Fc receptors, the receptors for the Fc portion of immunoglobulins, play an essential role in antibody-dependent immune responses. An Fc receptor is a protein found on the surface of certain cells, and are detected on many types of hematopoietic cells including macrophages, neutrophils, dendritic cells, eosinophils, basophils, mast cells, and NK cells. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens.
Figure 1. Fc Receptor
Plasma cells produce five classes of antibodies, IgA, IgD, IgE, IgG and IgM. Fc receptors with an Ig superfamily related structure exist that correspond to each of these classes of immunoglobulins. They include the IgG receptors (FcγR), high-affinity IgE receptor (FcεR), IgA receptor (FcαR) and polymeric immunoglobulin receptor for IgA and IgM. The second category of Fc receptors is the neonatal Fc receptor for IgG (FcRn), which is a unique FcR that has three major functions with respect to IgG; IgG transport across epithelial barriers, protection of IgG from catabolism and antigen presentation.
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FcγR (Fc-gamma receptors）
All of the Fcγ receptors (FcγR) belong to the immunoglobulin superfamily and are the most important Fc receptors for inducing phagocytosis of opsonized (marked) microbes. This family includes several members, FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b), which differ in their antibody affinities due to their different molecular structure. For instance, FcγRI binds to IgG more strongly than FcγRII or FcγRIII does. FcγRI also has an extracellular portion composed of three immunoglobulin (Ig)-like domains, one more domain than FcγRII or FcγRIII has. This property allows FcγRI to bind a sole IgG molecule (or monomer), but all FcγR must bind multiple IgG molecules within an immune complex to be activated. FcγRs play an important role in determining the therapeutic activity of monoclonal IgG antibodies (mAbs) by their ability to activate the cytotoxic activity of FcγR-positive cells such as NK cells, monocytes, macrophages and neutrophils and by increasing antigen presentation by DC when ligated by the Fc portion of therapeutic antibodies. Recent studies in Fc receptor-deficient nude mice show that the anti-tumor effects of mAbs such as those directed at-CD20 (Rituximab) and HER2 (Herceptin) require the presence of the signal transducing Fcγ chain that is involved in the activation of FcγRI and FcγRIII receptors that are expressed on monocytes, macrophages, and NK cells.
FcαR (Fc-alpha receptors)
Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89). FcαRI is found on the surface of neutrophils, eosinophils, monocytes, some macrophages (including Kupffer cells), and some dendritic cells. It is composed of two extracellular Ig-like domains, and is a member of both the immunoglobulin superfamily and the multi-chain immune recognition receptor (MIRR) family. It signals by associating with two FcRγ signaling chains. Another receptor can also bind IgA, although it has higher affinity for another antibody called IgM. This receptor is called the Fc-alpha/mu receptor (Fcα/μR) and is a type I transmembrane protein. With one Ig-like domain in its extracellular portion, this Fc receptor is also a member of the immunoglobulin superfamily.
FcεR (Fc-epsilon receptors)
There are two types of FcεR are known- FcεRI and FcεRII, FcεRI is a member of the immunoglobulin superfamily (it has two Ig-like domains). FcεRI is found on epidermal Langerhans cells, eosinophils, mast cells and basophils. As a result of its cellular distribution, this receptor plays a major role in controlling allergic responses. FcεRI is also expressed on antigen-presenting cells, and controls the production of important immune mediators called cytokines that promote inflammation. FcεRII (CD23) is a C-type lectin. FcεRII has multiple functions as a membrane-bound or soluble receptor; it controls B cell growth and differentiation and blocks IgE-binding of eosinophils, monocytes, and basophils.
FcRn (neonatal Fc receptor)
The neonatal Fc receptor for IgG (FcRn) has been well characterized in the transfer of passive humoral immunity from a mother to her fetus. In addition, throughout life, FcRn protects IgG from degradation, thereby explaining the long half-life of this class of antibody in the serum. In recent years, it has become clear that FcRn is expressed in various sites in adults, where its potential function is now beginning to emerge. In addition, recent studies have examined the interaction between FcRn and the Fc portion of IgG with the aim of either improving the serum half-life of therapeutic monoclonal antibodies or reducing the half-life of pathogenic antibodies. The neonatal Fc receptor for IgG (FcRn) is responsible for the transfer of passive humoral immunity from the mother to the newborn in rodents and humans. Throughout life, FcRn contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation.
1 Atsuhiro Masuda, Masaru Yoshida, “Role of Fc Receptors as a Therapeutic Target.” Inflamm Allergy Drug Targets. 2009, 03; 8(1): 80–86.