Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes.
Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: functional role of exosomes.
复制标题
DOI：
10.1186/s40169-018-0204-7
复制
发表时间：
2018-08-27
影响因子：
10.6
通讯作者：
Jacobson S
中科院分区：
文献类型：
--
作者：
Anderson MR;Pleet ML;Enose-Akahata Y;Erickson J;Monaco MC;Akpamagbo Y;Velluci A;Tanaka Y;Azodi S;Lepene B;Jones J;Kashanchi F;Jacobson S
HTLV-1感染全球超过2000万人，并在被称为HTLV-1相关脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）的感染个体亚组中引起进行性神经炎性病症。在脑脊液（CSF）中检测到HTLV-1特异性T细胞表明这种疾病是免疫病理介导的，并且可能由病毒抗原驱动。外来体是源自内体区室的微泡，其通过各种细胞类型脱落到细胞外空间中。现在可以理解，几种病毒也利用这种细胞间通讯模式包装病毒组分。我们试图了解在HTLV-1感染中是否存在这种情况，特别是在我们知道不存在游离病毒的HAM/TSP患者的CSF中是否可以发现HTLV-1蛋白，此外，含有HTLV-1 Tax的外泌体是否具有功能性后果。通过从培养物上清液中捕获外来体，从离体培养物中的HAM/TSP患者PBMC（25/36）分离通过蛋白质印迹对HTLV-1 Tax呈阳性的外来体。HTLV-1血清阴性PBMC不具有具有Tax的外来体（0/12），（Fisher精确检验，p = 0.0001）。我们能够观察到HAM/TSP患者CSF（12/20）含有Tax+外泌体，但在HTLV-1血清阴性MS供体（0/5）中没有，尽管在CSF上清液中没有检测到病毒（Fisher精确检验p = 0.0391）。此外，从HAM/TSP PBMC培养的外来体能够使靶细胞对HTLV-1特异性CTL裂解敏感。累积起来，这些结果表明，在无病毒CSF中发现的外来体中存在HTLV-1蛋白。HAM/TSP PBMC，特别是CD 4 + CD 25 + T细胞，可以分泌这些含有HTLV-1 Tax的外泌体，并且可能是患者CSF中发现的外泌体的来源。重要的是，这些外来体能够使HTLV-1特异性免疫应答敏感，表明它们可能在HAM/TSP中观察到的免疫病理学中发挥作用。考虑到HTLV-1 Tax特异性CTL浸润到HAM/TSP患者的CNS中，外泌体可能也有助于在HAM/TSP中观察到的持续活化和炎症，并可能提示这种疾病的未来靶向治疗。本文的在线版本（10.1186/s40169-018-0204-7）包含补充材料，可供授权用户使用。
HTLV-1 infects over 20 million people worldwide and causes a progressive neuroinflammatory disorder in a subset of infected individuals called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The detection of HTLV-1 specific T cells in the cerebrospinal fluid (CSF) suggests this disease is immunopathologically mediated and that it may be driven by viral antigens. Exosomes are microvesicles originating from the endosomal compartment that are shed into the extracellular space by various cell types. It is now understood that several viruses take advantage of this mode of intercellular communication for packaging of viral components as well. We sought to understand if this is the case in HTLV-1 infection, and specifically if HTLV-1 proteins can be found in the CSF of HAM/TSP patients where we know free virus is absent, and furthermore, if exosomes containing HTLV-1 Tax have functional consequences. Exosomes that were positive for HTLV-1 Tax by Western blot were isolated from HAM/TSP patient PBMCs (25/36) in ex vivo cultures by trapping exosomes from culture supernatants. HTLV-1 seronegative PBMCs did not have exosomes with Tax (0/12), (Fisher exact test, p = 0.0001). We were able to observe HAM/TSP patient CSF (12/20) containing Tax+ exosomes but not in HTLV-1 seronegative MS donors (0/5), despite the absence of viral detection in the CSF supernatant (Fisher exact test p = 0.0391). Furthermore, exosomes cultivated from HAM/TSP PBMCs were capable of sensitizing target cells for HTLV-1 specific CTL lysis. Cumulatively, these results show that there are HTLV-1 proteins present in exosomes found in virus-free CSF. HAM/TSP PBMCs, particularly CD4+CD25+ T cells, can excrete these exosomes containing HTLV-1 Tax and may be a source of the exosomes found in patient CSF. Importantly, these exosomes are capable of sensitizing an HTLV-1 specific immune response, suggesting that they may play a role in the immunopathology observed in HAM/TSP. Given the infiltration of HTLV-1 Tax-specific CTLs into the CNS of HAM/TSP patients, it is likely that exosomes may also contribute to the continuous activation and inflammation observed in HAM/TSP, and may suggest future targeted therapies in this disorder. The online version of this article (10.1186/s40169-018-0204-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.2
作者：
Ferrucci, Adriano;Nonnemacher, Michael R.;Wigdahl, Brian
通讯作者：
Wigdahl, Brian
影响因子：
1.6
作者：
Jarrin I;Sellier P;Lopes A;Morgand M;Makovec T;Delcey V;Champion K;Simoneau G;Green A;Mouly S;Bergmann JF;Lloret-Linares C
通讯作者：
Lloret-Linares C
使用差分超速离心和三种商业试剂对血清外泌体分离的比较研究。
影响因子：
3.7
作者：
Helwa I;Cai J;Drewry MD;Zimmerman A;Dinkins MB;Khaled ML;Seremwe M;Dismuke WM;Bieberich E;Stamer WD;Hamrick MW;Liu Y
通讯作者：
Liu Y
影响因子：
4.8
作者：
Barclay, Robert A.;Schwab, Angela;Kashanchi, Fatah
通讯作者：
Kashanchi, Fatah
影响因子：
5.4
作者：
Admyre, Charlotte;Johansson, Sara M.;Gabrielsson, Susanne
通讯作者：
Gabrielsson, Susanne