PDF(Pubmed)
Abstract：
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that displays considerable heterogeneity not only in its symptoms, but also in its environmental and genetic causes. Studies in SLE patients have revealed that many genetic variants contribute to disease development. However, often its etiology remains unknown. Existing efforts to determine this etiology have focused on SLE in mouse models revealing not only that mutations in specific genes lead to SLE development, but also that epistatic effects of several gene mutations significantly amplify disease manifestation. Genome-wide association studies for SLE have identified loci involved in the two biological processes of immune complex clearance and lymphocyte signaling. Deficiency in an inhibitory receptor expressed on B lymphocytes, Siglec-G, has been shown to trigger SLE development in aging mice, as have mutations in DNA degrading DNase1 and DNase1l3, that are involved in clearance of DNA-containing immune complexes. Here, we analyze the development of SLE-like symptoms in mice deficient in either Siglecg and DNase1 or Siglecg and DNase1l3 to evaluate potential epistatic effects of these genes. We found that germinal center B cells and follicular helper T cells were increased in aging Siglecg -/- x Dnase1 -/- mice. In contrast, anti-dsDNA antibodies and anti-nuclear antibodies were strongly increased in aging Siglecg-/- x Dnase1l3-/- mice, when compared to single-deficient mice. Histological analysis of the kidneys revealed glomerulonephritis in both Siglecg -/- x Dnase1 -/- and Siglecg-/- x Dnase1l3-/- mice, but with a stronger glomerular damage in the latter. Collectively, these findings underscore the impact of the epistatic effects of Siglecg with DNase1 and Dnase1l3 on disease manifestation and highlight the potential combinatory effects of other gene mutations in SLE.
摘要：
系统性红斑狼疮（SLE）是一种严重的自身免疫性疾病，不仅在症状上表现出相当大的异质性，但也有其环境和遗传原因。对SLE患者的研究表明，许多遗传变异有助于疾病的发展。然而,通常其病因仍然未知。确定这种病因的现有努力集中在小鼠模型中的SLE上，不仅揭示了特定基因的突变导致SLE的发展。而且，几种基因突变的上位效应显着放大了疾病的表现。SLE的全基因组关联研究已经确定了参与免疫复合物清除和淋巴细胞信号传导这两个生物学过程的基因座。B淋巴细胞上表达的抑制性受体缺乏，Siglec-G,已被证明会引发衰老小鼠的SLE发展，在DNA降解DNase1和DNase1l3中存在突变，这些突变与清除含DNA的免疫复合物有关。这里,我们分析了缺乏Siglecg和DNase1或Siglecg和DNase1l3的小鼠中SLE样症状的发展，以评估这些基因的潜在上位效应。我们发现，衰老的Siglecg-/-xDnase1-/-小鼠的生发中心B细胞和滤泡辅助性T细胞增加。相比之下,抗dsDNA抗体和抗核抗体在衰老的Siglecg-/-xDnase1l3-/-小鼠中强烈增加，与单一缺陷小鼠相比。肾脏的组织学分析显示Siglecg-/-xDnase1-/-和Siglecg-/-xDnase1l3-/-小鼠的肾小球肾炎，但后者的肾小球损伤更强。总的来说，这些发现强调了Siglecg与DNase1和Dnase1l3的上位效应对疾病表现的影响,并强调了SLE中其他基因突变的潜在组合效应.
