Cunningham Melissa A, Wirth Jena R, Scott Jennifer L, Eudaly Jackie, Collins Erin L, Gilkeson Gary S
Division of Rheumatology and Immunology, Ralph H. Johnson Veterans Affairs Hospital, Medical University of South Carolina , Charleston, SC , USA.
Front Immunol. 2016 Feb 15;7:31. doi: 10.3389/fimmu.2016.00031. eCollection 2016.
Ninety percent of those diagnosed with systemic lupus erythematosus are female, with peak incidence between the ages of 15 and 45, when women are most hormonally active. Despite significant research effort, the mechanisms underlying this sex bias remain unclear. We previously showed that a functional knockout of estrogen receptor alpha (ERα) resulted in significantly reduced renal disease and increased survival in murine lupus. Dendritic cell (DC) development, which requires both estrogen and ERα, is impacted, as is activation status and cytokine production. Since both estrogen and testosterone levels have immunomodulating effects, we presently studied the phenotype of NZM2410 lupus-prone mice following post- and prepubertal ovariectomy (OVX) ± estradiol (E2) replacement to determine the impact of hormonal status on disease expression and DC development in these mice. We observed a trend toward survival benefit in addition to decreased proteinuria and improved renal histology in the early OVX, but not late OVX- or E2-repleted WT mice. Interestingly, there was also a significant difference in splenic DC subsets by flow cytometry. Spleens from NZM mice OVX'd early had a significant decrease in proinflammatory CD11c+CD11b+ DCs (vs. unmanipulated WTs, late OVX- and E2-repleted mice). These early OVX'd animals also had a significant increase in tolerogenic CD11c+CD8a+ DCs vs. WT. These data join a growing body of evidence that supports a role for hormone modulation of DCs that likely impacts the penetrance and severity of autoimmune diseases, such as lupus.
被诊断为系统性红斑狼疮的患者中90%为女性，发病高峰在15至45岁之间，此时女性的激素最为活跃。尽管进行了大量研究，但这种性别差异背后的机制仍不清楚。我们之前发现，雌激素受体α（ERα）功能敲除可显著减轻小鼠狼疮的肾脏疾病并提高生存率。树突状细胞（DC）的发育需要雌激素和ERα，其激活状态和细胞因子产生也会受到影响。由于雌激素和睾酮水平都具有免疫调节作用，我们目前研究了青春期后和青春期前卵巢切除（OVX）±雌二醇（E2）替代的NZM2410狼疮易感小鼠的表型，以确定激素状态对这些小鼠疾病表达和DC发育的影响。我们观察到，早期OVX小鼠除了蛋白尿减少和肾脏组织学改善外，还有生存获益的趋势，但晚期OVX或E2补充的野生型小鼠则没有。有趣的是，通过流式细胞术检测脾DC亚群也有显著差异。早期进行OVX的NZM小鼠脾脏中促炎性CD11c+CD11b+ DC显著减少（与未处理的野生型、晚期OVX和E2补充的小鼠相比）。与野生型相比，这些早期进行OVX的动物中耐受性CD11c+CD8a+ DC也显著增加。这些数据加入了越来越多的证据，支持激素对DC的调节作用可能影响自身免疫性疾病（如狼疮）的发病率和严重程度。
