Genetic Interdependence of Lyn and Negative Regulators of B Cell Receptor Signaling in Autoimmune Disease Development
- Author(s)
- Tsantikos, E; Maxwell, MJ; Kountouri, N; Harder, KW; Tarlinton, DM; Hibbs, ML;
- Details
- Publication Year 2012-08-15,Volume 189,Issue #4,Page 1726-1736
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- Abstract
- 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. The Journal of Immunology, 2012, 189: 1726-1736.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- SYSTEMIC-LUPUS-ERYTHEMATOSUS; DEFICIENT MICE; TYROSINE KINASE; AUTOANTIBODY PRODUCTION; SERUM IMMUNOGLOBULINS; VIABLE MOTHEATEN; PIR-B; SHIP; CD22; ACTIVATION
- Research Division(s)
- Immunology
- Publisher's Version
- https://doi.org/10.4049/jimmunol.1103427
- Terms of Use/Rights Notice
- Copyright ©2013 by The American Association of Immunologists, Inc. All rights reserved
Creation Date: 2012-08-15 12:00:00