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A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency¹

Anne M. Verhagen^*, Morgan E. Wallace^*, Ankita Goradia^*, Sarah A. Jones^*, Hayley A. Croom^*, Donald Metcalf, Janelle E. Collinge, Mhairi J. Maxwell, Margaret L. Hibbs, Warren S. Alexander, Douglas J. Hilton, Benjamin T. Kile and Robyn Starr^2,*

^* Signal Transduction Laboratory, St. Vincent’s Institute, Fitzroy, Victoria, Australia; Cancer and Haematology and Molecular Medicine Divisions, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia; and Signal Transduction Laboratory, Ludwig Institute for Cancer Research, Parkville, Victoria, Australia

Lyn kinase, a member of the Src family of tyrosine kinases, functions as both a positive and negative regulator of B cell activation. In the absence of Lyn, BCR signaling is unregulated, leading to perturbed B cell development, hyperactive B cells, and lethal Ab-mediated autoimmune disease. We have generated a mutant mouse pedigree, termed Mld4, harboring a novel mutation in the gene encoding Lyn, which renders the protein devoid of kinase activity. Despite similarities between the phenotypes of Lyn^Mld4/Mld4 and Lyn^–/– mice, the spectrum of defects in Lyn^Mld4/Mld4 mice is less severe. In particular, although defects in the B cell compartment are similar, splenomegaly, myeloid expansion, and autoantibody production, characteristic of Lyn^–/– mice, are absent or mild in Lyn^Mld4/Mld4 mice. Critically, immune complex deposition and complement activation in Lyn^Mld4/Mld4 glomeruli do not result in fulminant glomerulonephritis. Our data suggest that BCR hypersensitivity is insufficient for the development of autoimmune disease in Lyn^–/– mice and implicate other cell lineages, particularly proinflammatory cells, in autoimmune disease progression. Furthermore, our results provide evidence for an additional role for Lyn kinase, distinct from its catalytic activity, in regulating intracellular signaling pathways.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Program Grant 461219 and fellowships (to M.J.M., M.L.H., W.S.A., and D.J.H.) from the Australian National Health and Medical Research Council, fellowships from the Australian Research Council (to B.T.K.), the Cancer Council of Victoria (to D.M.), and the Sylvia and Charles Viertel Foundation (to R.S.). This study was supported in part by research funding from MuriGen Pty Ltd.

² Address correspondence and reprint requests to Dr. Robyn Starr, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail address: rstarr{at}svi.edu.au

³ Abbreviations used in this paper: SFK, Src family kinase; SH, Src homology; SHP-1, SH2 domain-containing phosphatase 1; EPO, erythropoietin; ENU, N-ethyl-N-nitrosourea; Syk, spleen tyrosine kinase; IC, immune complex; wt/WT, wild type.