Intracellular signaling
The polypeptide chains of membrane Fc receptors are linked by disulfide bonds. The main feature of these structures is the presence of specific signaling sequences in the cytoplasmic portion that dictate the cell's subsequent behavior.
Two motifs with opposite effects are distinguished:
- ITAM (Immunoreceptor tyrosine-based activation motif). Mediates activation. Upon phosphorylation of tyrosine residues, this motif binds to tyrosine kinases of the Syk family, initiating the activation cascade.
- ITIM (Immunoreceptor tyrosine-based inhibition motif). Responsible for inhibition. Phosphorylated tyrosine recruits specific phosphatases (SHP1, SHP2, SHIP), which quench the activation signal, reducing cell activity.
Receptors for immunoglobulin G (Fcγ receptors)
This group of receptors recognizes IgG class antibodies. Depending on ligand affinity and structural features, they are divided into three main types.
High-affinity FcγRI receptor (CD64)
The only representative of the family capable of fixing native (free) antibodies that have not yet bound to an antigen. The affinity (Kd) is 10⁻⁸–10⁻⁹ M, and the mass is 72–75 kDa. It best binds IgG1 and IgG3 isotypes.
- Structure: consists of an α-chain (3 extracellular domains, no signaling region) and a γ-chain (bears the ITAM motif).
- Localization: at rest, present only on macrophages. Neutrophils and eosinophils begin to synthesize it only after activation.
- Function: the binding of free antibodies by macrophages turns them into so-called “armed” macrophages (active centers of antibodies “face” outward, waiting for antigen).
FcγRII receptors (CD32)
The most common receptors, found on almost all innate immune cells and B lymphocytes. Affinity is lower — about 10⁻⁷ M (mass 40–50 kDa).
- Structure: consist of a single α-chain with an unusually long intracellular region and two extracellular domains.
- Subtypes:
- FcγRIIA (contains ITAM). Located on phagocytes, helps recognize opsonizing antibodies.
- FcγRIIB (contains ITIM). Located on B cells and performs the function of inhibiting their activity.
Low-affinity FcγRIII receptors (CD16)
Have an affinity of 10⁻⁶ M and a mass of 50–65 kDa. Recognize IgG1 and IgG3. Structurally consist of a main α-chain and two additional chains (similar to the γ-chains of FcγRI) bearing ITAM.
- FcγRIIIA (main): the α-chain spans the membrane and interacts with the γ-chain inside the cell. Expressed on NK cells, monocytes, and macrophages.
- FcγRIIIB (alternative): the α-chain does not span the membrane completely, but is “anchored” via glycosylphosphatidylinositol. Characteristic of neutrophils.
Receptors for IgA and IgE
In addition to IgG, specific structures exist for recognizing other classes of immunoglobulins.
Receptors for IgA (Fcα receptors): Represented by the FcαR (CD89) receptor. Its molecular mass ranges from 55 to 75 kDa. It is found on the surface of T and B lymphocytes, neutrophils, as well as activated macrophages and eosinophils.
Receptors for IgE (Fcε receptors):
- FcεRI (no CD marker): High-affinity receptor (Kd 10⁻⁹–10⁻¹⁰ M) capable of binding free IgE. Has a complex structure: α-chain (29.6 kDa), β-chain (26.5 kDa), and γ-chain (9.7 kDa). Typical for mast cells, eosinophils, dendritic cells, and B cells.
- FcεRII (CD23): Low-affinity receptor (Kd 10⁻⁷ M), mass 45–50 kDa. Found on B cells, follicular dendritic cells, as well as activated eosinophils, T cells, and macrophages.
C3 receptors (Complement system receptors)
This group of receptors is characterized by high structural heterogeneity. Their main task is to control the complement system: they prevent the C3 component from binding to the body's own tissues and help rapidly cleave complement from immune complexes.
- CR1 (CD35): Present on classical phagocytes, erythrocytes, and B cells. On follicular dendritic cells (FDCs), it fixes immune complexes, which is critical for humoral immunity. Binds C3b and C3d.
- CR2 (CD21): Binds C3 fragments at various stages of breakdown (C3b, iC3b, C3d). Absent on phagocytes, but present on B lymphocytes and FDCs, where it activates the humoral response in germinal centers. This is the exact receptor used by the Epstein-Barr virus to enter the cell.
- CR3 and CR4: Belong to the β2-integrin family. CR3 is known as Mac-1 (CD11b/CD18), and CR4 as p150,95 (CD11c/CD18). Their main ligand is the inactive iC3b fragment.
Briefly: answers to topical questions
Which intracellular enzymes and secondary messengers are activated downstream of Syk kinases in the ITAM signaling cascade?
Downstream of the Syk kinase in the signaling cascade, phospholipases, protein kinases, and small GTP-binding proteins are activated, and secondary messengers are generated. The single signaling pathway divides into three main branches:
- Phospholipase C (PLC / PLCγ) — cleaves membrane phosphatidylinositol bisphosphate (PIP2) into secondary messengers: diacylglycerol (DAG) and inositol trisphosphate (IP3).
- Calcium ions (Ca2+) — are released from intracellular stores under the action of IP3.
- Protein kinase C (PKC) — is activated jointly by DAG and Ca2+, causing myosin phosphorylation and degranulation.
- Phospholipase A2 (PLA2 / PLA) — releases arachidonic acid for subsequent eicosanoid synthesis.
- Ras protein (Ras) — triggers the MAP cascade, activating transcription factors (Fos/Jun) for cytokine synthesis and secretion.
Which specific cytokines stimulate the synthesis and expression of the FcγRI receptor on the surface of neutrophils and eosinophils?
The sources directly indicate interferon-gamma (IFNγ): its action leads to the activation of gene transcription, among which the gene for high-affinity FcγRI (FCγR1) is listed. FcγRI is expressed on neutrophils and eosinophils following their activation; on resting cells, it is indicated only on macrophages.
To easily remember the signaling motifs: ITAM contains the letter “A” — Activation. ITIM contains the letter “I” — Inhibition.
Class and exam questions
Which of the Fc receptors can bind antibodies that have not yet bound to an antigen?
High-affinity receptors, such as FcγRI (CD64) for IgG and FcεRI for IgE, possess this ability. They can fix native antibody molecules.
What are "armed" macrophages?
These are macrophages on whose surface (via the FcγRI receptor) free antibodies are fixed. The active centers of these antibodies are directed into the extracellular environment and are ready to capture antigen.
Does the CR2 (CD21) receptor participate in the phagocytosis process?
No, CR2 is not expressed on phagocytes and is not involved in phagocytosis. It is located on B lymphocytes and follicular dendritic cells, being responsible for B cell activation.
What else to study on this topic
- Structural features of the intracellular domains of FcγRIIA and FcγRIIB
- The role of Syk kinases and SHP/SHIP phosphatases in the signal transduction cascade
- The anchoring mechanism of the alternative FcγRIIIB receptor in the membrane
- The function of follicular dendritic cells and CR1 in germinal centers
- The interaction of the Epstein-Barr virus with the CD21 receptor
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