Fc-EpsilonRI Pathway
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Fc-EpsilonRI Pathway

The formation of antigen-antibody complexes plays a fundamental role in our immune defense system. Interaction of these complexes with many cells of the immune system results in a variety of critical functions, including phagocytosis, antibody-dependent cytotoxicity, modulation of antibody secretion, cell secretion and sometimes the secretion and generation of an array of mediators that induce allergic inflammations (Ref.1). Receptors involved in antigen recognition by cells of the immune system include BCRs (B-Cell Receptors), TCRs (T-Cell Receptors), and the FcRs (Fc Receptors) that bind to their corresponding Igs (Immunoglobulins) through Fc domains. FcRs exist for every antibody class: Fc-GammaRs bind IgG, Fc-AlphaRs bind IgA, FcEpsilonRs bind IgE, FcMuRs bind IgM and FcDeltaRs bind IgD (Ref.2). The multisubunit high-affinity IgE receptor, FcEpsilonRI (FcEpsilonReceptorI) expressed on mast cells and basophils evokes the activation of multiple signaling pathways, culminating in degranulation, lipid mediator release and cytokine gene transcription, resulting in secretion of molecules such as IL-3, IL-4, IL-5, IL-6, IL-10, IL-13 (Interleukins), IFN-Gamma (Interferon- Gamma), TNF-Alpha (Tumor-Necrosis Factor-Alpha), GCSF (Granulocyte-macrophage Colony-Stimulating Factor) and chemokines such as MCP1 (Monocyte Chemotactic Protein-1) and macrophage inhibitory proteins that play a central role in allergic reactions of the immediate type and may confer physiological protection in parasitic infections (Ref.3). Expression of human FcEpsilonRI also extends to the function of antigen presentation by the Antigen-Presenting Cells: monocytes, eosinophils, platelets, Langerhans cells, and dendritic cells.

Human FcEpsilonRI is expressed as both trimeric (AlphaGamma2) and tetrameric (AlphaBetaGamma2) structures (Ref.1). The tetrameric (AlphaBetaGamma2) structure comprises of an IgE-binding Alpha subunit, a Beta subunit, and a disulfide-bound Gamma dimmer whereas the trimeric (AlphaGamma2) structure includes one Alpha subunit and the Gamma dimmer. The Alpha-chain has an extracellular domain that binds monomeric IgE with high affinity while the Beta- and Gamma-chains contain unique cytoplasmic domains essential for downstream signaling, called ITAMs (Immunoreceptor Tyrosine-based Activation Motifs). On the mast cell and basophil surface a mixture of AlphaBetaGamma2 and AlphaGamma2 complexes are expressed, whereas only AlphaGamma2 structures are expressed on the professional Antigen Presenting Cells (Ref.4). The systemic response begins with binding of circulating multivalent allergens that form a complex with IgE antibodies already bound to the high-affinity FcR for IgE-FcEpsilonRI. Antigens bind and cross link IgE molecules held at the cell surface by FcEpsilonRI-Alpha followed rapidly by aggregation of receptors in the plane of the plasma membrane and a chain of phosphate transfer events within the receptor microenvironment which facilitates binding of additional protein kinases and regulator molecules that comprise the signaling cascade (Ref.5).

Information concerning aggregation is passed, by an unknown mechanism, to the Beta- and Gamma-chain signaling subunits and results in phosphorylation of the Beta and Gamma2 subunits by the Src family PTK (Protein Tyrosine Kinase), Lyn that is attached to the inner leaflet of the cell membrane. Lyn phosphorylation of the ITAM within FcEpsilonRI-Gamma subunits allows the ZAP70 (Zeta-Associated Protein of 70 kDa)-related PTK, SYK (Spleen Tyrosine Kinase), present in the cytosol, to associate with the receptor via its two SH2 (Src Homology 2) domains (Ref.5). This recruitment and consequent activation of SYK leads to further downstream signaling, including phosphorylation and activation of PLC-Gamma (Phospholipase-C-Gamma), PI3K (Phosphoinositide-3-Kinase), Vav, PKC (Protein kinase-C), mobilization of intracellular calcium, and activation of the LAT (Linker for Activation of T-Cells) (Ref.6). The activated PLC-Gamma hydrolyzes PIP2 (PhosphatidylInositol-4,5-bisphosphate) to IP3 (Inositol Trisphosphate) and DAG (Diacylglycerol). These signaling molecules are responsible for calcium release from intracellular stores and activation of various PKC isoforms, respectively. BTK (Brutons Tyrosine Kinase) is first membrane-targeted by binding of a PIP3 (PhosphatidylInositol-3, 4, 5-trisphosphate) moiety to its PH (Pleckstrin-Homology) domain. BTK then phosphorylates and activates PLC-Gamma , a process that requires the adapter SLP76 (SH2 domain-containing Leukocyte Protein of 76 kDa) (Ref.4). On the other hand, stimulation of PI3K results in transient accumulation of micromolar levels of PIP3 and PIP2. In addition PI3K has been shown to be important in the regulation of intracellular Ca2+, which may be attained by PLC-Gamma activation facilitated via BTK or Ca2+ mobilization across plasma membranes. PI3K and PLC-Gamma act in a concerted manner on the mutual substrate PIP2 to generate PIP3 and IP3 respectively, which activate Ca2+ channels at different cellular compartments (primarily the ER [Endoplasmic Reticulum]), to provide the elevated Ca2+ required for optimal physiological responses which are then depleted of calcium. Store depletion causes the influx of calcium from the surrounding environment through a class of SOCC (Store-Operated Calcium Channels) (Ref.4).

MAPK (Mitogen-Activated Protein Kinase) pathways including ERK1/2 (Extracellular Signal Regulated Kinases), JNK (c-Jun N-terminal kinase) and p38 MAPKs are also activated by antigen-IgE ligation of FcEpsilonRI. An important role for these MAPK pathways in mast cell function is predicted based on the ability of ERK1/2, JNK and p38 to regulate the transcriptional activity of cytokine genes. (Ref.7). FcEpsilonRI aggregation results in activation of GEFs (Guanine nucleotide Exchange Factors) that promote the GTP loading and hence increased activity of the small GTPases: Ras, Rac and Rho. The Ras GTPase recruited by GRB2 initiates a classical Ras /Raf1/MEK /ERK signaling cascade that targets the Elk1 transcription factor, which is involved in immediate early gene regulation. Two prominent GRB2 effector molecules are SOS and SLP76. GRB2 contributes to the recruitment and presumably the orientation of SOS towards its substrate, the Ras GTPase. SOS promotes GTP loading and hence activation of Ras and its multiple downstream effector pathways. Activation of MAPK pathway mediates arachidonic acid release catalyzed by cytosolic PLA2 (Phospholipase A2), contributing to the secretion of lipid mediators, including leukotrienes and PtgD2 (Prostaglandin D2). The major leukotriene produced is LTC4 (Leukotriene-C4); which is converted to LTD4 and LTE4, leading to inflammatory responses, prolonged bronchoconstriction, increased bronchial mucus production, increased venular permeability and arterial constriction, and cutaneous wheal-and-flare responses. Rac1, on the other hand, uses an unknown effector pathway to regulate the subcellular location of the cytokine gene transcription factor, NFAT (Nuclear Factor of Activated T-Cells). Both Ras and Rac1 are involved in regulation of the Activating Protein-1 class of transcription factors, which independently regulate some sites and act in concert with NFAT (Ref.4). The guanine nucleotide exchange factor, Vav1 has been demonstrated to regulate a specific subset of the activities, including activation of MAPKs regulated by a family of proteins known as MKKs (MAPK kinases), PAK65 (p21-Activated Kinase65), MAP2K4 (Mitogen-Activated Protein Kinase Kinase-4) and JNK /SAPK (Stress-Activated Protein Kinase) that lead to the transcriptional activity of ATF2 (Activating Transcription Factor-2) and c-Jun genes.

As AlphaGamma2 complexes are less competent at signaling than the AlphaBetaGamma2 on mast cells and basophils (they lack the Beta-signal amplifier), the function of antigen presentation by the Antigen Presenting Cells may be accomplished with only moderate induction of intracellular signaling pathways that are critical to the long-term maintenance of an IgE-driven immune response. Modulation of FcEpsilonRI responses has long been considered as a therapeutic strategy in allergy (Ref.4). Autoimmune diseases, asthma, and chronic allergies comprise a wide spectrum of pathologies associated with the inappropriate activation of the immune system by environmental antigens. The interaction of the IgE antibody with FcEpsilonRI is central to these immune reactions, and provides an attractive target for the inhibition of all IgE-mediated allergic diseases. Clinical studies of allergic individuals using anti-IgE monoclonal antibody therapy have shown that this is an effective approach to disease treatment (Ref.8). Recent studies show that IgE/FcEpsilonRI-mediated pathways and inflammatory cascade play a beneficial role in our defense system against parasites and further research in this field may present the components of FcEpsilonRI signaling pathway as attractive sets of potential targets of pharmaceutical interference for the treatment of allergic and other immunology diseases (Ref.9).