FCGR3B - Fc gamma receptor IIIb |Elisa - Clia - Antibody - Protein

Background

FCGR3B, or Fc gamma receptor IIIb, is a low-affinity receptor for the Fc portion of immunoglobulin G (IgG) antibodies, primarily expressed on neutrophils. It is a member of the Fc gamma receptor (FcγR) family, which plays a pivotal role in mediating immune responses through the recognition of the Fc region of IgG antibodies. FCGR3B is one of the two isoforms of FcγRIII, the other being FCGR3A (CD16A). While both isoforms share sequence similarity and belong to the same gene family, they have distinct tissue distributions, membrane anchoring mechanisms, and functional roles in the immune system.

FCGR3B is especially important for facilitating immune complex clearance, phagocytosis, and neutrophil activation, processes that are crucial in maintaining immune homeostasis and defending against pathogens. Dysregulation of FCGR3B or mutations in its gene have been associated with a range of clinical conditions, including autoimmune diseases and chronic inflammatory disorders. Furthermore, genetic polymorphisms in the FCGR3B gene can affect an individual’s susceptibility to infections and autoimmune disorders, as well as their response to therapeutic interventions involving IgG antibodies.

Protein Structure

FCGR3B is a type I glycosylphosphatidylinositol (GPI)-anchored membrane protein that is structurally distinct from its counterpart FCGR3A, which is a transmembrane protein. The structure of FCGR3B consists of the following key domains:

Extracellular Domain:

• The extracellular domain of FCGR3B contains two immunoglobulin-like (Ig-like) domains. These domains are responsible for binding to the Fc region of IgG antibodies, specifically to IgG1 and IgG3, which are the subclasses that FCGR3B has the highest affinity for.
• The Ig-like domains consist of a constant domain and a variable domain. These domains form the receptor’s binding pocket, which interacts with glycosylated residues on IgG molecules, establishing the receptor’s role in immune complex recognition and clearance.

GPI Anchor:

• One of the distinguishing features of FCGR3B is its GPI anchor. Instead of a transmembrane domain, FCGR3B is tethered to the cell surface via a GPI anchor, which is linked to the C-terminal end of the protein. This form of membrane attachment limits its ability to participate directly in intracellular signaling.
• Unlike FCGR3A, which interacts with signaling adaptor proteins to transduce signals into the cell, FCGR3B does not contain intracellular signaling motifs such as immunoreceptor tyrosine-based activation motifs (ITAMs). However, it can still participate in immune responses through cross-talk with other Fc receptors and signaling pathways, primarily through neutrophils.

Glycosylation:

• FCGR3B is heavily glycosylated, with several N-linked glycosylation sites that are essential for proper folding, stability, and function. These glycan residues contribute to the binding affinity between FCGR3B and IgG antibodies, and changes in glycosylation patterns can influence the receptor’s function in various immune responses.

Ligand Binding:

• The Fc region of IgG interacts with FCGR3B primarily through a combination of protein-protein and protein-carbohydrate interactions. The binding affinity of FCGR3B for different IgG subclasses is lower than that of FCGR3A due to structural variations between the two receptors.

Classification and Subtypes

FCGR3B is a member of the Fc gamma receptor family, which is divided into three main groups based on their affinity for IgG and their functional roles:

• FcγRI (CD64): A high-affinity receptor for IgG.
• FcγRII (CD32): A low to moderate-affinity receptor with multiple isoforms (A, B, and C) that modulate immune responses.
• FcγRIII (CD16): A low-affinity receptor with two isoforms: FCGR3A (CD16A) and FCGR3B (CD16B).

Among these, FCGR3B is unique due to its GPI anchoring and exclusive expression on neutrophils, whereas FCGR3A is a transmembrane receptor found on natural killer (NK) cells, monocytes, and macrophages. FCGR3B lacks intrinsic signaling capacity but can still contribute to immune responses through phagocytosis and immune complex clearance.

Function and Biological Significance

FCGR3B plays an essential role in innate immunity by mediating immune complex clearance and neutrophil activation. The receptor is primarily expressed on neutrophils, which are critical for the rapid response to infections and inflammatory stimuli. The primary functions of FCGR3B include:

Immune Complex Clearance:

• One of the key functions of FCGR3B is to mediate the clearance of immune complexes (antibody-bound antigens) from circulation. Neutrophils expressing FCGR3B can bind to these complexes and internalize them for degradation. This process is crucial for preventing excessive inflammation and tissue damage that can arise from persistent immune complex accumulation.
• Impaired immune complex clearance due to FCGR3B dysfunction can lead to the development of autoimmune diseases like systemic lupus erythematosus (SLE), where immune complexes are not properly removed, resulting in chronic inflammation and tissue damage.

Phagocytosis:

• Although FCGR3B does not directly transduce signals, it facilitates phagocytosis of immune complexes by neutrophils in concert with other Fc receptors. By binding IgG-coated particles or pathogens, FCGR3B enhances neutrophil recognition and promotes their engulfment by adjacent neutrophils and macrophages.

Neutrophil Activation:

• FCGR3B can activate neutrophils indirectly through its interaction with IgG-bound immune complexes. This leads to neutrophil degranulation, respiratory burst, and the release of pro-inflammatory cytokines and chemokines, which further amplify the immune response.

Role in Inflammation:

• By promoting immune complex clearance and activating neutrophils, FCGR3B plays a role in regulating inflammatory responses. However, excessive activation or dysfunction of this receptor can contribute to inflammatory diseases.

Clinical Issues

Alterations in FCGR3B function, whether due to genetic mutations, polymorphisms, or dysregulation, can lead to several clinical conditions. Key clinical issues related to FCGR3B include:

Autoimmune Diseases:

• Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with impaired function or reduced expression of FCGR3B. In these autoimmune diseases, defective clearance of immune complexes contributes to chronic inflammation and tissue destruction. The accumulation of immune complexes can trigger excessive activation of neutrophils, leading to damage in tissues such as the kidneys, joints, and skin.
• FCGR3B copy number variations have been linked to increased susceptibility to SLE. Individuals with fewer copies of the FCGR3B gene tend to have a higher risk of developing autoimmune diseases due to reduced receptor function.

Chronic Granulomatous Disease (CGD):

• CGD is a genetic disorder that affects neutrophil function, leading to recurrent infections and chronic inflammation. FCGR3B may play a role in the altered neutrophil function observed in CGD, contributing to defective immune responses in these patients.

Neutrophil Dysfunction Syndromes:

• Mutations or polymorphisms in the FCGR3B gene can lead to various neutrophil dysfunction syndromes, where neutrophils fail to respond adequately to immune complexes or pathogens. This results in an increased susceptibility to bacterial infections and a reduced ability to resolve inflammation.

Infectious Diseases:

• Altered expression or function of FCGR3B may also impact susceptibility to infectious diseases. Defects in immune complex clearance can lead to prolonged infection and inflammation, exacerbating the severity of diseases caused by pathogens such as bacteria and viruses.

Therapeutic Implications:

• Given its role in immune complex clearance, FCGR3B has been considered a target for therapies aimed at modulating the immune system in autoimmune diseases. Understanding FCGR3B expression and function could help in developing treatments that improve immune complex clearance and reduce inflammation in diseases like SLE and RA.

Summary

FCGR3B (Fc gamma receptor IIIb) is a low-affinity receptor for IgG antibodies, primarily expressed on neutrophils. Structurally, it is a GPI-anchored protein, which differentiates it from its counterpart, FCGR3A, a transmembrane receptor. While FCGR3B lacks intrinsic signaling capacity, it plays a vital role in immune complex clearance and neutrophil activation, processes that are essential for maintaining immune homeostasis and defending against infections.

FCGR3B’s biological significance lies in its role in facilitating the clearance of IgG-coated pathogens and immune complexes, as well as modulating neutrophil responses. Its dysregulation or mutations can contribute to various autoimmune diseases, chronic inflammatory conditions, and increased susceptibility to infections.

In summary, FCGR3B represents an important receptor in the immune system, particularly in the context of autoimmunity and inflammation. Its role in immune complex clearance and neutrophil function makes it a key player in the body’s defense mechanisms against pathogens and a potential therapeutic target in autoimmune diseases.