Systems Immunology Program and.
Diabetes Clinical Research Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
JCI Insight. 2019 Feb 21;4(4). doi: 10.1172/jci.insight.125556.
The rate of decline in insulin secretion after diagnosis with type 1 diabetes (T1D) varies substantially among individuals and with age at diagnosis, but the mechanism(s) behind this heterogeneity are not well understood. We investigated the loss of pancreatic β cell function in new-onset T1D subjects using unbiased whole blood RNA-seq and verified key findings by targeted cell count measurements. We found that patients who lost insulin secretion more rapidly had immune phenotypes ("immunotypes") characterized by higher levels of B cells and lower levels of neutrophils, especially neutrophils expressing primary granule genes. The B cell and neutrophil immunotypes showed strong age dependence, with B cell levels in particular predicting rate of progression in young subjects only. This age relationship suggested that therapy targeting B cells in T1D would be most effective in young subjects with high pretreatment B cell levels, a prediction which was supported by data from a clinical trial of rituximab in new-onset subjects. These findings demonstrate a link between age-related immunotypes and disease outcome in new-onset T1D. Furthermore, our data suggest that greater success could be achieved by targeted use of immunomodulatory therapy in specific T1D populations defined by age and immune characteristics.
1 型糖尿病（T1D）患者确诊后胰岛素分泌下降的速度在个体间和诊断时的年龄间存在很大差异，但这种异质性的机制尚不清楚。我们使用无偏倚的全血 RNA 测序研究了新诊断的 T1D 患者中胰岛β细胞功能的丧失，并通过靶向细胞计数测量验证了关键发现。我们发现，胰岛素分泌下降更快的患者具有免疫表型（“免疫型”），其特点是 B 细胞水平较高，中性粒细胞水平较低，尤其是表达初级颗粒基因的中性粒细胞。B 细胞和中性粒细胞免疫型具有强烈的年龄依赖性，尤其是 B 细胞水平仅能预测年轻患者的进展速度。这种年龄关系表明，针对 T1D 中 B 细胞的治疗在高预处理 B 细胞水平的年轻患者中最有效，这一预测得到了新诊断患者接受利妥昔单抗临床试验数据的支持。这些发现表明，在新诊断的 T1D 患者中，年龄相关的免疫型与疾病结局之间存在关联。此外，我们的数据表明，通过针对特定的 T1D 人群（根据年龄和免疫特征定义）使用免疫调节治疗，可能会取得更大的成功。
