FCER2 - Fc epsilon receptor II |Elisa - Clia - Antibody - Protein

Background

FCER2, also known as CD23, is a low-affinity receptor for the Fc region of Immunoglobulin E (IgE). It is an important protein involved in the regulation of IgE-mediated immune responses and plays a key role in allergy, asthma, and immune regulation. FCER2 was first recognized for its role in B cell differentiation and later found to be expressed in several other immune cell types, including monocytes, eosinophils, dendritic cells, and macrophages.

The interaction of CD23 with IgE is critical in the regulation of IgE levels and in modulating allergic responses. Unlike Fc epsilon receptor I (FCERI), which is a high-affinity receptor for IgE and is found on mast cells and basophils, CD23 has a much lower affinity for IgE and is expressed predominantly on B cells. This difference in affinity and cellular distribution allows CD23 to play a different role in immune regulation, particularly in controlling the production of IgE and mediating the interaction between IgE and antigen-presenting cells.

The role of CD23 in allergy is significant, given its involvement in the regulation of IgE, which is the immunoglobulin type central to allergic reactions. Beyond allergy, CD23 also has broader roles in immune regulation, influencing B-cell activation, antigen presentation, and immune tolerance. Due to its critical functions, CD23 has become a potential target for therapeutic interventions, particularly in diseases involving dysregulated IgE responses, such as asthma and atopic dermatitis.

Protein Structure

CD23 (FCER2) is a type II transmembrane glycoprotein, consisting of several structural domains, each of which contributes to its function in IgE binding and immune regulation. CD23 is encoded by the FCER2 gene located on chromosome 19 in humans.

The structure of the CD23 protein is characterized by the following features:

Extracellular Domain:

• The extracellular region of CD23 is composed of a C-type lectin domain that is responsible for binding to IgE. This domain shows structural homology with other C-type lectins but with modifications that allow it to bind IgE with low affinity. The binding affinity of CD23 for IgE is approximately 10^6 M^-1, which is significantly lower than that of the high-affinity FcεRI receptor.
• CD23 binds to the CH3 domain of the IgE heavy chain, and this interaction is essential for regulating IgE homeostasis. This interaction can be disrupted or enhanced depending on the valency of IgE and the presence of immune complexes.

Coiled-Coil Region:

• A distinctive feature of CD23 is its coiled-coil stalk region, which extends from the membrane and positions the C-type lectin domain away from the cell surface. This stalk region contains sites for proteolytic cleavage, which release soluble forms of CD23 (sCD23). The release of sCD23 from the membrane-bound form has important functional implications, as sCD23 can act in an autocrine or paracrine manner to influence B-cell activity and IgE regulation.

Transmembrane Domain:

• The transmembrane domain of CD23 is responsible for anchoring the protein to the cell membrane and plays a role in the assembly of CD23 into homotrimers. The trimerization of CD23 is thought to enhance its ability to bind IgE and mediate immune functions.

Cytoplasmic Tail:

• The cytoplasmic tail of CD23 contains motifs that are involved in signaling and internalization. This region interacts with adaptor proteins and signaling molecules that influence CD23-mediated endocytosis and antigen presentation. CD23 can internalize IgE-antigen complexes and present these antigens to T cells, linking humoral immunity to the cellular immune response.

Classification and Subtypes

CD23 is classified as a low-affinity receptor for IgE and is distinct from the high-affinity Fc epsilon receptor I (FCERI). It belongs to the C-type lectin superfamily, which includes various receptors that bind carbohydrates or other ligands through their C-type lectin domains.

There are two isoforms of CD23, generated by alternative splicing of the FCER2 gene:

1. CD23a: This isoform is primarily expressed on B cells and is involved in the regulation of IgE synthesis. It plays a critical role in feedback mechanisms that modulate the production of IgE in response to antigen stimulation.
2. CD23b: This isoform is inducible and expressed on various cell types, including monocytes, eosinophils, and dendritic cells, in response to proinflammatory cytokines like IL-4. CD23b plays a broader role in immune regulation, particularly in allergic inflammation.

Function and Biological Significance

CD23 is multifunctional, with critical roles in both the regulation of IgE levels and the modulation of immune responses. The main functions of CD23 include:

Regulation of IgE Production:

• CD23 on B cells provides feedback regulation of IgE synthesis. When CD23 binds to IgE, it can suppress further IgE production by signaling through its cytoplasmic tail. This helps prevent excessive IgE responses, which are characteristic of allergic diseases. Conversely, under certain conditions, CD23 can also enhance IgE production, especially in the presence of antigen-IgE complexes.

Antigen Presentation:

• CD23 is involved in the uptake and presentation of antigens to T cells. It can internalize IgE-antigen complexes and present processed antigens to T cells in the context of MHC class II molecules. This links the humoral immune response to cell-mediated immunity and helps shape the overall immune response to allergens.

Regulation of B-Cell Activation:

• CD23 influences B-cell activation and proliferation. The soluble form of CD23 (sCD23), released from the membrane-bound form, can act as a cytokine-like molecule that enhances B-cell growth and differentiation, particularly in response to IL-4. This function is important in the immune response to allergens and infections.

Role in Allergy and Asthma:

• CD23 plays a central role in the pathogenesis of allergic diseases, including asthma and atopic dermatitis. By regulating IgE production and facilitating IgE-antigen interactions, CD23 contributes to the development of type I hypersensitivity reactions. Increased levels of soluble CD23 are often found in individuals with allergic diseases, and targeting CD23 has been explored as a potential therapeutic strategy to reduce allergic inflammation.

Modulation of Immune Complexes:

• CD23 can mediate the clearance of IgE-containing immune complexes, particularly through interactions with complement receptors. This function helps regulate the size and persistence of immune complexes in circulation, preventing prolonged immune activation.

Clinical Issues

Allergic Diseases:

• CD23 is critically involved in the pathogenesis of allergic diseases, such as allergic rhinitis, asthma, and food allergies. Increased expression of CD23, particularly the soluble form, has been associated with elevated IgE levels and enhanced allergic responses. Therapeutic strategies that block CD23-IgE interactions or reduce CD23 expression are being investigated to treat IgE-mediated diseases.
• Omalizumab, an anti-IgE monoclonal antibody used in the treatment of allergic asthma, indirectly affects CD23 by reducing IgE levels, thus limiting CD23’s ability to promote allergic inflammation.

Chronic Lymphocytic Leukemia (CLL):

• CD23 is highly expressed in B-cell chronic lymphocytic leukemia (CLL), where it serves as a diagnostic marker for the disease. CD23 expression in CLL is linked to abnormal B-cell proliferation, and targeting CD23 has been explored as a potential therapeutic approach. The CD23 monoclonal antibody lumiliximab has been evaluated in clinical trials for CLL treatment, aiming to inhibit CD23-mediated B-cell growth and survival.

Autoimmune Diseases:

• Alterations in CD23 expression and function have been implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The role of CD23 in regulating B-cell activation and immune complex clearance suggests that dysregulated CD23 activity could contribute to the chronic inflammation and autoantibody production seen in these conditions.

Therapeutic Targeting of CD23:

• Given its involvement in allergic diseases and B-cell malignancies, CD23 is an attractive target for therapeutic intervention. Antibodies that block CD23-IgE interactions or reduce CD23 expression are being developed to treat IgE-mediated disorders and certain types of B-cell cancers.

Summary

FCER2 (CD23) is a low-affinity receptor for IgE with critical roles in IgE regulation, allergy, and immune modulation. Structurally, CD23 is a C-type lectin with a coiled-coil stalk region and a transmembrane domain that enables it to function as a membrane-bound receptor or in its soluble form. CD23's primary functions include regulating IgE production, presenting antigens to T cells, and modulating B-cell activation. Clinically, CD23 is implicated in allergic diseases, B-cell malignancies, and autoimmune disorders, making it a key target for therapeutic strategies aimed at regulating IgE levels or inhibiting B-cell proliferation.