FCGR2C - Fc gamma receptor IIc |Elisa - Clia - Antibody - Protein

Background

FCGR2C (Fc gamma receptor IIc), also known as CD32C, is a member of the Fc gamma receptor (FcγR) family, which binds to the Fc portion of immunoglobulin G (IgG). This receptor is of significant interest due to its functional variability and implications in immune regulation. FCGR2C is a low-affinity receptor and, unlike other Fc gamma receptors, is expressed in only a subset of immune cells due to complex regulation at the genetic and transcriptional levels. FCGR2C is unique because it arises from a combination of genetic recombination between its closely related genes, FCGR2A (an activating receptor) and FCGR2B (an inhibitory receptor), resulting in hybrid characteristics.

The FCGR2C gene is located on chromosome 1q23, a region where other Fcγ receptor family members are also found. This region is known for its genetic variability, contributing to differential expression of these receptors in the population. While FCGR2C was originally thought to be a pseudogene in many individuals, subsequent studies revealed that a significant proportion of the population expresses a functional receptor due to specific genetic recombination events.

FCGR2C plays a role in several immunological processes, including immune complex handling, modulation of antibody responses, and autoimmunity. Its expression is largely limited to natural killer (NK) cells, monocytes, and other immune effector cells, where it can contribute to processes such as antibody-dependent cellular cytotoxicity (ADCC). Due to its genetic and functional variability, FCGR2C is implicated in different clinical outcomes, particularly in autoimmune diseases and responses to therapeutic monoclonal antibodies.

Protein Structure

FCGR2C is a type I transmembrane glycoprotein that shares structural features with other Fc gamma receptors, particularly FCGR2A and FCGR2B, from which it is derived. The overall protein structure can be divided into three main domains: extracellular, transmembrane, and cytoplasmic.

Extracellular Domain:

• The extracellular region consists of two immunoglobulin-like (Ig-like) domains that are responsible for binding the Fc region of IgG. The binding affinity of FCGR2C for monomeric IgG is relatively low, but it can effectively bind to immune complexes, similar to other Fcγ receptors.
• The Ig-like domains in FCGR2C are structurally homologous to those found in FCGR2A and FCGR2B. However, due to its hybrid nature, the specific binding properties and affinity may vary depending on genetic variants.

Transmembrane Domain:

• The transmembrane domain is a short hydrophobic region that anchors the receptor to the cell membrane. This region is not directly involved in IgG binding but is essential for the receptor’s proper localization on the cell surface.

Cytoplasmic Domain:

• The cytoplasmic tail of FCGR2C is highly variable depending on the genetic recombination events. In many individuals, the receptor contains an immunoreceptor tyrosine-based activation motif (ITAM), similar to the activating receptor FCGR2A. This ITAM motif is crucial for transmitting activating signals into the cell, leading to cellular responses such as phagocytosis, cytotoxicity, or cytokine production.
• In contrast, individuals who express a non-functional isoform or lack the ITAM motif do not have activating functions. This functional diversity is primarily determined by genetic polymorphisms at the FCGR2C locus.
• When the ITAM motif is functional, downstream signaling is initiated by the phosphorylation of tyrosine residues within the ITAM, leading to the recruitment of Src family kinases and subsequent activation of immune effector functions.

Classification and Subtypes

FCGR2C belongs to the Fc gamma receptor family, which includes both activating and inhibitory receptors that bind to the Fc portion of IgG antibodies. Within this family, FCGR2C is classified as a low-affinity receptor but can function as either an activating or non-functional receptor depending on genetic variants.

• Activating Receptors: These include FCGR2A, FCGR3A, and FCGR3B, all of which contain ITAM motifs and trigger immune cell activation, promoting processes like phagocytosis and antibody-dependent cellular cytotoxicity (ADCC).
• Inhibitory Receptors: The main inhibitory receptor in this family is FCGR2B, which contains an ITIM motif in its cytoplasmic tail, mediating inhibitory signaling.

FCGR2C is particularly interesting because of its hybrid nature. The receptor is derived from a recombination event between FCGR2A (an activating receptor) and FCGR2B (an inhibitory receptor). As a result, FCGR2C can exhibit activating properties, similar to FCGR2A, in individuals who express a functional isoform with an ITAM motif. However, in individuals who express a non-functional variant of FCGR2C, the receptor may be unable to trigger activation.

Function and Biological Significance

The function of FCGR2C is largely dependent on its genetic polymorphisms. When a functional variant is expressed, FCGR2C can act as an activating receptor involved in a variety of immune responses. Its key roles include:

Antibody-Dependent Cellular Cytotoxicity (ADCC):

• FCGR2C, when expressed on NK cells or monocytes, mediates ADCC, a process in which immune cells recognize and destroy target cells that are opsonized with IgG antibodies. This function is particularly relevant in the context of viral infections and tumor immunity.

Phagocytosis:

• On macrophages and dendritic cells, FCGR2C contributes to the phagocytosis of antibody-coated pathogens or cellular debris. This function is shared with other activating FcγRs, such as FCGR2A, and is crucial for the clearance of immune complexes and apoptotic cells.

Regulation of Inflammation:

• FCGR2C plays a role in modulating inflammatory responses by activating immune cells to produce pro-inflammatory cytokines when immune complexes are present. This can amplify the immune response, especially during infections or immune complex-mediated diseases.

Clearance of Immune Complexes:

• FCGR2C, through its binding to immune complexes, participates in their clearance from circulation. The efficient clearance of immune complexes is necessary to prevent immune complex-mediated diseases, such as systemic lupus erythematosus (SLE).

The expression and function of FCGR2C vary among individuals due to genetic recombination events at the FCGR2C gene locus. In individuals where FCGR2C is non-functional or expressed at low levels, the contribution of this receptor to immune processes may be diminished.

Clinical Issues

The genetic variability of FCGR2C has significant implications for several clinical conditions, particularly in autoimmune diseases and responses to monoclonal antibody therapies.

Autoimmune Diseases:

• Polymorphisms in the FCGR2C gene have been linked to susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these diseases, the balance between activating and inhibitory signals is crucial, and altered FCGR2C expression or function can skew immune responses toward excessive activation.
• In SLE, for instance, defective clearance of immune complexes can exacerbate inflammation and tissue damage, and individuals with certain FCGR2C variants may have a higher risk of developing the disease.

Monoclonal Antibody Therapies:

• FCGR2C plays a role in the efficacy of therapeutic monoclonal antibodies. For example, rituximab, an anti-CD20 monoclonal antibody used to treat B-cell malignancies and autoimmune diseases, relies on Fc receptors like FCGR2C to mediate ADCC and phagocytosis of target cells. Variants of FCGR2C that affect its expression or function can influence the therapeutic response to such treatments.
• Individuals with functional FCGR2C may have enhanced responses to antibody therapies that depend on Fc-mediated effector functions.

Infectious Diseases:

• Certain genetic variants of FCGR2C have been associated with susceptibility to infectious diseases, particularly those that involve immune complex formation. For instance, alterations in FCGR2C expression or function can influence the body’s ability to clear pathogens or infected cells that are opsonized with IgG antibodies.

Summary

FCGR2C (CD32C) is a hybrid Fc gamma receptor that plays a variable role in immune responses depending on its genetic variants. Structurally, FCGR2C contains Ig-like domains for binding IgG, a transmembrane region, and a cytoplasmic domain that can contain an ITAM motif, allowing it to function as an activating receptor. However, in some individuals, FCGR2C may be non-functional due to genetic recombination events.

Functionally, FCGR2C contributes to processes such as ADCC, phagocytosis, and the clearance of immune complexes. Its role in immune regulation makes it an important player in autoimmune diseases, therapeutic antibody responses, and infectious disease susceptibility. The clinical significance of FCGR2C lies in its genetic variability, which can influence immune system function and disease outcomes, highlighting its importance in personalized medicine and immune therapy strategies.