Fc receptor

Fc receptors are membrane receptors for various immunoglobulin isotypes. All molecules except the FcRn receptor belong to the immunoglobulin superfamily. The name is based on the binding specificity of the receptors to a part of the C-terminus of an antibody called the Fc fragment (fragment crystallizable) and the constant region of an antibody. Fc receptors are glycosylated. This type of receptor is mainly produced by myeloid cells of the immune system. They are found on the surface of various immune cells, e.g. leukocytes, mast cells and others.

Keratinocytes also express Fc receptors (FcγRI, FcγRII and FcγRIII), among others. They also have complement receptors and mannose receptors, which enable them to attack a variety of microorganisms. Keratinocytes are therefore important modulators of the innate and adaptive immune response (Ali SM et al. 2013).

According to their affinity, Fc receptors can be divided into five subtypes, which are named according to the immunoglobulin they bind:

The Fcα receptor (CD89) binds the Fc domain of IgA. The receptor is found on the surface of monocytes, macrophages, neutrophils and eosinophils.

The Fcγ receptors bind the Fc domain of IgG. They are found on the surface of phagocytes, B lymphocytes, NK cells and dendritic cells. These receptors can recognize aggregated IgG molecules and bind them. The binding triggers different reactions depending on the cell type: e.g. opsonization or ADCC (by NK cells). There are different structural types of the Fcγ receptor:

• FcγRI(CD64)
• FcγRII(CD32)
• FcγRIII(CD16).

The Fcε receptors bind the Fc domain of free IgE. They are found on the surface of mast cells and basophilic granulocytes. Binding of antigens to these bound antibodies leads to activation of the mast cell. This process plays a decisive role in type I allergy. Two types of Fcε receptors are distinguished (mammals) depending on their affinity to IgE

• FcεRI with high affinity
• FcεRII with low affinity to IgE.

Fcμ receptors bind the Fc domain of IgM.

The neonatal Fcγ receptor (FcRn) belongs to the MHC superfamily and binds IgG with low affinity. Biochemically, this type of receptor is similar to an MHC class I molecule. It is responsible for the transport of IgG through the maternal placenta and the recycling of immunoglobulin G (IgG). The neonatal Fc receptor is encoded by the FCGRT gene on chromosome 19 at gene locus 19q13.3. The FcRn receptor is found in mucosal epithelial cells, endothelial cells and podocytes of the kidney. Its expression is increased by proinflammatory cytokines such as TNF-α. Interferon-gamma leads to reduced expression. In the kidney, FcRn receptors on podocytes prevent IgG and albumin from being deposited in the glomeruli. In the placenta, immunoglobulin G from the maternal blood is taken up by endocytosis into the syncytiotrophoblast. Here IgG binds to the neonatal Fc receptor in the endosomes and reaches the fetal side of the syncytiotrophoblast by transcytosis. There it is released into the fetal bloodstream and forms the basis of nest protection, but also of neonatal hemolytic disease. FcRn blockers are used therapeutically in myasthenia gravis to reduce circulating autoantibodies and thereby improve the symptoms. These include:

• Batoclimab
• Efgartigimod alfa
• nipocalimab
• Rozanolixizumab

The use in other autoimmune diseases is being investigated in clinical studies.

Note: TRIM21 binds Fc regions of IgG, IgA and IgM in the course of intracellular antibody-mediated degradation.

Bacterial Fc-binding proteins are protein A and protein G.

In addition to the membrane receptors, FcγR are also found as soluble IgG binding factors (IBF), primarily in serum and to a lesser extent in other body fluids. Elevated levels of soluble FcγRIII are observed in synovial fluid and bronchoalveolar lavage in RA (rheumatoid arthritis) and ARDS (acute respiratory distress syndrome) patients and in serum in systemic lupus erythematosus (SLE) and Sjögren's syndrome.

Various polymorphisms are detectable. polymorphisms (e.g. FCGR3A V158F) that influence, for example, the binding affinity of the Fcγ receptor for IgG. These variants can influence the effect of antibody therapies (such as rituximab). Mutations or deletions in the FCGR3B gene are associated with autoimmune diseases such as systemic lupus erythematosus (SLE).

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3. Ochiai K et al. (2006) A review on Fc epsilon RI on human epidermal Langerhans cells [J]. International Archives of Allergy and Immunology 104 Suppl 1: 63-64.
4. Otten MA et al. (2004) The Fc receptor for IgA (FcalphaRI, CD89). Immunology Letters 92 (1-2): 23-31.
5. Ravetch JV et al. (1989) Alternative membrane forms of Fc gamma RIII (CD16) on human natural killer cells and neutrophils [J]. J Exp Med 170:481 - 497.