Leete Pia, Willcox Abby, Krogvold Lars, Dahl-Jørgensen Knut, Foulis Alan K, Richardson Sarah J, Morgan Noel G
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K.
Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway.
Diabetes. 2016 May;65(5):1362-9. doi: 10.2337/db15-1615. Epub 2016 Feb 8.
Type 1 diabetes (T1D) results from a T cell-mediated destruction of pancreatic β-cells following the infiltration of leukocytes (including CD8(+), CD4(+), and CD20(+) cells) into and around pancreatic islets (insulitis). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the U.K. and that these differ principally in the proportion of infiltrating CD20(+) B cells (designated CD20Hi and CD20Lo, respectively). We have now extended this analysis to include patients from the Network for Pancreatic Organ Donors with Diabetes (U.S.) and Diabetes Virus Detection (DiViD) study (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals who received a diagnosis beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their β-cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at the onset of T1D. Importantly, those receiving a diagnosis in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than an absolute β-cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D.
1型糖尿病（T1D）是由于白细胞（包括CD8(+)、CD4(+)和CD20(+)细胞）浸润到胰岛及其周围（胰岛炎）后，T细胞介导的胰腺β细胞破坏所致。最近，我们报道了英国近期发病的T1D患者中出现了两种不同的胰岛炎模式，主要区别在于浸润的CD20(+) B细胞比例（分别称为CD20Hi和CD20Lo）。我们现在将这项分析扩展到包括来自美国胰腺器官捐赠者糖尿病网络和挪威糖尿病病毒检测（DiViD）研究队列的患者，并证实这两种胰岛炎模式更广泛地存在。此外，我们表明患者可以根据其胰岛炎模式直接分层，7岁前确诊的患者总是表现出CD20Hi模式。相比之下，13岁以后确诊的个体均被定义为CD20Lo。这意味着这两种胰岛炎形式具有不同的侵袭性，CD20Hi模式的患者β细胞丢失速度更快。支持这一点的是，我们还发现残余含胰岛素胰岛（ICI）的比例与T1D发病时的年龄平行增加。重要的是，在青少年时期或之后确诊的患者在确诊时保留约40%的ICI，这意味着功能缺陷而非绝对的β细胞丢失可能是这些患者发病的原因。我们得出结论，适当的患者分层对于正确解释针对T1D中胰岛浸润免疫细胞的干预治疗结果至关重要。
