title: B cell-specific loss of Lyn kinase leads to autoimmunity.
abstract: The Lyn tyrosine kinase regulates inhibitory signaling in B and myeloid cells: loss of Lyn results in a lupus-like autoimmune disease with hyperactive B cells and myeloproliferation. We have characterized the relative contribution of Lyn-regulated signaling pathways in B cells specifically to the development of autoimmunity by crossing the novel lyn(flox/flox) animals with mice carrying the Cre recombinase under the control of the Cd79a promoter, resulting in deletion of Lyn in B cells. The specific deletion of Lyn in B cells is sufficient for the development of immune complex-mediated glomerulonephritis. The B cell-specific Lyn-deficient mice have no defects in early bone marrow B cell development but have reduced numbers of mature B cells with poor germinal centers, as well as increased numbers of plasma and B1a cells, similar to the lyn(-/-) animals. Within 8 mo of life, B cell-specific Lyn mutant mice develop high titers of IgG anti-Smith Ag ribonucleoprotein and anti-dsDNA autoantibodies, which deposit in their kidneys, resulting in glomerulonephritis. B cell-specific Lyn mutant mice also develop myeloproliferation, similar to the lyn(-/-) animals. The additional deletion of MyD88 in B cells, achieved by crossing lyn(flox/flox)Cd79a-cre mice with myd88(flox/flox) animals, reversed the autoimmune phenotype observed in B cell-specific Lyn-deficient mice by blocking production of class-switched pathogenic IgG autoantibodies. Our results demonstrate that B cell-intrinsic Lyn-dependent signaling pathways regulate B cell homeostasis and activation, which in concert with B cell-specific MyD88 signaling pathways can drive the development of autoimmune disease.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Lamagna
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Hu
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D020013:Calcium Signaling / Q000276:immunology; D002452:Cell Count; D004195:Disease Models, Animal; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D006706:Homeostasis; D007105:Immune Complex Diseases / Q000276:immunology / Q000473:pathology; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000201:enzymology / Q000209:etiology / Q000276:immunology; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D009928:Organ Specificity; D010950:Plasma Cells / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases