Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice.
Relative Impact of Complement Receptors CD21/35 (Cr2/1) on Scrapie Pathogenesis in Mice.
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DOI：
10.1128/mspheredirect.00493-17
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发表时间：
2017-11
期刊：
影响因子：
4.8
通讯作者：
Zabel MD
中科院分区：
文献类型：
--
作者：
Kane SJ;Swanson E;Gordon EO;Rocha S;Bender HR;Donius LR;Aguzzi A;Hannan JP;Zabel MD
哺乳动物朊病毒疾病是由朊病毒引起的，朊病毒是一种独特的感染因子，主要（如果不是完全）由正常宿主蛋白——细胞朊病毒蛋白（PrPC）的病理性错误折叠形式组成。朊病毒在没有遗传蓝图的情况下进行复制，而是接触 PrPC 并迫使其错误折叠成更多朊病毒，从而导致神经变性，类似于其他蛋白质错误折叠疾病（如阿尔茨海默病）。单个基因产生两个选择性剪接的 mRNA 转录物，编码小鼠补体受体 CD21/35，促进朊病毒在淋巴系统中有效复制并最终移动到大脑。在这里，我们表明CD21/35是高亲和力朊病毒受体，但仅表达CD21的小鼠比表达CD35的小鼠更早死于朊病毒疾病，而表达CD35的小鼠在感染后早期含有较少的朊病毒并表现出迟发性终末期疾病，这可能是由于它们的脾滤泡组织较差。因此，CD21 似乎对于定义影响朊病毒发病机制的脾结构更为重要。补体受体 1 和 2（CR1/2 或 CD35/CD21）识别补体调理抗原，分别启动先天免疫和适应性免疫。 CD35 刺激巨噬细胞的吞噬作用和滤泡树突状细胞 (FDC) 上的抗原呈递。 CD21 作为 B 细胞辅助受体的一部分与 CD19 和 CD81 一起帮助激活 B 细胞。小鼠 Cr2 基因转录物的差异剪接产生具有共享和独特的补体结合能力和细胞类型表达的同种型。在小鼠模型中，Cr2 基因缺失会导致朊病毒病的延迟或完全预防，但 CD35 与 CD21 在促进朊病毒病方面的相对重要性仍不清楚。在这里，我们证明两种亚型都充当高亲和力的细胞表面朊病毒受体。然而，缺乏CD21的小鼠死于终末朊病毒病的时间明显晚于缺乏CD35的小鼠或野生型和半合子小鼠。感染后早期，CD21缺陷型小鼠的脾脏朊病毒含量比CD35敲除小鼠少，这导致了朊病毒神经侵袭延迟和晚期疾病，尽管形成了更靠近近端神经的滤泡网络。虽然我们观察到 B 细胞网络、PrPC 表达或卵泡数量没有差异，但与野生型或 CD35 缺陷型小鼠相比，CD21 缺陷型小鼠形成了更多碎片化、组织性较差的滤泡网络，其中 Mfge8 阳性 FDC 和/或可染体巨噬细胞 (TBMφ) 更少。总而言之，这些数据表明，与表达 CD35 同种型的小鼠相比，CD21 对于正确的卵泡发育和组织具有更重要的作用，从而导致更有效的淋巴朊病毒复制和加速朊病毒疾病。重要性 哺乳动物朊病毒疾病是由朊病毒引起的，朊病毒是一种独特的感染因子，主要（如果不是完全）由正常宿主蛋白——细胞朊病毒蛋白（PrPC）的病理性错误折叠形式组成。朊病毒在没有遗传蓝图的情况下进行复制，而是接触 PrPC 并迫使其错误折叠成更多朊病毒，从而导致神经变性，类似于其他蛋白质错误折叠疾病（如阿尔茨海默病）。单个基因产生两个选择性剪接的 mRNA 转录物，编码小鼠补体受体 CD21/35，促进朊病毒在淋巴系统中有效复制并最终移动到大脑。在这里，我们表明CD21/35是高亲和力朊病毒受体，但仅表达CD21的小鼠比表达CD35的小鼠更早死于朊病毒疾病，而表达CD35的小鼠在感染后早期含有较少的朊病毒并表现出迟发性终末期疾病，这可能是由于它们的脾滤泡组织较差。因此，CD21 似乎对于定义影响朊病毒发病机制的脾结构更为重要。
Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer’s disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis. Complement receptors 1 and 2 (CR1/2 or CD35/CD21) recognize complement-opsonized antigens to initiate innate and adaptive immunity, respectively. CD35 stimulates phagocytosis on macrophages and antigen presentation on follicular dendritic cells (FDCs). CD21 helps activate B cells as part of the B cell coreceptor with CD19 and CD81. Differential splicing of transcripts from the mouse Cr2 gene generates isoforms with both shared and unique complement binding capacities and cell-type expression. In mouse models, genetic depletion of Cr2 causes either a delay or complete prevention of prion disease, but the relative importance of CD35 versus CD21 in promoting prion disease remains unknown. Here we show that both isoforms act as high-affinity cell surface prion receptors. However, mice lacking CD21 succumbed to terminal prion disease significantly later than mice lacking CD35 or wild-type and hemizygous mice. CD21-deficient mice contained fewer splenic prions than CD35 knockout mice early after infection that contributed to delayed prion neuroinvasion and terminal disease, despite forming follicular networks closer to proximal nerves. While we observed no difference in B cell networks, PrPC expression, or number of follicles, CD21-deficient mice formed more fragmented, less organized follicular networks with fewer Mfge8-positive FDCs and/or tingible body macrophages (TBMφs) than wild-type or CD35-deficient mice. In toto, these data demonstrate a more prominent role for CD21 for proper follicular development and organization leading to more efficient lymphoid prion replication and expedited prion disease than in mice expressing the CD35 isoform. IMPORTANCE Mammalian prion diseases are caused by prions, unique infectious agents composed primarily, if not solely, of a pathologic, misfolded form of a normal host protein, the cellular prion protein (PrPC). Prions replicate without a genetic blueprint, but rather contact PrPC and coerce it to misfold into more prions, which cause neurodegeneration akin to other protein-misfolding diseases like Alzheimer’s disease. A single gene produces two alternatively spliced mRNA transcripts that encode mouse complement receptors CD21/35, which promote efficient prion replication in the lymphoid system and eventual movement to the brain. Here we show that CD21/35 are high-affinity prion receptors, but mice expressing only CD21 die from prion disease sooner than CD35-expressing mice, which contain less prions early after infection and exhibit delayed terminal disease, likely due to their less organized splenic follicles. Thus, CD21 appears to be more important for defining splenic architecture that influences prion pathogenesis.