FceRI human basophils

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 ... 

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]. 

Brief exposure to low pH removes most of the IgE bound to FceRI-l- cells and completely blocks the effects exerted by gpl20 and by anti-IgE on IL-4 and IL-13 secretion from basophils [55, 56]. This indicated that gpl20-induced activation of FceRI-l- cells occurs via the interaction with basophil-bound IgE [57]. Preincubation of gpl20 with human monoclonal IgM VH3 + inhibited the effect of gpl20 on cytokine secretion from basophils. In contrast, preincubation with a monoclonal IgM VH6+ had no effect. Thus, binding to the Vh3 domain prevents gpl20 interaction with IgE bound to FceRI on basophils and mast cells. 

We previously showed that protein L induces proinflammatory mediator release from human basophils and mast cells, probably by interacting with FceRI-bound IgE [72, 79], We next evaluated whether protein L and a fragment of protein L denoted B1-B4 , which comprises four of the five immunoglobulinbinding repeats [73], induce cytokine (IL-4 and IL-13) synthesis and secretion from human basophils. Protein L and B,-B4 stimulated IL-4 release from basophils [80] and there was a significant correlation between IL-4 release induced by protein L and by B,-B4. These data demonstrate that protein L induces the secretion of IL-4 and IL-13, which are important for the polarization of Th2 cells [81], from basophils. 

Figure 1 Diagrammatic representation of the secretogogues released from human basophils and mast cells following IgE/FceRI crosslinking. The binding of specific antigen to receptor-bound IgE initiates signals that culminate in the release of preformed pro-inflammatory mediators and the synthesis of immunoregulatory cytokines. IL-3 and SCF enhance these secretory events in basophils and mast cells, respectively.

We now know, however, that the concentration of IgE antibody also determines the expression of FceRI on basophils and mast cells (see below), although a direct demonstration of this observation on human tissue mast cells has not yet been made. Thus, if IgE titers fall, so too does FceRI expression. This dynamic considerably alters the prediction made above. Much more modest and achievable changes in IgE titer, 50- to 100-fold, significantly reduce the function of basophils. The details of this prediction are borne out in therapeutic trials of anti-IgE antibody. 

B. In Vitro Regulation of FceRI on Human Basophils from Treated Subjects... 

Thompson HL, Metcalfe DD, Kinet JP. Early expression of high-affinity receptor for immunoglobulin E (FceRI) during differentiation of mouse mast cells and human basophils J Chn Invest 1990 85 1227-1233. 

Saini S, MacGlashan DW Jr., KUon A, Holland S, Hamilton R, Bochner B. Relationship between serum IgE and FceRI levels on human basophils, monocytes, and eosinophils. J Allergy Clin Immunol 1999 103 8168. 

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. 

Protein Fv binds specifically to the VH domain of immunoglobulins [22], Consequently, this endogenous protein is similar to multivalent antigens or to divalent anti-IgE antibodies. To evaluate the mechanism whereby this protein activates basophils, we incubated protein Fv with human monoclonal IgM from diverse VH families [19,29], Preincubation of basophils with three preparations of human monoclonal IgM VH3+ concentration-dependently inhibited the histamine-releasing activity of protein Fv. In contrast, a monoclonal IgM that has a Vh6 domain had no such effect. These results are compatible with the hypothesis that protein Fv binds to IgE VH3 + bound to FceRI+ cells. 

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