von Herrath M, Holz A
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Autoimmun. 1997 Jun;10(3):231-8. doi: 10.1006/jaut.1997.0131.
RIP-LCMV transgenic mice that express the viral glycoprotein (GP) or nucleoprotein (NP) from lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta-cells develop autoimmune diabetes (IDDM) after infection with LCMV. Previous reports have described that the viral infection activates naive, potentially autoreactive CD8+ cytotoxic T-lymphocytes (CTL) that are present in the periphery of these mice, thus leading to the breaking of immunological unresponsiveness to the viral self-antigen expressed on beta-cells. However, we find that adoptive transfer of such CTL that were active in vitro and in vivo into uninfected RIP-LCMV recipients rarely resulted in hyperglycemia nor in insulitis, despite their ability to home to the islets and induce peri-insulitis. These observations indicated that, in addition to activated autoreactive lymphocytes, other factor(s) were required for beta-cell destruction. The present study shows that upregulation of MHC class II molecules associated with the attraction/activation of antigen presenting cells (APCs) to the islets occurs as soon as 2 days after LCMV inoculation of transgenic mice, clearly before CD4+ and CD8+ lymphocytes are found entering the islets (days 6 and 7 after LCMV inoculation). In contrast, although some MHC class II upregulation is also found in islets of non-transgenic mice 2-4 days after LCMV infection, no insulitis or IDDM develops and MHC is downregulated to normal (pre-infection) levels by day 7-10 in these mice. Associated with the activation of APCs and MHC upregulation observed in transgenic mice, viral (LCMV) infection of islets was detectable 2 days post-viral inoculation in some mice. Thus, beta-cell destruction by activated autoreactive lymphocytes is a multifactorial process that is likely to require changes within the islet milieu or dysfunction of islets.
在大鼠胰岛素启动子（RIP）控制下，胰腺β细胞中表达来自淋巴细胞性脉络丛脑膜炎病毒（LCMV）的病毒糖蛋白（GP）或核蛋白（NP）的RIP-LCMV转基因小鼠，在感染LCMV后会发生自身免疫性糖尿病（IDDM）。先前的报道描述，病毒感染会激活这些小鼠外周存在的幼稚、潜在自身反应性CD8 + 细胞毒性T淋巴细胞（CTL），从而导致对β细胞上表达的病毒自身抗原的免疫无反应性被打破。然而，我们发现，将在体外和体内都具有活性的此类CTL过继转移到未感染的RIP-LCMV受体小鼠中，尽管它们能够归巢到胰岛并诱导胰岛周围炎，但很少导致高血糖或胰岛炎。这些观察结果表明，除了活化的自身反应性淋巴细胞外，β细胞破坏还需要其他因素。本研究表明，转基因小鼠接种LCMV后2天，与抗原呈递细胞（APC）向胰岛的吸引/活化相关的MHC II类分子上调就会发生，明显早于发现CD4 + 和CD8 + 淋巴细胞进入胰岛（接种LCMV后第6天和第7天）。相比之下，虽然在LCMV感染后2 - 4天，非转基因小鼠的胰岛中也发现了一些MHC II类上调，但这些小鼠没有发生胰岛炎或IDDM，并且到第7 - 10天，MHC下调至正常（感染前）水平。与转基因小鼠中观察到的APC活化和MHC上调相关联，在一些小鼠中，病毒接种后2天可检测到胰岛的病毒（LCMV）感染。因此，活化的自身反应性淋巴细胞对β细胞的破坏是一个多因素过程，可能需要胰岛微环境内的变化或胰岛功能障碍。
