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Fc Epsilon RI Signaling Pathway


Figure1. Fc epsilon RI signaling pathway.

Introduction

Fc epsilon RI, also known as FcεRI, is a high-affinity receptor for IgE that binds to the Fc portion of IgE. Its structural characteristics are as follows: Fc ε RI is a heteromultimeric complex that is multiple strands of immunological recognition receptors. It exists in the form of an αβγ2 tetramer or an αγ2 trimer. The alpha subunit includes an extracellular region and a transmembrane region. The extracellular domain contains two immunoglobulin-like regions, the near-membrane-end structural region that binds to the IgE Fc segment, and the other structural region that is involved in high-affinity binding. The alpha subunit contains seven glycosylation sites of N-chain that affect receptor secretion and stability. Further studies indicate that these glycosylation sites are not required for proper folding of the alpha chain and do not affect its binding to IgE. Additionally, the alpha subunit is a key site that triggers an allergic reaction. Studies by David et al. have confirmed that mice that remove the alpha subunit do not fully express Fc ε RI and have no IgE-mediated allergic reactions. The beta subunit has a transmembrane region and an intracellular region. It is an antigenic receptor that penetrates the membrane four times and is now named as the MS4A gene family with CD20 and HTM4. Therefore, both the N-terminus and the C-terminus are in the cytoplasm; the N-terminus contains a characteristic proline, and its function is unknown; the C-terminus contains an immunoreceptor tyrosine activation motif (ITAM). The β subunit is a gamma subunit-mediated amplification of the Syk tyrosine kinase activation effect, which can amplify the activity of tyrosine kinase and calcium influx by 5 to 7 times, while itself has little or produces no signal transduction by crosslinking of FcεRI. Researchers find that the β subunit has a second amplification function, which is to amplify the expression of FcεRI on the cell surface. The above findings also provide a possible explanation for the large differences in the distribution density of FcεRI between different cells, such as the differential between β-negative cells (monocytes, dendritic cells) and β-positive cells (mast cells, basophils). The gamma subunit exists as a homodimer. Extracellularly, two gamma subunits are linked by a disulfide bond, and each has a transmembrane region. The intracellular region has an ITAM motif, and the gamma subunit belongs to the same family member with the TCR δ chain, which can be activated after cross-linking of FcεRI. FcεRI is required for cell membrane expression and intracellular signal transduction. Another well-defined function of the gamma subunit is to facilitate expression of the human alpha subunit on the cell surface. Both the intracellular regions of the β and γ subunits have ITAM motifs, and they can mediate signal transduction with non-receptor tyrosine kinases, such as Lyn and Syk (spleen tyrosine kinase), respectively. In humans, αβγ2 and αγ2 can be expressed simultaneously on one cell, and the proportion of their expression varies from individual to individual. They all have the function of activating hematopoietic cells. Due to the amplification of β subunits, the expression ratio determines the size of the FcεRI/IgE-mediated immune response. Meanwhile, this phenomenon indicates that the beta subunit is unnecessary in some aspects of FcεRI mediated signal transduction. Saini et al. used flow cytometry and PCR to measure the ratio of Fcε RI α and β subunits on the cell surface. The results show that the ratio is related to the surface expression of the α subunit, and the variation among individuals is large. In rodents, FcεRI is expressed only in the form of αβγ2.

FcεRI mediated signal transduction

When allergens invade the nasopharyngeal, tonsil, trachea, and lymphoid tissues inherent in the gastrointestinal mucosa, it will stimulate TH2 helper cells to produce large amounts of IL-4. As the production of IgE depends on IL-4, IgEs are produced by plasma cell in the intrinsic lymphoid tissues of nasopharyngeal, tonsil, trachea, and gastrointestinal mucosa. The up-regulated IgE, due to its affinity for cells, can bind to the high affinity FcεRI of the mast cell or basophil surface by its Fc segment without binding to the antigen. Mast cells can be activated when the multivalent antigen binds to IgE causing cross-linking of at least two FcεRIs. After FcεRI aggregation and cross-linking, the PTK (protein tyrosine kinase) of Lyn and Src family is activated, and the activation of Lyn phosphorylates β-chain, γ-chain and adjacent protein tyrosine, and then phosphorylated β and γ subunits are further active Lyn, Syk. Activated Lyn phosphorylates Btk and Emt, both of which are Tec families, and their activation causes intracellular Ca efflux and PKC activation, respectively. Studies show that the activation of PKC and an increase in extracellular calcium are necessary for the degranulation reaction.

After the cross-linking of FcεRI, signal can be transmitted by several pathways. 1. mitogen-activated protein kinase pathway (MAPK). Members of the MAPK family include: ERK, P38, JNK, and ERK5. In this process, these pathways activate a variety of effector proteins. After FcεRI cross-linking, activated Lyn and Syk will activate Vav and Shc and enhance the interaction between Shc and Grb2. And then, the complex of Shc, Grb2 and SOS activates the Ras protein, thereby activating the following pathways: Raf1→MEK1→ERK1/ 2, which promote the expression of cytokines and related genes. The current study found that JNK has multiple activation pathways in mast cells, Bruton's tyrosine kinase (BTK), a Tec family of PTK, which is activated by Lyn phosphorylation after FcεRI cross-linking. When it is in cells, JNK can be activated by PKC-dependent and independent pathways, respectively, as follows: (A)BTK→PLC-γ→DAG→PKC→JNK; (B)PAK65→MEKK1→MAPKK4→JNK. P38 can also be activated by cross-linking of the receptor. Kimata.M et al. used inhibitors of the EPK and P38 MAPK pathways to block this pathway, and found that the release of arachidonic acid metabolites in HCMC (human cultured mast cells) cells is mediated by the ERK pathway; the P38 MAPK pathway negatively regulates the JNK pathway. Therefore, this suggests the role of the MAPK pathway in the release of inflammatory mediators in HCMC. 2. Rho family signaling pathway. The Rho family belongs to the small G protein superfamily and can be divided into 6 families of Ras, Rho, Rab, Arf, Sarl and Ran according to the homology of its primary structure. The current study found that the Ras and Rho families are involved in the activation of downstream of FcεRI. The Rho family, including Rho, Rac and Cdc42, is an important regulator of the actin cytoskeleton. Recent studies suggest that Rho-GTPase is also involved in the activation of FcεRI in RBL cells, including the redistribution of the actin cytoskeleton, mobilization of calcium ions, and degranulation and the activation of JNK. For example, RBL cells that do not express Rac and Cdc42 inhibit FcεRI-mediated degranulation. Field K.A et al. Constructed mutant RBL mast cells. Due to the lack of FcεRI signal and lipid carrier, the cross-linking of FcεRI could not cause mobilization of calcium ions, and the antigen-stimulated degranulation was restored after expressing human Cdc42 and Rac in cells. This proves that activation of Cdc42 and/or Rac is important for the FcεRI-mediated mobilization of calcium ions and degranulation. 3. PI3K signaling pathways. After Fc ε RI cross-linking, the activated PI3K pathway is involved in the activation of the JNK pathway.

Clinical significance

Activation of the IgE/FcεRI signaling pathway in humans causes mast cells or basophils to release biologically active mediators that mediate type I hypersensitivity reactions, such as histamine, kininogen, prostaglandin D2 (PGD2), LTs, PAF and cytokines. The release of these active substances causes smooth muscle spasm, increased permeability of small blood vessels, increased secretion of mucosal glands, and sensitivity to nerve endings. Therefore, the disease caused by the IgE/FcεRI signaling pathway is mainly an allergic reaction. According to different allergy distribution, it can be divided into systemic allergic reactions and local allergic reactions. Systemic allergic reactions are mainly caused by two kinds of allergens. One is drug-induced anaphylactic shock, such as penicillin; the other is anaphylactic shock caused by immune serum. Both of them cause anaphylactic shock and death in severe cases. Local allergic reactions mainly include respiratory allergic reactions (eg, allergic rhinitis and allergic asthma), allergic reactions to the digestive tract (eg, allergic gastroenteritis), and skin allergic reactions (eg, urticaria and eczema). Clinical treatments mainly include avoiding contact with allergens, desensitization therapy, drug control (inhibition of active substance release and function) and immunobiological therapy (by immunological methods to inhibit IL-4 production, thereby reducing the production of IgE, to achieve the purpose of treatment.). The binding of IgE to the target cell surface high affinity receptor FcεRI is key to type I hypersensitivity diseases. Due to the prevalence and lethality of type I hypersensitive reactive diseases, designing drugs to treat hypersensitivity diseases with this pathway has become a hot spot for drug development. Humanized anti-IgE monoclonal antibodies and Syk inhibitors play an important role in clinical practice, confirming that it is feasible to use IgE/FcεRI signaling pathway as a drug target for the treatment of type I hypersensitivity diseases. Therefore, this pathway has potential prospects in the treatment of type I hypersensitivity diseases.

References:

  1. Pawankar R. Mast cells as orchestrators of the allergic reaction: the IgE-IgE receptor mast cell network. Curr Opin Allergy Clin Immunol. 2001, 1 (1): 3–6.
  2. Von Bubnoff D. et al. The central role of FcepsilonRI in allergy. Clin Exp Dermatol. 2003, 28 (2): 184–7.
  3. Siraganian R.P. "Mast cell signal transduction from the high-affinity IgE receptor". Curr. Opin. Immunol. 2003, 15 (6): 639–46.
  4. Saini S.S., MacGlashan, D. How IgE upregulates the allergic response. Curr Opin Immunol. 2002, 14(6):694-7.
  5. Kimata M. et al. Roles of mitogen-activated protein kinase pathways for mediator release from human cultured mast cells. Biochem Pharmacol. 2000, 60(4):589-94.
  6. Field K.A. et al. Mutant RBL mast cells defective in Fc epsilon RI signaling and lipid raft biosynthesis are reconstituted by activated Rho-family GTPases. Mol Biol Cell. 2000, 11(10):3661-73.

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