Measles immune suppression: lessons from the macaque model.
Measles immune suppression: lessons from the macaque model.
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DOI：
10.1371/journal.ppat.1002885
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
de Swart RL
中科院分区：
文献类型：
--
作者：
de Vries RD;McQuaid S;van Amerongen G;Yüksel S;Verburgh RJ;Osterhaus AD;Duprex WP;de Swart RL
麻疹仍然是一种重要的儿童疾病，与短暂的免疫抑制有关。麻疹病毒（MV）感染也会引起强烈的MV特异性免疫应答。目前关于麻疹免疫抑制机制的假说主要集中在由MV感染或暴露引起的淋巴细胞或抗原呈递细胞的功能受损。我们已经产生了稳定的重组MV，其表达增强的绿色荧光蛋白，并且在非人灵长类动物中保持毒性。通过对MV感染后不同时间点安乐死动物的病毒学、免疫学、血液学和组织病理学观察进行综合研究，我们建立了一个符合“麻疹悖论”的麻疹免疫抑制模型。在这里，我们发现MV优先感染CD 45 RA-记忆T淋巴细胞和滤泡B淋巴细胞，导致这些人群中的高感染水平。在病毒血症高峰后，MV感染的淋巴细胞在几天内被清除，随后是免疫激活和淋巴结肿大。在此期间，结核菌素特异性T淋巴细胞反应消失，而出现了强烈的MV特异性T淋巴细胞反应。淋巴组织的组织学分析显示，在不存在凋亡细胞的情况下，B和T细胞区域中的淋巴细胞耗竭，随后T淋巴细胞浸润到B细胞滤泡中并重新出现增殖细胞。我们的研究结果表明，MV感染的CD 45 RA-记忆T淋巴细胞和滤泡B淋巴细胞的免疫介导的清除，导致暂时的免疫遗忘。MV特异性淋巴细胞和旁观者细胞的快速寡克隆扩增掩盖了这种消耗，解释了麻疹淋巴细胞减少症持续时间短但免疫抑制持续时间长的原因。麻疹与短暂的免疫抑制有关，导致对机会性感染的易感性增加。事实上，麻疹死亡的主要原因是呼吸道和消化道的继发感染。虽然麻疹与淋巴细胞减少症有关，但淋巴细胞的耗竭通常被认为是免疫抑制的原因。淋巴细胞计数在病毒清除后迅速恢复正常，而免疫抑制持续数周至数月。许多研究集中在淋巴细胞增殖的抑制作为免疫抑制的体外相关性。然而，非人灵长类动物的实验感染表明，麻疹后体内淋巴细胞增殖不受影响。相反，我们假设MV特异性和旁观者淋巴细胞的大量扩增掩盖了预先存在的记忆淋巴细胞已经耗尽的事实。我们的结论是，麻疹病毒感染消除了免疫记忆，使个人容易受到通常由免疫系统控制的机会性感染因子的影响。
Measles remains a significant childhood disease, and is associated with a transient immune suppression. Paradoxically, measles virus (MV) infection also induces robust MV-specific immune responses. Current hypotheses for the mechanism underlying measles immune suppression focus on functional impairment of lymphocytes or antigen-presenting cells, caused by infection with or exposure to MV. We have generated stable recombinant MVs that express enhanced green fluorescent protein, and remain virulent in non-human primates. By performing a comprehensive study of virological, immunological, hematological and histopathological observations made in animals euthanized at different time points after MV infection, we developed a model explaining measles immune suppression which fits with the “measles paradox”. Here we show that MV preferentially infects CD45RA− memory T-lymphocytes and follicular B-lymphocytes, resulting in high infection levels in these populations. After the peak of viremia MV-infected lymphocytes were cleared within days, followed by immune activation and lymph node enlargement. During this period tuberculin-specific T-lymphocyte responses disappeared, whilst strong MV-specific T-lymphocyte responses emerged. Histopathological analysis of lymphoid tissues showed lymphocyte depletion in the B- and T-cell areas in the absence of apoptotic cells, paralleled by infiltration of T-lymphocytes into B-cell follicles and reappearance of proliferating cells. Our findings indicate an immune-mediated clearance of MV-infected CD45RA− memory T-lymphocytes and follicular B-lymphocytes, which causes temporary immunological amnesia. The rapid oligoclonal expansion of MV-specific lymphocytes and bystander cells masks this depletion, explaining the short duration of measles lymphopenia yet long duration of immune suppression. Measles is associated with a transient immune suppression, resulting in increased susceptibility to opportunistic infections. Indeed, the main causes of measles mortality are secondary infections in the respiratory and digestive tract. Although measles is associated with lymphopenia, depletion of lymphocytes has often been dismissed as a cause of immune suppression. Lymphocyte counts rapidly return to normal after clearance of the virus, while immune suppression lasts several weeks to months. Many studies have focused on suppression of lymphocyte proliferation as an in vitro correlate of immune suppression. However, experimental infections of non-human primates show that in vivo lymphocyte proliferation is not impaired after measles. Instead, we hypothesize that massive expansion of MV-specific and bystander lymphocytes masks the fact that pre-existing memory lymphocytes have been depleted. We conclude that measles virus infection wipes out immunological memory, leaving individuals susceptible to opportunistic infectious agents that would normally be controlled by the immune system.
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影响因子：
8.7
作者：
Griffin DE
通讯作者：
Griffin DE
影响因子：
6.7
作者：
de Witte, Lot;de Vries, Rory D.;van der Vlist, Michiel;Yuksel, Selma;Litjens, Manja;de Swart, Rik L.;Geijtenbeek, Teunis B. H.
通讯作者：
Geijtenbeek, Teunis B. H.
DOI：
10.1016/0090-1229(84)90184-3
发表时间：
1984-01-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
HIRSCH, RL;GRIFFIN, DE;VAISBERG, A
通讯作者：
VAISBERG, A
影响因子：
4.4
作者：
De Salort, Jose;Sintes, Jordi;Engel, Pablo
通讯作者：
Engel, Pablo
DOI：
10.1073/pnas.201404898
发表时间：
2001-09-25
影响因子：
11.1
作者：
Langermans, JAM;Andersen, P;Thomas, AW
通讯作者：
Thomas, AW