Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells

Abstract

Background Rapid desensitization transiently prevents severe allergic reactions, allowing administration of life-saving therapies in previously sensitized patients. However, the mechanisms underlying successful rapid desensitization are not fully understood. Objectives We sought to investigate whether the mast cell (MC) is an important target of rapid desensitization in mice sensitized to exhibit IgE-dependent passive systemic anaphylaxis in vivo and to investigate the antigen specificity and underlying mechanisms of rapid desensitization in our mouse model. Methods C57BL/6 mice (in vivo) or primary isolated C57BL/6 mouse peritoneal mast cells (PMCs; in vitro) were passively sensitized with antigen-specific anti–2,4-dinitrophenyl IgE, anti-ovalbumin IgE, or both. MCs were exposed over a short period of time to increasing amounts of antigen (2,4-dinitrophenyl–human serum albumin or ovalbumin) in the presence of extracellular calcium in vitro or by means of intravenous administration to sensitized mice in vivo before challenging the mice with or exposing the PMCs to optimal amounts of specific or irrelevant antigen. Results Rapidly exposing mice or PMCs to progressively increasing amounts of specific antigen inhibited the development of antigen-induced hypothermia in sensitized mice in vivo and inhibited antigen-induced PMC degranulation and prostaglandin D2 synthesis in vitro. Such MC hyporesponsiveness was induced antigen-specifically and was associated with a significant reduction in antigen-specific IgE levels on MC surfaces. Conclusions Rapidly exposing MCs to progressively increasing amounts of antigen can both enhance the internalization of antigen-specific IgE on the MC surface and also desensitize these cells in an antigen-specific manner in vivo and in vitro.

Global microRNA expression is essential for murine mast cell development in vivo

“…We also examined mast cell-specific Dicer deletion in the passive systemic anaphylaxis (PSA) murine model which is dependent on mast cells [19,20]. As shown in Figure 2C, IgE sensitized WT mice showed symptoms of anaphylaxis as evidenced by marked hypothermia with antigen; however, MC-Dicer −/− mice were completely protected against systemic anaphylaxis.…”

Mast cell activation: A complex interplay of positive and negative signaling pathways

“…Although the mechanisms involved are not detailed, this protocol induced early-and late-stage hyporesponsiveness, with almost complete inhibition of the release of both prestored β-hexosaminidase and newly synthesized TNF-α and IL-6, through the reduced activation of p38 and STAT-6 and impaired internalization of the FcεRI/IgE complex [64]. In a recent work, Oka et al [65] developed a similar protocol to induce desensitization of peritoneal mast cells. In this study, desensitization was achieved by internalization of the IgE complex during rapid desensitization [65], suggesting that this process might be ascribed either to the phosphorylation of the receptor or to the enhancement of endocytic signaling, rather than to the modification of the Src activation cascade itself.…”

Immunotherapy in allergy and cellular tests

“…31,32 VIT effectiveness is strictly dependent on allergy desensitization mechanisms, and an understanding of this represents a major goal of immunotherapy. [33][34][35] This would mean that performing a BAT by simply investigating membrane upregulation of CD63 and CD203c, must take into account the complexity of HoBV interaction with cell response to VIT and the BAT gating protocol employed in the test, in order to better optimize its performance. 23 Such a consideration raised from AIT with hymenoptera venom, may fit to many other immunotherapy protocols with defined allergens, such as dust mites.…”