Brigham and Women's Hospital Department of Neurology, Division of Neuromuscular Disease, and Harvard Medical School, Boston, MA, USA.
Computational Health Informatics Program, Boston Children's Hospital, Boston, MA and Harvard Medical School, Boston, MA, USA.
Brain. 2019 Sep 1;142(9):2590-2604. doi: 10.1093/brain/awz207.
Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.
包涵体肌炎是一种迟发性、治疗抵抗的骨骼肌自身免疫性疾病，与血液自身抗体（抗-CN1A）、HLA 自身免疫单倍型和以细胞毒性 CD8+T 细胞破坏肌纤维为特征的肌肉病理学有关。在这里，我们报告了包涵体肌炎患者肌肉的转化研究结果，并与其他多种肌肉疾病样本进行了比较。我们利用 411 名包涵体肌炎患者（n=40）、其他肌肉疾病患者（n=265）和无神经肌肉疾病患者（正常，n=106）的可用微阵列数据，鉴定出包涵体肌炎肌肉中 T 细胞细胞毒性的特征，以及高分化 CD8+T 细胞效应记忆和终末分化效应细胞的特征。此外，我们研究了杀伤细胞凝集素样受体 G1（KLRG1）作为该细胞群的标志物，证明了 KLRG1 基因表达与 28870 个人类组织样本中的淋巴细胞细胞毒性之间的相关性，并在致病包涵体肌炎肌肉入侵 T 细胞中鉴定出 KLRG1 的存在，并在包涵体肌炎血液中增加了 KLRG1 表达的 T 细胞。我们通过 Ki67 免疫组织化学检查了包涵体肌炎肌肉 T 细胞的增殖，结果表明，患病肌肉入侵的 T 细胞很少或不增殖，这与高度分化或终末分化 T 细胞的已知特性一致。我们发现感染保护性人类淋巴组织中央记忆 T 细胞和自身免疫保护性人类血液调节性 T 细胞上 KLRG1 的低表达。靶向高度分化的细胞毒性 T 细胞可能是治疗包涵体肌炎的一种有利方法。
