Genetic interdependence of Lyn and negative regulators of B cell receptor signaling in autoimmune disease development.
Ab-mediated autoimmune disease is multifaceted and may involve many susceptibility loci. The majority of autoimmune patients are thought to have polymorphisms in a number of genes that interact in different combinations to contribute to disease pathogenesis. Studies in mice and humans have implicated the Lyn protein tyrosine kinase as a regulator of Ab-mediated autoimmune disease. To examine whether haploinsufficiency of Lyn gives rise to cellular and clinical manifestations of autoimmune disease, we evaluated the phenotype of Lyn(+/-) mice. We find that their B cell compartment is significantly perturbed, with reduced numbers of marginal zone and transitional stage 2 B cells, expansion of plasma cells, downregulation of surface IgM, and upregulation of costimulatory molecules. Biochemical studies show that Lyn(+/-) B cells have defects in negative regulation of signaling, whereas Lyn(+/-) mice develop IgG autoantibodies and glomerulonephritis with age. Because Lyn has a pivotal role in the activation of inhibitory phosphatases, we generated mice harboring double heterozygous loss-of-function mutations in Lyn and SHP-1 or Lyn and SHIP-1. Partial inactivation of SHP-1 or SHIP-1 amplifies the consequence of Lyn haploinsufficiency, leading to an accelerated development of autoantibodies and disease. Our data also reveal that the BALB/c background is protective against autoimmune-mediated glomerulonephritis, even in the face of high titer autoantibodies, whereas the C57BL/6 background is susceptible. This study demonstrates that Lyn is a haploinsufficient gene in autoimmune disease and importantly shows that quantitative genetic variation in Lyn-regulated pathways can mirror the complete loss of a single critical inhibitory molecule.
Leukocyte Signaling Laboratory, Department of Immunology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
Evelyn
E
Tsantikos
Mhairi J
MJ
Maxwell
Nicole
N
Kountouri
Kenneth W
KW
Harder
David M
DM
Tarlinton
Margaret L
ML
Hibbs
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics* / Q000276:immunology
D011947:Receptors, Antigen, B-Cell; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases