Anna Kordowski1, Anna T Reinicke1, David Wu2, Zane Orinska3,4, Philipp Hagemann3,4, Markus Huber-Lang5, Jee-Boong Lee2, Yui-Hsi Wang2, Simon P Hogan2, Jörg Köhl1,4,6. 1. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany. 2. Division of Allergy and Immunology, Cincinnati Children's Hospital and University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA. 3. Division of Experimental Pneumology, Research Center Borstel, Leibniz Lung Center, Borstel, Germany. 4. Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany. 5. Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany. 6. Division of Immunobiology, Cincinnati Children's Hospital and University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA.
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.
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.
Authors: Yining Jin; Haoran Gao; Rick Jorgensen; Jillian Salloum; Dan Ioan Jian; Perry K W Ng; Venugopal Gangur Journal: Int J Mol Sci Date: 2020-05-01 Impact factor: 5.923
Authors: Peter W West; Rajia Bahri; Karen M Garcia-Rodriguez; Georgia Sweetland; Georgia Wileman; Rajesh Shah; Angeles Montero; Laura Rapley; Silvia Bulfone-Paus Journal: Front Immunol Date: 2021-02-01 Impact factor: 7.561