Role of G-CSF and C-CSF receptor gene polymorphisms for the development of lupus nephritis

系统性红斑狼疮（SLE）是一种复杂的多基因疾病，是一种典型的抗体介导的自身免疫性疾病，其特征是产生针对多种自身抗原和免疫复合物（IC）型组织炎症的自身抗体，最显著的是在肾脏。在sled易感（NZB x NZW） Fl小鼠中，由于NZB和NZW菌株的易感基因的贡献，ic型狼疮性肾炎比亲本NZB更严重。我们对（NZB x NZW） Fl回交小鼠与NZB或NZW小鼠进行全基因组扫描，寻找狼疮性肾炎的易感基因。结果表明，位于第4染色体上Clq和G-CSF受体基因附近的NZB基因和位于第11染色体上G-CSF基因附近的NZW基因参与了严重肾炎的发生。Clq和G-CSF受体基因的序列和功能分析表明，4号染色体上的候选基因可能是Clq。G-CSF基因序列分析显示，NZB与NZW在3′UTR区存在序列多态性。可能由于这些多态性，NZW组巨噬细胞的G-CSF mRNA水平和G-CSF生产能力显著高于NZB组。此外，NZW组的外周中性粒细胞数量明显高于NZB组，NZW组的中性粒细胞似乎更活跃，通过细胞大小的增大来估计。此外，抗cd3抗体刺激的脾T细胞的体外细胞因子分析显示，G-CSF能够增强th2型细胞因子IL-4。综上所述，nzw型多态G-CSF基因可能与高G-CSF水平有关，而高G-CSF水平通过增加中性粒细胞数量和活性，以及通过高水平的Th2细胞因子产生上调ic形成，从而导致狼疮性肾炎易感性。

Systemic lupus erythematosus(SLE), a complex multigenic disease, is a typical antibody-mediated autoimmune disease characterized by production of autoantibodies against a variety of autoantigens and immune complex(IC)-type tissue inflammation, most prominently in the kidney. In SLE-prone (NZB x NZW) Fl mice, IC-type lupus nephritis more severe than parental NZB develop due to the contribution of susceptibility genes derived from both NZB and NZW strains. Our genome-wide scans to search for susceptibility genes for lupus nephritis in backcross mice of (NZB x NZW) Fl to NZB or NZW mice showed evidence that the NZB gene located in the vicinity of Clq and G-CSF receptor gene on chromosome 4 and NZW gene located in the vicinity of G-CSF gene on chromosome 11 are involved in severe nephritis. Sequence and functional analyses of Clq and G-CSF receptor genes revealed that the candidate gene on chromosome 4 seems to be Clq. Sequence analysis of G-CSF genes showed that there are sequence polymorphisms in 3' UTR region between NZB and NZW. Possibly due to these polymorphisms, G-CSF mRNA level and G-CSF production capacity by macrophages were significantly higher in NZW than in NZB. Furthermore, number of peripheral neutrophil was significantly higher in NZW than in NZB, and NZW neutrophil seemed to be more activated, estimated by enlarged cell size. In addition, in vitro cytokine analysis in anti-CD3 antibody-stimulated splenic T cells showed that G-CSF is able to enhance Th2-type cytokine, IL-4.Based on these findings, it was suggested that NZW-type polymorphic G-CSF gene possibly contribute to high G-CSF levels, which in turn contribute to the susceptibility to lupus nephritis due to the increase in neutrophil number and activity, and due to the up-regulation of IC-formation through the high level of Th2 cytokine production.