Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.
Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.
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DOI：
10.2337/db14-0213
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发表时间：
2014-10
期刊：
影响因子：
7.7
通讯作者：
Savinov AY
中科院分区：
文献类型：
--
作者：
Radichev IA;Maneva-Radicheva LV;Amatya C;Parker C;Ellefson J;Wasserfall C;Atkinson M;Burn P;Savinov AY
针对分泌胰岛素的胰腺β细胞的T细胞应答是突出1型糖尿病（T1 D）的关键事件。因此，T细胞活化的缺陷控制被认为是T1 D发展的基础。最近的研究涉及B7样负共刺激蛋白，V-set域含有T细胞活化抑制剂-1（VTCN 1），作为能够抑制T细胞活化的分子，并且可能是T1 D实验模型中的重要成分。在这里，我们揭示了VTCN 1通路中的一个普遍缺陷，该缺陷在糖尿病易感小鼠和T1 D患者的一个子集之间共享。抗原呈递细胞膜系VTCN 1的逐渐丧失与可溶性VTCN 1（sVTCN 1）释放增加的结合与自然T1 D发展平行发生，增强致糖尿病T细胞的过度增殖。从机制上讲，我们证明了膜系VTCN 1的损失与金属蛋白酶nardilysin介导的蛋白水解裂解有关。在53%的T1 D患者的外周血中检测到高水平的裂解sVTCN 1片段，而健康受试者中仅为9%。升高的血液sVTCN 1水平出现在疾病进展的早期，并与疾病的侵袭性步伐相关，突出了sVTCN 1作为新的T1 D生物标志物的潜在用途，并确定了nardilysin作为潜在的治疗靶点。
T-cell responses directed against insulin-secreting pancreatic β-cells are the key events highlighting type 1 diabetes (T1D). Therefore, a defective control of T-cell activation is thought to underlie T1D development. Recent studies implicated a B7-like negative costimulatory protein, V-set domain-containing T-cell activation inhibitor-1 (VTCN1), as a molecule capable of inhibiting T-cell activation and, potentially, an important constituent in experimental models of T1D. Here, we unravel a general deficiency within the VTCN1 pathway that is shared between diabetes-prone mice and a subset of T1D patients. Gradual loss of membrane-tethered VTCN1 from antigen-presenting cells combined with an increased release of soluble VTCN1 (sVTCN1) occurs in parallel to natural T1D development, potentiating hyperproliferation of diabetogenic T cells. Mechanistically, we demonstrate that the loss of membrane-tethered VTCN1 is linked to proteolytic cleavage mediated by the metalloproteinase nardilysin. The cleaved sVTCN1 fragment was detected at high levels in the peripheral blood of 53% T1D patients compared with only 9% of the healthy subjects. Elevated blood sVTCN1 levels appeared early in the disease progression and correlated with the aggressive pace of disease, highlighting the potential use of sVTCN1 as a new T1D biomarker, and identifying nardilysin as a potential therapeutic target.
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DOI：
10.1084/jem.20070432
发表时间：
2007-06-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Katschke KJ Jr;Helmy KY;Steffek M;Xi H;Yin J;Lee WP;Gribling P;Barck KH;Carano RA;Taylor RE;Rangell L;Diehl L;Hass PE;Wiesmann C;van Lookeren Campagne M
通讯作者：
van Lookeren Campagne M
影响因子：
15.8
作者：
Azuma T;Zhu G;Xu H;Rietz AC;Drake CG;Matteson EL;Chen L
通讯作者：
Chen L
影响因子：
2.2
作者：
LYONS, AB;PARISH, CR
通讯作者：
PARISH, CR
影响因子：
7
作者：
Haskins K;Cooke A
通讯作者：
Cooke A
影响因子：
15.9
作者：
Gaglia, Jason L.;Guimaraes, Alexander R.;Weissleder, Ralph
通讯作者：
Weissleder, Ralph