title: Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis.
abstract: Anaphylaxis is a rapid, life-threatening hypersensitivity reaction. Until recently, it was mainly attributed to histamine released by mast cells activated by allergen crosslinking (XL) of FcεRI-bound allergen-specific IgE. However, recent reports established that anaphylaxis could also be triggered by basophil, macrophage, and neutrophil secretion of platelet-activating factor subsequent to FcγR stimulation by IgG/Ag complexes. We have investigated the contribution of Fyn and Lyn tyrosine kinases to FcγRIIb and FcγRIII signaling in the context of IgG-mediated passive systemic anaphylaxis (PSA). We found that mast cell IgG XL induced Fyn, Lyn, Akt, Erk, p38, and JNK phosphorylation. Additionally, IgG XL of mast cells, basophils, and macrophages resulted in Fyn- and Lyn-regulated mediator release in vitro. FcγR-mediated activation was enhanced in Lyn-deficient (knockout [KO]) cells, but decreased in Fyn KO cells, compared with wild-type cells. More importantly, Lyn KO mice displayed significantly exacerbated PSA features whereas no change was observed for Fyn KO mice, compared with wild-type littermates. Intriguingly, we establish that mast cells account for most serum histamine in IgG-induced PSA. Taken together, our findings establish pivotal roles for Fyn and Lyn in the regulation of PSA and highlight their unsuspected functions in IgG-mediated pathologies.
authors.affiliation: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA.
authors.forename: Yves T
authors.initials: YT
authors.lastname: Falanga
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Chaimowitz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charles
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Pullen
authors.forename: Suzanne
authors.initials: S
authors.lastname: Barbour
authors.forename: Kevin
authors.initials: K
authors.lastname: Dholaria
authors.forename: Travis
authors.initials: T
authors.lastname: Faber
authors.forename: Motunrayo
authors.initials: M
authors.lastname: Kolawole
authors.forename: Bernice
authors.initials: B
authors.lastname: Huang
authors.forename: Sandra
authors.initials: S
authors.lastname: Odom
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
authors.forename: Jason
authors.initials: J
authors.lastname: Carlyon
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Conrad
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
mesh_terms: D000485:Allergens / Q000235:genetics / Q000276:immunology; D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D000485:Allergens; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D017452:Receptors, IgG; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4