Immunoglobulin Fc receptors (FcRs) are membrane molecules expressed by several hematopoietic cells that connect antibody-mediated recognition of pathogens with cellular responses. FcRs recognize the Fc region (constant portion) of antibodies, facilitating the immune response against infections and other threats.
When antibodies bind to pathogens or infected cells, FcRs enable immune cells to recognize these complexes and act accordingly. These interactions drive key immune processes such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and the release of inflammatory signals.
Main functions of Fc receptors. DOI:10.1038/nri856
Types of Fc Receptors
Fc receptors are classified based on the specific antibody class they bind to. The main types include:
Fcγ Receptors (FcγRs): These bind to immunoglobulin G (IgG) and play crucial roles in ADCC and phagocytosis. Subtypes include:
FcγRI (CD64): A high-affinity receptor for IgG.
FcγRII (CD32): A low-affinity receptor with both activating and inhibitory variants.
FcγRIII (CD16): Expressed on NK cells, neutrophils, and macrophages.
Fcε Receptors (FcεRs): These interact with IgE and mediate allergic reactions. They are primarily found on mast cells and basophils, triggering the release of histamine upon activation
Fcα Receptors (FcαRs): These bind to IgA and are involved in mucosal immunity, helping clear pathogens from mucosal surfaces.
Fc receptors deliver intracellular signals when crosslinked by antibodies bound to antigens or pathogens. This crosslinking triggers signaling cascades within the immune cell, mediated by specific motifs within the receptor:
Immunoreceptor Tyrosine-Based Activation Motifs (ITAMs): Found in activating Fc receptors, ITAMs initiate signaling through tyrosine kinases, such as Src and Syk, leading to processes like phagocytosis, cytokine release, or cytotoxic activity.
Immunoreceptor Tyrosine-Based Inhibitory Motifs (ITIMs): Found in inhibitory Fc receptors, such as FcγRIIB, ITIMs recruit phosphatases like SHIP and SHP1, which counteract activation signals and maintain immune tolerance.
This balance between activation and inhibition is needed to prevent immune system overactivation, which can lead to autoimmune diseases or chronic inflammation.
Fc Receptor Contributions to Immunity
Fc receptors act as gatekeepers for several immune cell functions, such as:
Phagocytosis: Fc receptors on macrophages and neutrophils enable these cells to engulf antibody-coated pathogens or debris for destruction.
Cytotoxicity: NK cells use FcγRIII to detect and eliminate antibody-labeled infected or cancerous cells.
Antigen Presentation: Fc receptors on dendritic cells enhance antigen presentation to T cells, bridging innate and adaptive immunity.
Additionally, Fc receptors help regulate antibody levels in the body and facilitate antibody transport across epithelial barriers, such as the maternal transfer of IgG via FcRn.
Therapeutic Applications and Targeting Fc Receptors
Engineers can modify antibodies to improve their interactions with Fc receptors, tailoring immune responses for specific diseases:
Cancer Therapy: Antibodies like trastuzumab are designed to maximize ADCC by enhancing binding to activating FcγRIII on NK cells.
Autoimmune Disease Management: Fc receptor pathways can be targeted to suppress harmful immune activation. For instance, enhancing FcγRIIB signaling or blocking activating Fc receptors may help reduce inflammation in autoimmune conditions.
Fc Fusion Proteins: Biopharmaceuticals that combine Fc regions with therapeutic proteins or peptides leverage the stability and receptor-binding properties of Fc domains.
Ongoing studies continue to explore the role of Fc receptors in immunity, with particular focus on their involvement in disease and therapeutic potential. Polymorphisms, regulatory mechanisms, and signaling pathways are under investigation to identify new ways to manipulate Fc receptor functions for improved clinical outcomes.
Biotechnology companies and researchers are also developing Fc receptor-targeted therapies that aim to either boost the immune response against cancer or dampen it in autoimmune disorders. By unlocking the full potential of Fc receptor biology, these efforts promise a new generation of precision immunotherapies.
References:
Takai, T. (2002). Roles of Fc receptors in autoimmunity. Nature Reviews Immunology, 2(8), 580-592. https://doi.org/10.1038/nri856
Ben Mkaddem, S., Benhamou, M., & Monteiro, R. C. (2019). Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools. Frontiers in Immunology, 10, 445798. https://doi.org/10.3389/fimmu.2019.00811
