FCGR2B - Fc gamma receptor Iib |Elisa - Clia - Antibody - Protein

Background

FCGR2B (Fc gamma receptor IIB), also known as CD32B, is a low-affinity receptor for the Fc portion of IgG antibodies, primarily responsible for regulating immune responses by mediating inhibitory signaling. It plays a crucial role in the balance between activation and inhibition of immune cells, preventing excessive inflammation and autoimmunity. Unlike its closely related receptor, FCGR2A, which triggers activating signals, FCGR2B is the only inhibitory receptor within the Fc gamma receptor family. This receptor is predominantly expressed on B cells, dendritic cells, macrophages, and other immune cells.

FCGR2B is part of the larger family of Fc gamma receptors (FcγRs), which bind the Fc region of immunoglobulin G (IgG) to mediate immune responses such as phagocytosis, cytokine release, and the clearance of immune complexes. Its inhibitory role is vital in the prevention of autoimmune reactions and the modulation of inflammatory responses. The gene encoding FCGR2B is located on chromosome 1q23, within a region encoding other Fc gamma receptors, and its expression is tightly regulated by immune and inflammatory stimuli.

The regulation of FCGR2B expression and function has profound implications in autoimmune diseases, infectious diseases, and cancer. Genetic polymorphisms in FCGR2B have been linked to altered susceptibility to autoimmune disorders and the efficacy of antibody-based therapies.

Protein Structure

FCGR2B is a type I transmembrane glycoprotein composed of approximately 310 amino acids. Its structure is typical of Fc receptors, with distinct extracellular, transmembrane, and cytoplasmic domains that facilitate its inhibitory function.

Extracellular Domain:

• The extracellular portion of FCGR2B consists of two immunoglobulin (Ig)-like domains, which are responsible for binding the Fc portion of IgG. These Ig-like domains are structurally similar to those found in other Fc gamma receptors (such as FCGR2A), but their function in FCGR2B is specialized for inhibitory purposes.
• The affinity of FCGR2B for monomeric IgG is low, but it binds effectively to immune complexes, especially when IgG is aggregated or in high concentrations, such as during an immune response.

Transmembrane Domain:

• The transmembrane region is composed of a hydrophobic sequence of amino acids that anchor the receptor into the plasma membrane. This region does not participate directly in ligand binding but ensures proper receptor localization on the cell surface.

Cytoplasmic Domain:

• The cytoplasmic tail of FCGR2B contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), which is the key to its inhibitory signaling. When the receptor is engaged by immune complexes, the ITIM motif is phosphorylated, leading to the recruitment of SH2 domain-containing phosphatases, such as SHP-1 and SHP-2. These phosphatases dephosphorylate signaling molecules downstream of activating receptors, counteracting the pro-inflammatory signals initiated by other receptors like FCGR2A or FcεR.
• This inhibitory signal prevents excessive immune activation, helping to maintain immune homeostasis and prevent tissue damage from chronic inflammation.

Classification and Subtypes

FCGR2B belongs to the Fc gamma receptor (FcγR) family, which includes both activating and inhibitory receptors. The members of this family are broadly classified based on their intracellular signaling motifs:

1. Activating Receptors: These receptors, such as FCGR2A (CD32A) and FCGR3A (CD16A), contain ITAM motifs in their cytoplasmic domains and mediate immune cell activation, leading to functions like phagocytosis, cytotoxicity, and cytokine production.
2. Inhibitory Receptors: FCGR2B is the only Fcγ receptor that contains an ITIM motif, making it the exclusive inhibitory receptor within this family. It counterbalances the signals from activating receptors and ensures immune regulation.

FCGR2B can exist in different isoforms generated through alternative splicing, though the majority of its inhibitory functions are consistent across these variants. The primary difference between FCGR2B and its closely related activating receptor, FCGR2A, lies in their intracellular signaling motifs, which direct them toward either activating or inhibitory roles.

Function and Biological Significance

The primary function of FCGR2B is to provide negative regulation of immune responses. This inhibitory receptor is crucial for maintaining immune tolerance and preventing autoimmunity.

Inhibition of B Cell Activation:

• On B cells, FCGR2B acts as a crucial inhibitory receptor, downregulating B cell receptor (BCR)-mediated signaling. When both the BCR and FCGR2B are co-engaged by immune complexes containing IgG, the ITIM motif of FCGR2B is phosphorylated, leading to the recruitment of SHP-1 phosphatase. This deactivates signaling pathways downstream of the BCR, limiting B cell activation and preventing overproduction of antibodies.
• This mechanism is essential in preventing autoantibody production and controlling humoral immune responses.

Modulation of Phagocytosis:

• On macrophages and dendritic cells, FCGR2B plays a role in modulating phagocytosis. While activating Fc receptors promote phagocytosis of opsonized targets, FCGR2B can inhibit this process by downregulating signals from activating receptors like FCGR2A or FCGR3A. This ensures that phagocytosis occurs in a controlled manner, preventing excessive inflammation and tissue damage.

Control of Inflammatory Responses:

• FCGR2B also inhibits inflammatory cytokine production by dendritic cells and other antigen-presenting cells. By doing so, it prevents the overactivation of T cells and other immune cells, limiting the extent of immune-mediated tissue injury.
• This inhibition is especially important in chronic infections and autoimmune diseases, where unchecked inflammation can lead to significant tissue destruction.

Role in Immune Complex Clearance:

• FCGR2B is involved in the clearance of immune complexes from the circulation. By limiting the activation of cells that bind immune complexes, it reduces the risk of immune complex-mediated diseases, such as systemic lupus erythematosus (SLE).

Clinical Issues

The regulatory function of FCGR2B has profound implications in several clinical conditions:

Autoimmune Diseases:

• Dysregulation of FCGR2B expression or function is strongly linked to autoimmune diseases. For example, in systemic lupus erythematosus (SLE), reduced FCGR2B function on B cells leads to excessive B cell activation and autoantibody production. Similarly, in rheumatoid arthritis (RA), alterations in FCGR2B expression contribute to the excessive inflammatory responses characteristic of the disease.
• Polymorphisms in the FCGR2B gene have been associated with increased susceptibility to autoimmune conditions. One such polymorphism, Ile232Thr, affects the receptor’s ability to localize to lipid rafts on the plasma membrane, reducing its inhibitory capacity and increasing the risk of autoimmunity.

Cancer:

• In cancer, FCGR2B plays a role in modulating the efficacy of antibody-based therapies. Overexpression of FCGR2B on tumor cells has been linked to resistance to anti-CD20 monoclonal antibodies, such as rituximab, which are used to treat B-cell lymphomas. By inhibiting Fc-mediated effector functions, FCGR2B can dampen the immune system’s ability to clear tumor cells, reducing the therapeutic efficacy of these treatments.

Therapeutic Antibodies and Immune Responses:

• FCGR2B influences the outcome of therapeutic antibodies used in treating cancer, autoimmune diseases, and chronic inflammatory conditions. Understanding the balance between activating and inhibitory Fc receptors, including FCGR2B, is crucial for optimizing the design of these therapies.
• Targeting FCGR2B to modulate its inhibitory functions has been proposed as a therapeutic strategy to enhance the efficacy of monoclonal antibodies, particularly in patients with poor responses due to high levels of FCGR2B expression.

Infectious Diseases:

• Polymorphisms in FCGR2B have been implicated in susceptibility to infectious diseases, including malaria and HIV. In malaria, certain FCGR2B variants are associated with increased severity of infection, likely due to impaired clearance of immune complexes and dysregulated inflammatory responses.

Summary

FCGR2B (CD32B) is a critical inhibitory receptor for the Fc region of IgG, playing a central role in maintaining immune homeostasis. Structurally, it consists of extracellular Ig-like domains that bind IgG, a transmembrane domain for membrane anchoring, and a cytoplasmic tail containing an ITIM motif, which mediates its inhibitory signaling. FCGR2B functions to dampen immune responses, particularly by inhibiting B cell activation, phagocytosis, and inflammatory cytokine production. Its role is essential in preventing autoimmunity and controlling inflammation. Clinically, dysregulation of FCGR2B contributes to autoimmune diseases, affects the efficacy of antibody-based therapies, and influences susceptibility to infectious diseases. Genetic polymorphisms in FCGR2B further underscore its importance in disease pathogenesis and therapeutic interventions.