Leukocyte Signaling Laboratory, Department of Immunology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
J Immunol. 2012 Aug 15;189(4):1726-36. doi: 10.4049/jimmunol.1103427. Epub 2012 Jul 13.
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.
Ab 介导的自身免疫性疾病是多方面的，可能涉及许多易感基因座。大多数自身免疫性疾病患者被认为存在许多基因的多态性，这些基因以不同的组合相互作用，导致疾病的发病机制。在小鼠和人类中的研究表明，Lyn 蛋白酪氨酸激酶是 Ab 介导的自身免疫性疾病的调节因子。为了研究 Lyn 单倍不足是否会导致 Ab 介导的自身免疫性疾病的细胞和临床表型，我们评估了 Lyn(+/-)小鼠的表型。我们发现它们的 B 细胞区室受到显著干扰，边缘区和过渡阶段 2 B 细胞数量减少，浆细胞扩增，表面 IgM 下调，共刺激分子上调。生化研究表明，Lyn(+/-)B 细胞在信号转导的负调节中存在缺陷，而 Lyn(+/-)小鼠随着年龄的增长会发展出 IgG 自身抗体和肾小球肾炎。由于 Lyn 在激活抑制性磷酸酶中起着关键作用，我们生成了 Lyn 和 SHP-1 或 Lyn 和 SHIP-1 双杂合功能丧失突变的小鼠。SHP-1 或 SHIP-1 的部分失活放大了 Lyn 单倍不足的后果，导致自身抗体和疾病的加速发展。我们的数据还表明，即使在高滴度自身抗体的情况下，BALB/c 背景对自身免疫性肾小球肾炎具有保护作用，而 C57BL/6 背景则易感。这项研究表明，Lyn 是自身免疫性疾病中的单倍不足基因，重要的是表明 Lyn 调节途径中的定量遗传变异可以反映单个关键抑制性分子的完全缺失。
