IgE Receptor Crosslinking And Activation Of Apcs

The first direct evidence of DC and IgE interaction was via immunohistochemical and immunoelectron microscope demonstrations of IgE bearing LCs in AD patients (29). Subsequently, FceRI expression in normal human LCs was also demonstrated simultaneously by two groups (30,31). Binding of an allergen to the FceRI on APCs from an atopic individual who expresses high levels of this receptor leads to receptor cross-linking and subsequent activation of these cells. In nonatopic individuals this is not the case, since the receptor is only expressed at low levels.

Thomas Bieber and his group have shown this to be the mechanism for epidermal LCs in their extensive studies on the mechanisms underlying atopic dermatitis. APC activation results in the release of mediators and cytokines, like MIP-1 and MCP-1, which act to attract more APCs to the site of inflammation (4).

The cross-linking of the FceRI receptor induces cytokine production, but, for these cellular responses to occur, the activation of the intracellular signaling pathways is required. When the IgE bound receptors are cross-linked by multivalent antigens, tyrosine residues of ITAMs on both the 3 (in the case of mast cells)

Table 3 Localization of Cells Expressing Various Cell Surface Markers in the Eyelid of the A/J Mouse

CD11c CD11b CD8a MHC class II

Epidermis

Anterior lamellar layer

Tarsal plate (with meibomian glands)

Substantia propria of conjunctiva

Source: Ohbayashi et al., (data submitted for publication, 2006).

and y chains (on APCs) are transphosphorylated by the src family protein tyrosine kinase (PTK) called lyn. This process is followed by propagation of intracellular signal transduction, recruitment and activation of syk PTK, phosphorylation of protein kinase Cy1, phophoinositols breakdown, and the elevation of intracellular calcium concentration (16,17). In normal human LCs, FceRI cross-linking does induce de novo tyrosine phosphorylation of several proteins but the increase in intracellular calcium concentration is not observed. Conversely, in atopes, calcium mobilization via FceRI cross-linking has been demonstrated in the LCs of these individuals (16,32). This suggests that some steps of the FceRI-mediated signaling cascade might be upregulated in atopic individuals.

As previously mentioned, DCs play a critical role in the regulation of TH cell responses via the secretion of various soluble factors and the expression of membrane associated co-stimulatory molecules. Since interaction of allergen with surface bound IgE-FceRI complex results in the release of inflammatory mediators and upregulates the production of various cytokines, it is conceivable to assume that FceRI could be a key molecule which connects IgE-mediated allergic reaction and the preferential induction of TH2 type T-cell activation, as observed in AD patients (17).

The cross-linking of IgE bound to FceRI on DCs in peripheral blood results in a different response to that seen in LCs in the skin. In blood DCs, this aggregation of IgE-FceRI results in receptor internalization, antigen proteolysis and transport to the MHC class II compartment-like organelle where peptide loading of the MHC class II occurs. This enables the DCs to present the antigen bound to MHC class II at the secondary lymphoid tissues after their migration through the blood (33).

Recent data have also suggested a role of FceRI on the differentiation of APCs mediated by factors involved in anti-inflammatory pathways and known to promote a tolerogenic state. The production of the tolerogenic cytokine IL-10 has been induced by the engagement of FceRI on human monocytes from atopic donors at the beginning of the IL-4/GM-CSF driven culture process, and this prevented the differentiation of the DCs (34). This resulted in the production of macrophage-like cells that were poor stimulators of T cells. This area needs further study to characterize the precise role of FceRI in the modulation of DCs and the clinical consequences attached to this finding.

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  • felix
    How do receptors cross link?
    3 months ago

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