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.
Yuasa
T
T
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.
Ono
M
M
Watanabe
T
T
Takai
T
T
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