Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice.
Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice.
复制标题
DOI：
10.1002/eji.201343376
复制
发表时间：
2013-10
影响因子：
5.4
通讯作者：
Dai, Yang D.
中科院分区：
文献类型：
--
作者：
Bashratyan, Roman;Sheng, Huiming;Regn, Danielle;Rahman, M. Jubayer;Dai, Yang D.
Exosome(EXOS)是一种纳米级的分泌型微囊，可以作为佐剂和抗原的内源性载体发挥作用。为了研究EXOS在自身免疫中的可能作用，我们研究了EXO在非肥胖糖尿病(NOD)小鼠中诱导的免疫反应，NOD是一种组织特异性靶向于胰岛素分泌的β细胞的自身免疫易感品系。胰岛素瘤细胞释放的EXOS可激活多种抗原提呈细胞，分泌多种促炎细胞因子和趋化因子。B细胞亚群对EXO刺激的反应是增殖，并表达代表边缘带(MZ)B细胞的表面标志，这与辅助性T细胞无关。重要的是，糖尿病前期NOD鼠的脾B细胞对EXOS的反应性增强，这与高水平的血清EXOS有关。我们发现MyD88介导的天然TLR信号对B细胞的反应是必不可少的；表达胰岛素特异性表面免疫球蛋白的转基因B细胞对EXO刺激发生反应，钙调神经磷酸酶抑制剂FK506的加入抑制了EXO诱导的B细胞反应，这表明固有信号和抗原特异性信号可能都参与了这一反应。因此，EXOS可能部分通过激活自身反应性MZ样B细胞，促进NOD小鼠自身免疫和1型糖尿病(T1D)的发生。
Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in non-obese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone (MZ) B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes (T1D) in NOD mice, partially via activating autoreactive MZ-like B cells.
登录
查看更多内容
影响因子：
4.4
作者：
Kanayama, N;Cascalho, M;Ohmori, H
通讯作者：
Ohmori, H
影响因子：
3.8
作者：
Matyas, Gary R.;Wieczorek, Lindsay;Alving, Carl R.
通讯作者：
Alving, Carl R.
影响因子：
64.8
作者：
Nakayama, M;Abiru, N;Eisenbarth, GS
通讯作者：
Eisenbarth, GS
影响因子：
20.3
作者：
Qazi, Khaleda Rahman;Gehrmann, Ulf;Gabrielsson, Susanne
通讯作者：
Gabrielsson, Susanne
影响因子：
5.4
作者：
Barr, Tom A;Brown, Sheila;Ryan, Gemma;Zhao, Jiexin;Gray, David
通讯作者：
Gray, David