Fundamentals of Immunology - Lecture Course by M. V. Skok - Kyiv 2002

Chapter III. Immune Processes at the Organism Level

Appendix 2. Structure and Role of Fc Receptors

Fc receptors are a vital group of Cell surface molecules capable of binding immune complexes formed by various classes of IMMUNOGLOBULINS. They are found on monocytes, macrophages, basophils, eosinophils, B lymphocytes, platelets, natural killer Cells, certain subpopulations of T lymphocytes, and placental endothelial cells. Binding of Fc receptors on macrophages triggers the phagocytosis of opsonized Antigens, production of superoxide ions, and the release of pro-inflammatory cytokines such as IL-1, IL-6, and TNFα. The binding of immune complexes by B lymphocytes facilitates antigen presentation to T cells in the context of MHC Class II molecules and regulates antibody production by interfering with the signaling cascade of the B-cell antigen-specific receptor (see Lecture 9). The Fc receptor expressed on placental cells stabilizes The Structure of maternal Antibodies destined for the fetus; Fc receptors for IgE mediate the release of inflammatory mediators by mast cells and serve as drivers of allergic responses.

Immunoglobulins bind to Fc receptors via the constant domains of their heavy chains; the carbohydrate component of immunoglobulins may also participate in this binding. Fc receptors for IgG, IgM, IgE, and IgA are known, with Fcγ receptors—receptors for IgG—being the best characterized. Three types of such receptors have been described: FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16). All of them have a Molecular Weight of approximately 40 kDa, and their extracellular portion consists of immunoglobulin-like domains. Each of these molecules has several isoforms that differ in the number and structure of extracellular domains, membrane anchoring mechanism, and the presence of additional chains. The cytoplasmic domains of these receptors, similar to the antigen-specific receptors of T AND B lymphocytes, contain immunoreceptor Tyrosine-based activation motifs, or ITAMs. For decades, it has been known that immune complexes consisting of an antigen and IgG antibodies act as Inhibitors of the Immune Response. Only recently has their MECHANISM OF ACTION been elucidated. It turned out that the simultaneous binding of the antigen-specific receptor and the FcγRII receptor on B lymphocytes by immune complexes leads to the blockade of signals originating from the antigen-specific receptor. The cytoplasmic tail of the FcγRII receptor contains a special inhibitory motif known as ITIM (immunoreceptor tyrosine-based inhibitory motif). Engagement of this motif activates protein tyrosine phosphatase SHP-1 (PTP1C), which dephosphorylates the tyrosine kinase substrates downstream of the B-cell receptor. As a result, phospholipase activity and IP₃ production are blocked, preventing the antigen signal from propagating. This mechanism mediates the Regulation of the HUMORAL IMMUNE RESPONSE by the produced antibodies.

Soluble forms of Fcγ receptors also exist. Their function is to stabilize the structure of IgG, resulting in an IgG half-life of approximately 20 days (compared to just two days for IgM and IgA).

Fcγ receptors differ in their affinity for various IgG subclasses. Their affinity for an immune complex of an antibody bound to an antigen is significantly higher than for a free immunoglobulin, because antigen binding alters the conformation of the Fc fragment.

Most strains of human Herpesviruses possess genes encoding Fcγ receptors; it is believed that Viruses acquired this Genetic information from the mammalian genome in ancient times.

Fc receptors bridge the humoral and cellular arms of the immune response by mediating antibody-dependent cellular cytotoxicity. They also promote immune responses by enhancing antigen presentation and regulate antibody production levels via a negative feedback loop.