors for the Fc domain of immunoglobulins play an important role in immune defense. There are two well-defined functional classes of mammalian receptors. One class of receptors transports immunoglobulins across epithelial tissues to their main sites of action. This class includes the neonatal Fc receptor (FcRn), which transports immunoglobulin G (IgG), and the polymeric immunoglobulin receptor (pIgR), which transports immunoglobulin A (IgA) and immunoglobulin M (IgM). Another class of receptors present on the surfaces of effector cells triggers various biological responses upon binding antibody-antigen complexes. Of these, the IgG receptors (Fc gamma R) and immunoglobulin E (IgE) receptors (Fc epsilon R) are the best characterized. The biological responses elicited include antibody-dependent, cell-mediated cytotoxicity, phagocytosis, release of inflammatory mediators, and regulation of lymphocyte proliferation and differentiation. We summarize the current knowledge of the structures and functions of FcRn, pIgR, and the Fc gamma R and Fc epsilon RI proteins, concentrating on the interactions of the extracellular portions of these receptors with immunoglobulins.

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    • "Moreover, several pathways (other than proteolysis) are recognized as responsible for the removal of these therapeutic proteins from the blood, including nonspecific endocytosis and formation of immune-complexes (ICs) followed by Fcγ receptor-mediated clearance. Monoclonal antibodies and fusion proteins may bind to Fcγ receptors, where they get degraded via lysosomes following their internalization into monocytes and macrophages (Raghavan and Bjorkman, 1996; Mould and Green, 2010). Other factors that may influence the metabolism of these therapeutic proteins include their size, charge, structure, distribution, and hydro-or lipophilicity (Tang et al., 2004). "
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    ABSTRACT: Abstract: Therapeutic proteins have shown to be effective against a variety of diseases. Pharmaceutical companies are progressively focusing on research using proteins in search of novel effective therapeutics. The significant attention by researchers has resulted in considerable advances in the production and usage of therapeutic proteins in recent years. In the current study we focused on the understanding of therapeutic proteins and their impact on the human health care system. Advancements in the field of biotechnology have increased and facilitated the production of therapeutically significant proteins to combat various fatal diseases. Although protein- based therapeutics have taken center stage in drug discovery and development and enhanced safety for human beings, certain challenges remain, including safety and immunogenicity issues, protein stability, and degradation issues. We made an attempt to discuss all possible factors that are linked with the basis of therapeutic proteins and possible challenges that are currently being faced by scientists during the development of these therapeutic proteins.
    Full-text · Article · Jan 2015 · Turkish Journal of Biology
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    • "FcRn is located primarily intracellularly within the endolysosomal system of APC and less so on the cell surface where it could theoretically compete for IgG binding with FcγR (76). The critical binding site for FcRn on the IgG Fc region involves the I253, H310, and H435 residues within the CH2:CH3 domains of IgG Fc and is distinct from where FcγR binding to IgG occurs (77–84). In contrast to FcγRs, binding is entirely independent of IgG glycosylation. "
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    ABSTRACT: 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 (FcγR) which 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). Crosslinking of FcRn by multivalent IgG IC within antigen presenting cells such as dendritic cells (DC) initiates specific mechanisms which 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 MHC 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.
    Full-text · Article · Aug 2014 · Frontiers in Immunology
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    • "We know that orthologs of IgG first appeared in the common mammalian ancestor because monotremes have them (14). The neonatal Fc receptor (FCGRT), however, which is the gene that enables the crucial transfer of IgG from mother to offspring as well prolonging the beneficial effects of IgG by increasing its half-life (40), is only present in marsupial and placental genomes. Studies of human infant mortality to most common infections show an exponential decline with the age (4) with exception of the first year of life where transfer of maternal IgG plays a crucial role in infant survival through protective immunity. "
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    Full-text · Article · Jun 2014 · Frontiers in Immunology
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