Genetic interdependence of Lyn and negative regulators of B cell receptor signaling in autoimmune disease development.

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.

• Authors: Evelyn Tsantikos, Mhairi J Maxwell, Nicole Kountouri, Kenneth W Harder, David M Tarlinton, Margaret L Hibbs
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 4 Pg. 1726-36 (Aug 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22798664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Antigen, B-Cell
• lyn protein-tyrosine kinase
• src-Family Kinases

Topics

• Animals
• Autoimmune Diseases (genetics, immunology, pathology)
• B-Lymphocytes (immunology, pathology)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Glomerulonephritis (genetics, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Receptors, Antigen, B-Cell (immunology)
• Signal Transduction (genetics, immunology)
• src-Family Kinases (genetics, immunology)