Genetic interdependence of lyn and negative regulators of B cell receptor signalling in autoimmune disease development

Evelyn Tsantikos, Mhairi Jane Maxwell, Nicole Kountouri, Kenneth W Harder, David M Tarlinton, Margaret Hibbs

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1726 - 1736
Number of pages11
JournalJournal of Immunology
Volume189
Issue number4
DOIs
Publication statusPublished - 2012

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