B Cell–Specific Loss of Lyn Kinase Leads to Autoimmunity

• Published in: The Journal of immunology (1950) Vol. 192; no. 3; pp. 919 - 928
• Main Authors: Lamagna, Chrystelle, Hu, Yongmei, DeFranco, Anthony L, Lowell, Clifford A
• Format: Journal Article
• Language: English
• Published: United States 01.02.2014
• Subjects: Animals; Antibodies, Antinuclear - biosynthesis; Antibodies, Antinuclear - genetics; Antibodies, Antinuclear - immunology; Antibody Specificity; Autoimmunity - immunology; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; Calcium Signaling - immunology; Cell Count; Disease Models, Animal; Germinal Center - immunology; Germinal Center - pathology; Homeostasis; Immune Complex Diseases - immunology; Immune Complex Diseases - pathology; Immunoglobulin Class Switching; Immunoglobulin G - biosynthesis; Immunoglobulin G - immunology; Immunoglobulin M - biosynthesis; Immunoglobulin M - immunology; Kidney - immunology; Kidney - pathology; Lupus Nephritis - enzymology; Lupus Nephritis - etiology; Lupus Nephritis - immunology; Lymphocyte Activation; Lymphopoiesis - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - immunology; Myeloproliferative Disorders - enzymology; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - immunology; Organ Specificity; Plasma Cells - immunology; Spleen - immunology; Spleen - pathology; src-Family Kinases - deficiency; src-Family Kinases - genetics; src-Family Kinases - immunology; T-Lymphocyte Subsets - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1301979

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 lynflox/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 lynflox/floxCd79a-cre mice with myd88flox/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.