BACKGROUND: Food-induced anaphylaxis is a serious allergic reaction caused by Fcepsilon-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 wildtype (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 FcepsilonR1-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(-/-) 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, FcepsilonR1 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, FcepsilonR1-mediated MC degranulation and histamine-driven effector functions preferentially in male mice. This article is protected by copyright. All rights reserved.
- Kordowski, A.
- Reinicke, A. T.
- Wu, D.
- Orinska, Z.
- Hagemann, P.
- Huber-Lang, M.
- Lee, J. B.
- Wang, Y. H.
- Hogan, S. P.
- Kohl, J.
Keywords
- Complement
- IgE
- food allergy
- histamine
- mast cell
