Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells
Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells
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DOI：
10.1038/15264
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发表时间：
1999-11-01
期刊：
影响因子：
82.9
通讯作者：
Bruce, ME
中科院分区：
文献类型：
--
作者：
Brown, KL;Stewart, K;Bruce, ME
免疫系统在羊瘙痒病和其他传染性海绵状脑病（TSE）或朊病毒病的发病机制中起着重要作用（1）。通过外周（腹膜内或口服）途径感染后，大多数TSE因子在神经侵袭前在脾脏和淋巴结中复制（2）。表征这些组织中支持复制的细胞对于理解早期发病机制至关重要，并且可能指示治疗的潜在靶点，例如，在“新变体”克雅氏病中。宿主“朊病毒”蛋白（PrP）是TSE因子复制所需的（3，4），并以修饰形式在感染组织中积累。在“新变异型”克雅氏病患者（5）、自然感染羊瘙痒症的绵羊（6）和实验感染羊瘙痒症的小鼠（7）的淋巴组织中，可在滤泡树突状细胞（FDC）上轻易检测到异常PrP。正常蛋白质存在于未感染小鼠的FDC上（7），并且以较低水平存在于淋巴细胞上（8）。使用严重联合免疫缺陷（SCID）小鼠进行的研究，有和没有骨髓（BM）移植物，表明FDC和/或淋巴细胞参与瘙痒病发病机制（9）。为了阐明FDC和淋巴细胞的不同作用，我们通过将PrP缺陷敲除小鼠（4）的骨髓移植到PrP表达小鼠中，反之亦然，从而产生了FDC和免疫系统其他细胞之间PrP状态不匹配的嵌合小鼠。使用这些嵌合模型，我们获得了强有力的证据，FDCs本身产生PrP和复制的小鼠传代羊瘙痒病株在脾脏依赖于PrP表达FDCs，而不是淋巴细胞或其他骨髓来源的细胞。
The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases(1). After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion(2). Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication(3,4) and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease(5), sheep with natural scrapie(6) and mice experimentally infected with scrapie(7). The normal protein is present on FDCs in uninfected mice(7) and, at lower levels, on lymphocytes(8). Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis(9). To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice(4) into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.