Complement facilitates early prion pathogenesis
Complement facilitates early prion pathogenesis
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DOI：
10.1038/86567
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发表时间：
2001-04-01
期刊：
影响因子：
82.9
通讯作者：
Aguzzi, A
中科院分区：
文献类型：
--
作者：
Klein, MA;Kaeser, PS;Aguzzi, A
新变种克雅氏病和痒病通常是由脑外暴露于病原体引起的，并在淋巴器官中表现出早期朊病毒复制(1,2)。在小鼠痒病中，B 淋巴细胞的耗竭可防止腹膜内接种后的神经发病(3,4)，这可能是由于滤泡树突状细胞 (5) (FDC) 的淋巴毒素依赖性成熟受损所致，而滤泡树突状细胞是主要的脑外朊病毒库 (6)。 FDC 与 Fc-gamma 受体捕获免疫复合物，并与 CD21/CD35 补体受体捕获 C3d/C4b 调理抗原。我们检查了这些机制是否参与外周朊病毒的发病机制。如果 B 细胞成熟不受影响，循环免疫球蛋白或单个 Fc-γ 受体的消耗对痒病发病机制没有影响。然而，缺乏C3、C1q、Bf/C2、其组合(7,8) 或补体受体(9) 的小鼠在腹膜内暴露于有限量的朊病毒后可部分或完全免受海绵状脑病的影响。脾脏中朊病毒感染性和 PrPSc 的积累被延迟，表明特定补体成分的激活参与了感染后早期淋巴网状器官中朊病毒的初始捕获。
New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs(1,2). In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation(3,4), probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells(5) (FDCs), which are a major extracerebral prion reservoir(6). FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof(7,8) or complement receptors(9) were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.