McGovern Gillian, Jeffrey Martin
Veterinary Laboratories Agency Lasswade, Pentlands Science Park, Bush Loan, Penicuik, Midlothian, United Kingdom.
PLoS One. 2007 Dec 12;2(12):e1304. doi: 10.1371/journal.pone.0001304.
Transmissible spongiform encephalopathies (TSEs) or prion diseases often result in accumulation of disease-associated PrP (PrP(d)) in the lymphoreticular system (LRS), specifically in association with follicular dendritic cells (FDCs) and tingible body macrophages (TBMs) of secondary follicles. We studied the effects of sheep scrapie on lymphoid tissue in tonsils and lymph nodes by light and electron microscopy. FDCs of sheep were grouped according to morphology as immature, mature or regressing. Scrapie was associated with FDC dendrite hypertrophy and electron dense deposit or vesicles. PrP(d) was located using immunogold labelling at the plasmalemma of FDC dendrites and, infrequently, mature B cells. Abnormal electron dense deposits surrounding FDC dendrites were identified as immunoglobulins suggesting that excess immune complexes are retained and are indicative of an FDC dysfunction. Within scrapie-affected lymph nodes, macrophages outside the follicle and a proportion of germinal centre TBMs accumulated PrP(d) within endosomes and lysosomes. In addition, TBMs showed PrP(d) in association with the cell membrane, non-coated pits and vesicles, and also with discrete, large and random endoplasmic reticulum networks, which co-localised with ubiquitin. These observations suggest that PrP(d) is internalised via the caveolin-mediated pathway, and causes an abnormal disease-related alteration in endoplasmic reticulum structure. In contrast to current dogma, this study shows that sheep scrapie is associated with cytopathology of germinal centres, which we attribute to abnormal antigen complex trapping by FDCs and abnormal endocytic events in TBMs. The nature of the sub-cellular changes in FDCs and TBMs differs from those of scrapie infected neurones and glial cells suggesting that different PrP(d)/cell membrane interactions occur in different cell types.
传染性海绵状脑病（TSEs）或朊病毒病通常会导致疾病相关的朊蛋白（PrP(d)）在淋巴网状系统（LRS）中积累，特别是与次级滤泡的滤泡树突状细胞（FDCs）和可染小体巨噬细胞（TBMs）相关。我们通过光学显微镜和电子显微镜研究了绵羊瘙痒病对扁桃体和淋巴结中淋巴组织的影响。绵羊的FDCs根据形态分为未成熟、成熟或退化型。瘙痒病与FDC树突肥大以及电子致密沉积物或小泡有关。使用免疫金标记在FDC树突的质膜上定位PrP(d)，偶尔也在成熟B细胞上定位。FDC树突周围异常的电子致密沉积物被鉴定为免疫球蛋白，表明过量的免疫复合物被保留，这表明FDC功能障碍。在受瘙痒病影响的淋巴结内，滤泡外的巨噬细胞和一部分生发中心TBMs在内体和溶酶体内积累了PrP(d)。此外，TBMs的细胞膜、无被小窝和小泡以及离散的、大的和随机的内质网网络中也显示有PrP(d)，这些内质网网络与泛素共定位。这些观察结果表明，PrP(d)通过小窝蛋白介导的途径内化，并导致内质网结构发生异常的疾病相关改变。与当前的观点相反，本研究表明绵羊瘙痒病与生发中心的细胞病理学有关，我们将其归因于FDCs对异常抗原复合物的捕获以及TBMs中异常的内吞事件。FDCs和TBMs亚细胞变化的性质与瘙痒病感染的神经元和胶质细胞不同，这表明不同细胞类型中发生了不同的PrP(d)/细胞膜相互作用。
