Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis.
Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis.
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DOI：
10.1126/scitranslmed.abi9196
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发表时间：
2022-01-19
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
散发性包涵体肌炎（IBM）是50岁以上成年人中最常见的获得性肌肉疾病，但目前尚不清楚该疾病是否主要由T细胞介导的自身免疫引起。IBM肌肉活检显示肌肉细胞中TDP-43的核清除和细胞质聚集，这是一种最初在神经退行性疾病中观察到的病理发现，其中神经元中TDP-43的核丢失导致异常RNA剪接。在这里，我们发现tdp -43介导的剪接抑制的缺失，通过包含隐外显子来确定，发生在IBM受试者的骨骼肌中。在119例肌肉活检中，rt - pcr介导的隐外显子包涵体检测能够以84%的灵敏度和99%的特异性诊断IBM。为了确定T细胞在发病机制中的作用，我们通过将人类IBM肌肉移植到免疫缺陷小鼠的后肢中来建立异种移植模型。来自IBM患者的异种移植物显示出人类肌纤维的强劲再生，并重现了该疾病的炎症和退行性特征。IBM异种移植物的肌纤维受到人寡克隆CD8+ T细胞的侵袭，并表现出MHC-I上调、边缘空泡、线粒体病理、p62阳性包涵体、核清除和胞质中TDP-43的聚集，与隐性外显子包涵相关。通过腹腔注射抗cd3 （OKT3）抑制小鼠MHC-I上调，减少IBM异种移植物中的人T细胞。然而，边缘液泡和TDP-43功能的丧失仍然存在。这些数据表明，T细胞耗竭不会改变IBM的肌肉退行性病理。
Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over age 50, yet it remains unclear whether the disease is primarily driven by T cell–mediated autoimmunity. IBM muscle biopsies display nuclear clearance and cytoplasmic aggregation of TDP-43 in muscle cells, a pathologic finding observed initially in neurodegenerative diseases, where nuclear loss of TDP-43 in neurons causes aberrant RNA splicing. Here, we show that loss of TDP-43–mediated splicing repression, as determined by inclusion of cryptic exons, occurs in skeletal muscle of subjects with IBM. Of 119 muscle biopsies tested, RT-PCR–mediated detection of cryptic exon inclusion was able to diagnose IBM with 84% sensitivity and 99% specificity. To determine the role of T cells in pathogenesis, we generated a xenograft model by transplanting human IBM muscle into the hindlimb of immunodeficient mice. Xenografts from subjects with IBM displayed robust regeneration of human myofibers and recapitulated both inflammatory and degenerative features of the disease. Myofibers in IBM xenografts showed invasion by human, oligoclonal CD8+ T cells and exhibited MHC-I up-regulation, rimmed vacuoles, mitochondrial pathology, p62-positive inclusions, and nuclear clearance and cytoplasmic aggregation of TDP-43, associated with cryptic exon inclusion. Reduction of human T cells within IBM xenografts by treating mice intraperitoneally with anti-CD3 (OKT3) suppressed MHC-I up-regulation. However, rimmed vacuoles and loss of TDP-43 function persisted. These data suggest that T cell depletion does not alter muscle degenerative pathology in IBM.
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DOI：
10.1038/mt.2016.111
发表时间：
2016-08
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
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影响因子：
5.3
作者：
Keller CW;Schmidt J;Lünemann JD
通讯作者：
Lünemann JD
影响因子：
2.8
作者：
Lindgren, Ulrika;Roos, Sara;Oldfors, Anders
通讯作者：
Oldfors, Anders
影响因子：
1.2
作者：
Britson, Kyla A.;Black, Aaron D.;Lloyd, Thomas E.
通讯作者：
Lloyd, Thomas E.
影响因子：
56.9
作者：
KUNG, PC;GOLDSTEIN, G;SCHLOSSMAN, SF
通讯作者：
SCHLOSSMAN, SF