Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity.
The etiology of asthma, a chronic inflammatory disorder of the airways, remains obscure, although T cells appear to be central disease mediators. Lyn tyrosine kinase has been implicated as both a facilitator and inhibitor of signaling pathways that play a role in allergic inflammation, although its role in asthma is unclear because Lyn is not expressed in T cells. We show in the present study that Lyn-/- mice develop a severe, persistent inflammatory asthma-like syndrome with lung eosinophilia, mast cell hyperdegranulation, intensified bronchospasm, hyper IgE, and Th2-polarizing dendritic cells. Dendritic cells from Lyn-/- mice have a more immature phenotype, exhibit defective inhibitory signaling pathways, produce less IL-12, and can transfer disease when adoptively transferred into wild-type recipients. Our results show that Lyn regulates the intensity and duration of multiple asthmatic traits and indicate that Lyn is an important negative regulator of Th2 immune responses.
Beavitt
Sarah-Jane E
SJ
Lung Disease Research Group, Department of Medicine, University of Melbourne, Victoria, Australia.
Harder
Kenneth W
KW
Kemp
Joanna M
JM
Jones
Jessica
J
Quilici
Cathy
C
Casagranda
Franca
F
Lam
Ellen
E
Turner
Debra
D
Brennan
Siobhain
S
Sly
Peter D
PD
Tarlinton
David M
DM
Anderson
Gary P
GP
Hibbs
Margaret L
ML
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001986:Bronchial Spasm / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018928:Immunity, Mucosal / Q000235:genetics; D007073:Immunoglobulin E / Q000502:physiology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000276:immunology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D000485:Allergens; D018836:Inflammation Mediators; D007073:Immunoglobulin E; D010047:Ovalbumin; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases