Differential Insulitic Profiles Determine the Extent of -Cell Destruction and the Age at Onset of Type 1 Diabetes
Differential Insulitic Profiles Determine the Extent of -Cell Destruction and the Age at Onset of Type 1 Diabetes
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DOI：
10.2337/db15-1615
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发表时间：
2016-05-01
期刊：
影响因子：
7.7
通讯作者：
Morgan, Noel G.
中科院分区：
文献类型：
--
作者：
Leete, Pia;Willcox, Abby;Morgan, Noel G.
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（胰岛素炎）后，T细胞介导的胰腺细胞破坏而引起的。最近，我们报道了两种不同类型的胰岛素炎发生在英国的新发T1D患者中，这两种类型的差异主要在于浸润CD20(+) B细胞的比例（分别称为CD20Hi和CD20Lo）。我们现在已经扩展了这一分析，包括来自糖尿病胰腺器官供体网络（美国）和糖尿病病毒检测（DiViD）研究（挪威）队列的患者，并确认这两种类型的胰岛素更广泛地发生。此外，我们表明患者可以根据他们的胰岛素谱直接分层，并且在7岁之前接受诊断的患者总是显示CD20Hi谱。相比之下，13岁以上接受诊断的个体被统一定义为CD20Lo。这意味着两种形式的胰岛素具有不同的侵袭性，CD20Hi型患者的-细胞丢失速度更快。为了支持这一点，我们还发现，在T1D发病时，残留含胰岛素胰岛（ICIs）的比例与年龄平行增加。重要的是，那些在青少年时期或之后接受诊断的患者在诊断时保留了大约40%的ICIs，这意味着功能缺陷而不是绝对的细胞损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胰岛浸润免疫细胞的T1D干预治疗的结果至关重要。
Type 1 diabetes (T1D) results from a T cell-mediated destruction of pancreatic -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 -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 approximate to 40% ICIs at diagnosis, implying that a functional deficit rather than an absolute -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.