Human FceRI

It is generally accepted (based on clinical and in vitro studies) that mast cells (and basophils), IgE and FceRI are involved in most cases of allergen-induced anaphylaxis in humans. However, it is difficult to define the exact roles and relative importance of mast cells, basophils, and other potential effector cells (e.g monocytes/macrophages, dendritic cells) in either IgE-dependent or IgE-independent human anaphylaxis. Unlike in mice, we neither have access to mast cell- or basophil-deficient humans nor can we genetically manipulate human subjects to produce such phenotypes. 

Adding another layer of complexity to the regulation of mast cell activation levels in vivo is the observation that activated mast cells can respond to, and in some cases produce, a myriad of mediators that may serve to amplify FceRI-induced responses. For example, stem cell factor (SCF), the ligand for KIT, both can enhance FceRI-dependent activation of mouse or human mast cells and, under certain circumstances, can directly induce mast cell degranulation [6, 25, 62]. Thus, elevated SCF levels and/or activating KIT mutations (such as those that occur in mastocytosis) may exacerbate mast cell-driven reactions. Indeed, patients (both adult and children) with extensive skin disease associated with mastocytosis are at increased risk to develop severe anaphylaxis [63]. Moreover, it was recently reported that cases of idiopathic anaphylaxis are... 

Hamilton RG, Lichtenstein LM Down-regulation of FceRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997 158 ... 

The homology of the macaque s (cynomolgus and rhesus) protein sequences to the human sequence was over 90%. In contrast, dog, rat, and mouse sequences shared low homology with the human FceRI-alpha protein. Based on these results, the receptor of nonhuman primates would be more likely to bind a biopharmaceutical designed to interact with the human FceRI-alpha chain. This conclusion, however, would have to be confirmed in additional in vitro binding assays. 

Figure 9.11 Alignment FceRI-alpha chain protein sequences across species. Human, mouse, rat, dog, cynomolgus macaque, and rhesus macaque protein sequences coding for the alpha chain of the IgE receptor (FcsRI) were aligned and compared. Residues that are identical in all six species are highhghted in red. Residues common to more than half the sequences are listed in blue, and residues found to be identical in half the sequences or less are shown in black. See color insert.

Human basophils and mast cells are the only cells expressing the tetrameric high-affinity receptor of IgE (FceRI) and synthesizing histamine [26], Basophils and mast cells (FceRI + cells) play a prime role in the pathophysiology of allergic disorders through the elaboration and release of numerous proinflammatory and immunoregulatory molecules and the expression of a wide spectrum of receptors for cytokines and chemokines [27,28]. 

It is generally thought that these four canonical mechanisms of IgE-mediated activation of human FceRI + cells are responsible for the pathophysiological involvement of these cells in the majority of patients with allergic disorders [34], However, there is evidence that a significant percentage of allergic diseases (e.g. certain cases of intrinsic asthma and chronic idiopathic urticaria) cannot be explained by the four classical mechanisms of FceRI + cell activation. 

To assess the mechanism by which protein Fv activates FceRI + cells, the protein was preincubated with human monoclonal IgM of different VH families... 

Preincubation ofbasophils with three preparations oflgM VH3+ con-centration-dependently inhibited the histamine-releasing activity of protein Fv. By contrast, preincubation with a monoclonal IgM which has a VH6 domain had no such effect [32, 41]. Similar results were obtained when human lung mast cells were preincubated with three different preparations of human monoclonal IgM Vh3+ or IgM Vh6+ and then challenged with protein Fv (fig. 3). These results are compatible with the hypothesis that protein Fv binds to IgE VH3 + bound to FceRI+ cells. 

In conclusion, protein Fv, an endogenous protein present in normal liver and released in biological fluids during viral hepatitis [1], is a potent inducer of the release of proinflammatory mediators and cytokines from human FceRI+. This was the first evidence that a human protein induced by viral infections can act as an endogenous immunoglobulin superantigen. 

To assess the mechanism by which protein Fv activates cardiac mast cells, the protein was preincubated with human monoclonal IgM of different VH families [63], Preincubation of mast cells with preparations of monoclonal IgM that possess a VH3 domain concentration-dependently inhibited the releasing activity of protein Fv. By contrast, preincubation with a monoclonal IgM Vh6+ had no such effect. These results suggest that binding to the VH3 domain inhibits the binding of protein Fv to IgE bound to FceRI on cardiac mast cells. 

Patella Y Giuliano A, Bouvet JP, Marone G Endogenous superallergen protein Fv induces IL-4 secretion from human FceRI I cells through interaction with the VH3 region of IgE. J Immunol 1998 161 5647-5655. 

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