FCGR2A - Fc gamma receptor Iia |Elisa - Clia - Antibody - Protein

Background

FCGR2A (Fc gamma receptor IIa), also known as CD32a, is a low-affinity receptor for the Fc region of immunoglobulin G (IgG). It plays a crucial role in immune regulation by mediating various cellular responses, including phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), and the clearance of immune complexes. FCGR2A is part of a larger family of Fc gamma receptors (FcγRs), which are responsible for bridging adaptive and innate immunity by recognizing the Fc region of IgG and triggering effector cell responses.

FcγR family members, including FCGR2A, are broadly expressed on the surface of various immune cells such as monocytes, macrophages, neutrophils, dendritic cells, and platelets. FCGR2A is unique among Fc receptors because of its capacity to mediate both activating and inhibitory immune responses, depending on the cellular context and signaling pathways involved.

The gene encoding FCGR2A is located on chromosome 1q23, within a cluster of genes encoding other Fcγ receptors. Polymorphisms in FCGR2A have been associated with differential susceptibility to autoimmune diseases, infections, and responses to therapeutic antibodies. Understanding the structure, function, and clinical significance of FCGR2A is vital for developing therapeutic strategies targeting immune modulation.

Protein Structure

FCGR2A is a type I transmembrane protein composed of approximately 317 amino acids. It has a modular structure typical of Fc receptors, featuring an extracellular Ig-like domain, a transmembrane domain, and a cytoplasmic tail that contains signaling motifs. The structure of FCGR2A is as follows:

Extracellular Domain:

• The extracellular portion of FCGR2A is composed of two immunoglobulin (Ig)-like domains. These Ig-like domains are responsible for recognizing and binding the Fc portion of IgG molecules.
• FCGR2A has a relatively low affinity for monomeric IgG but can bind with higher affinity to IgG when it is aggregated, such as when IgG is part of an immune complex. This property allows FCGR2A to function efficiently in the clearance of immune complexes and pathogens.
• Notably, different subclasses of IgG have variable affinities for FCGR2A. IgG2 binds most strongly to FCGR2A, while IgG1 and IgG3 have lower affinities. This selective binding affects how FCGR2A participates in immune responses.

Transmembrane Domain:

• The transmembrane region of FCGR2A consists of a hydrophobic stretch of amino acids that anchors the protein into the plasma membrane. It is essential for the localization of FCGR2A on the cell surface but does not play a direct role in IgG binding.

Cytoplasmic Domain:

• The cytoplasmic tail of FCGR2A contains an immunoreceptor tyrosine-based activation motif (ITAM), which is a critical component for signal transduction. Upon IgG binding and receptor clustering, the ITAM motif is phosphorylated, initiating intracellular signaling cascades.
• These signaling events typically activate downstream kinases like Syk and PI3K, leading to the activation of various cellular processes such as phagocytosis, degranulation, and cytokine release. The ITAM signaling also contributes to the activation of pro-inflammatory responses, which are essential for pathogen clearance.

Classification and Subtypes

FCGR2A is a member of the Fc gamma receptor (FcγR) family, which is categorized into activating and inhibitory receptors based on their intracellular signaling motifs. FcγRs are classified into three major types:

1. High-Affinity Receptors (FcγRI): These receptors bind monomeric IgG with high affinity.
2. Low-Affinity Receptors (FcγRII and FcγRIII): These receptors, including FCGR2A, bind aggregated IgG or immune complexes with low affinity.
3. Inhibitory Receptors (e.g., FCGR2B): These receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails and inhibit immune responses.

Within the FcγRII subclass, FCGR2A is the activating receptor due to the presence of an ITAM motif. FCGR2A has a closely related isoform, FCGR2B, which is inhibitory in function, due to its ITIM motif. These two receptors are often co-expressed on immune cells and provide a balance between activation and inhibition, crucial for maintaining immune homeostasis.

Polymorphisms in the FCGR2A gene affect the receptor's affinity for IgG subclasses and have important clinical implications, particularly in the context of autoimmune diseases and therapeutic responses.

Function and Biological Significance

FCGR2A is a multifunctional receptor involved in several key immune processes:

Phagocytosis:

• FCGR2A mediates the phagocytosis of IgG-opsonized particles, including pathogens and apoptotic cells. This function is critical for clearing infections and maintaining tissue homeostasis by removing dying cells.
• Upon binding immune complexes or opsonized targets, FCGR2A clusters and activates downstream signaling pathways that lead to the internalization of the target into the immune cell, followed by degradation in phagolysosomes.

Antibody-Dependent Cellular Cytotoxicity (ADCC):

• In certain immune cells, such as natural killer (NK) cells, FCGR2A can participate in ADCC, where IgG-coated target cells (e.g., tumor cells or virus-infected cells) are recognized and killed by immune cells.
• FCGR2A-mediated ADCC is particularly important in cancer immunotherapy, where therapeutic monoclonal antibodies target tumor cells for immune-mediated destruction.

Clearance of Immune Complexes:

• FCGR2A plays a significant role in the clearance of immune complexes from circulation, helping to prevent excessive immune activation and inflammation.
• The receptor is expressed on liver Kupffer cells, where it helps to clear immune complexes from the blood, reducing the risk of systemic immune complex diseases such as lupus and vasculitis.

Inflammation and Cytokine Release:

• Activation of FCGR2A can lead to the production of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, which help orchestrate the immune response during infections or tissue injury.
• This receptor can also modulate the release of reactive oxygen species (ROS) and other cytotoxic molecules during inflammatory responses, contributing to the host defense against pathogens.

Platelet Activation:

• FCGR2A is uniquely expressed on platelets, where it mediates platelet aggregation and release of inflammatory mediators upon engagement with immune complexes. This function ties FCGR2A to thrombotic disorders, especially in conditions of systemic inflammation, such as sepsis.

Clinical Issues

FCGR2A has significant implications in various disease contexts, owing to its central role in immune modulation.

Autoimmune Diseases:

• Polymorphisms in FCGR2A are linked to the susceptibility and severity of several autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and immune thrombocytopenia (ITP).
• In these conditions, altered FCGR2A function can contribute to the defective clearance of immune complexes, leading to persistent immune activation and inflammation.

Infectious Diseases:

• Variations in FCGR2A expression and function are associated with different outcomes in infectious diseases. For instance, individuals with certain FCGR2A polymorphisms show a differential response to bacterial sepsis and malaria.
• FCGR2A plays a role in pathogen recognition and clearance, making it a crucial component of the host defense system.

Therapeutic Antibody Responses:

• FCGR2A is involved in the clinical efficacy of monoclonal antibody therapies used in cancer and autoimmune diseases. For example, the effectiveness of therapeutic antibodies like rituximab (targeting CD20 in B-cell lymphomas) is partly dependent on the receptor’s ability to mediate ADCC.
• Genetic variations in FCGR2A, which alter the receptor’s affinity for IgG, can influence the therapeutic response, making it an important consideration in personalized medicine.

Thrombosis and Vascular Disease:

• FCGR2A on platelets is implicated in the development of thrombosis and other vascular complications. In conditions like heparin-induced thrombocytopenia (HIT), FCGR2A mediates the platelet activation that leads to thrombosis.
• The receptor’s role in platelet aggregation and immune complex-mediated inflammation also links it to cardiovascular diseases.

Summary

FCGR2A (CD32a) is a type I transmembrane receptor and a member of the Fc gamma receptor (FcγR) family, playing a critical role in linking adaptive immunity (IgG) to innate immune responses. Structurally, it is characterized by extracellular Ig-like domains that bind IgG, a transmembrane segment, and a cytoplasmic tail containing an ITAM motif for signal transduction. FCGR2A mediates essential immune functions, including phagocytosis, ADCC, cytokine production, and immune complex clearance. Clinically, FCGR2A is implicated in the pathogenesis of autoimmune diseases, infections, therapeutic responses to monoclonal antibodies, and thrombosis. Genetic polymorphisms in FCGR2A affect its function, influencing disease susceptibility and therapeutic outcomes, making FCGR2A a key target in immunological research and clinical interventions.