Fc receptors (FcR) are proteins found on the surface of effector cells that link the humoral and cellular branches of the immune system. Fc receptors can be defined as “receptors present on a variety of cells for the Fc portion of an immunoglobulin”. They play a critical role in immunity and provide a defense against invading pathogens. They are responsible for initiating a cellular response to host defenses, determining the efficacy of therapeutic antibodies and in pathological autoimmune conditions. These receptors are found on effector cells such as: neutrophils, eosinophils, macrophages and NK cells. The FcRs on these effector cells, in turn, will then bind to antibodies that are attached to microbes or microbe infected cells. This aids cells in identifying and eliminating microbial pathogens. The interaction between the bound antibody and the cell surface Fc receptor activates the immune cell to kill microbes by phagocytosis of an opsonized microbe and intracellular killing.
Fc receptors result in downstream signal transduction in immune cells. Phagocytes, such as neutrophils, begin to ingest and kill an IgG-coated pathogen by phagocytosis following engagement of their Fcγ receptors. What is known of Fc receptors may lead to more advanced and personalized therapeutics for the treatment of different diseases. Studies of Fc receptors can further the understanding of the immune response and the genetic basis for Fc receptor activity. There is an expanding family of activation/inhibitory receptor pairs found in the immune system. The different classes of Fc receptors offer a paradigm for the biological significance of balancing activation and inhibitory signaling. The hyper-responsive state that results, when receptors are activated, will lead to a significantly magnified effector response by cytotoxic antibodies and immune complexes. A better understanding of Fc receptor ex
Immunoglobulins and Fc Receptors
Receptors for immunoglobulins (FcR) play a central role during an immune response as they mediate the specific recognition of antigens, thereby linking the humoral and cellular components of immunity. Engagement of Fc receptors by immunoglobulins initiate a range of immunoregulatory processes that also plays a role in disease pathogenesis. For example, there are 5 main isotypes of circulating immunoglobulins (Igs) in the cow. These immunoglobulins are known to be: IgM, IgA, IgD, IgG and IgE. Immunoglobulins help address a variety of issues that may arise from allergic reactions to invading pathogens. There are different families of Fc receptors (i.e. fc alpha receptors, fc epsilon receptors and fc gamma receptors) specific Ig isotypes previously listed. Immunoglobulin G provides the majority of antibody-based immunity against invading pathogens. IgG is known to be reactive with gram negative and gram positive bacteria both of which are causative agents of mastitis. The binding of IgG and FcγR genes is shown to be responsible for protection against pathogen invasion.
Fc receptors associated specifically with IgG are referred to as Fc gamma receptors (FcγR) and are generally divided into three main classes: FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16). They transduce signals through the immunoreceptor tyrosine-based activation motif (ITAM) in subunits or in the cytoplasmic domain. Inhibitory FcγR, such as FcγRIIB, are single chain receptors, transducing signals through an immunoreceptor tyrosine-based inhibitory motif (ITIM) in cytoplasmic domains. Both motifs are discussed briefly in the following section.
Each class of Fc gamma receptors possesses distinct structural and functional properties. FcγRI is a high-affinity receptor for monomeric IgG with three extracellular Ig-like domains expressed constitutively by monocytes and macrophages, as well as by many myeloid progenitor cells. Three genes coding for FcγRI have been characterized: FCGRIA, FCGRIB and FCGRIC. However, it is generally accepted that only FcγRIA is capable of high affinity IgG binding, whereas FCGRIB and FCGRIC possibly represent truncated or soluble forms of the receptor, with poorly characterized function.
Signaling of Fc receptors via Antibody Binding
The Fc receptors bind to antibodies at their Fc region or tail. Ligand binding activates the cell that possesses the Fc receptor. When IgG molecules specific for a certain antigen or surface component bind to the pathogen with their Fab region, their Fc regions point outward, in direct reach of phagocytes. Inhibitory Fc receptors prevent binding of antibodies in the absence of antigens, and therefore reduce the chance of immune cell activation in the absence of an infection. Absences of inhibitory receptors or malfunctioning receptors oftentimes lead to autoimmune conditions. Further, inhibitory receptors also prevent agglutination of phagocytes by antibody when there is no antigen. After a pathogen has been bound, interactions between the Fc region of the antibody and the Fc receptors of the phagocyte results in the initiation of phagocytosis. The interactions formed between receptor and antibody binding work together to tightly encase the antibody-coated microbe.
It is clear that Fc receptors are important to survey and identify pathogens, alert cytotoxic cells to react and ultimately initiate an immune response within the body. The way Fc receptors respond to antibodies, i.e. rate or aggression, can determine the effect on an individual, such as, if medications will be needed or if the body can respond fast enough to fend off the targeted microbe. It’s worth noting that polymorphisms within the sequences coding for different Fc receptor genes can regulate the probability of susceptibility among animals of the same species but different breeds.