Lyn is essential for fcgamma receptor III-mediated systemic anaphylaxis but not for the Arthus reaction.
The Src family kinase Lyn initiates intracellular signal transduction by associating with a variety of immune receptors such as antigen receptor on B cells and high-affinity Fc receptor (FcR) for immunoglobulin Ig(E) (FcepsilonRI) on mast cells. Involvement of Lyn in the IgE-mediated immediate-type hypersensitivity is well documented, but the physiological significance of Lyn in IgG-dependent, type III low-affinity FcR for IgG (FcgammaRIII)-mediated responses is largely unknown. In this study, we generated a double-mutant mouse strain deficient in both type II FcR for IgG (FcgammaRIIB) and Lyn to exclude any involvement of inhibitory signaling by FcgammaRIIB, which otherwise downregulates FcgammaRIII-mediated cellular responses. FcgammaRIIB-deficient but Lyn-sufficient mice served as controls. The Lyn deficiency attenuated IgG-mediated systemic anaphylaxis in vivo, and significantly reduced calcium mobilization and degranulation responses of bone marrow-derived mast cells (BMMCs) in vitro. However, we found that either interleukin 4 or tumor necrosis factor alpha release by BMMCs was comparable to that from Lyn-deficient and control mice, and the reverse-passive Arthus reaction was equally induced in both mutant mice, indicating that Lyn is not involved in the onset of the IgG-mediated, FcgammaRIII-dependent late phase responses of mast cells. These findings provide us with insight into distinct signaling mechanisms in mast cells underlying the development of diverse pathologies as well as a therapeutic potential for selective treatment of allergic disorders.
Department of Experimental Immunology and the Core Research for Evolutional Science and Technology (CREST) Program of Japan Science and Technology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
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Yuasa
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Ono
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Watanabe
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Takai
D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001183:Arthus Reaction / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006241:Haptens / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000276:immunology; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D016207:Cytokines; C080571:Fc gamma receptor IIB; D006241:Haptens; D007074:Immunoglobulin G; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; C038600:trinitrophenyl-ovalbumin; D015847:Interleukin-4; D012701:Serotonin; D007073:Immunoglobulin E; D010047:Ovalbumin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D002118:Calcium