C5a receptor 1−/− mice are protected from the development of IgE‐mediated experimental food allergy

Abstract Background Food‐induced anaphylaxis is a serious allergic reaction caused by Fcε‐receptor activation on mast cells (MCs). The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food‐induced anaphylaxis, we aimed to assess the role of C5a in disease pathogenesis. Methods Oral antigen‐induced food‐induced anaphylaxis was induced in BALB/c wild‐type (wt) and C5ar1−/− mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen‐specific serum IgE, MCPT‐1, and intestinal MC numbers, as well as FcεR1‐mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine‐mediated hypothermia and regulation of endothelial tight junctions were determined. Results Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA‐specific serum IgE, and MCPT‐1 levels in wt mice. Male C5ar1−/− mice were completely whereas female C5ar1−/− mice were partially protected from anaphylaxis development. Serum MCPT‐1 levels were reduced gender‐independent, whereas IgE levels were reduced in male but not in female C5ar1−/− mice. Mechanistically, IgE‐mediated degranulation and IL‐6 production from C5ar1−/− BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross‐linking strongly upregulated C5aR1 MC expression in vitro and in vivo. Finally, C5ar1−/− male mice were largely protected from histamine‐induced hypovolemic shock, which was associated with protection from histamine‐induced barrier dysfunction in vitro following C5aR targeting. Conclusions Our findings identify C5aR1 activation as an important driver of IgE‐mediated food allergy through regulation of allergen‐specific IgE production, FcεR1‐mediated MC degranulation, and histamine‐driven effector functions preferentially in male mice.