A kinase-dead allele of Lyn attenuates autoimmune disease normally associated with Lyn deficiency.
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.
Verhagen
Anne M
AM
Signal Transduction Laboratory, St. Vincent's Institute, Fitzroy, Victoria, Australia.
Wallace
Morgan E
ME
Goradia
Ankita
A
Jones
Sarah A
SA
Croom
Hayley A
HA
Metcalf
Donald
D
Collinge
Janelle E
JE
Maxwell
Mhairi J
MJ
Hibbs
Margaret L
ML
Alexander
Warren S
WS
Hilton
Douglas J
DJ
Kile
Benjamin T
BT
Starr
Robyn
R
D000483:Alleles; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007150:Immunohistochemistry; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics*
D001323:Autoantibodies; D011947:Receptors, Antigen, B-Cell; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases