Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Unit of Neurology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy.
Residency Program in Clinical Pathology and Clinical Biochemistry, Università degli Studi di Milano, Milan, Italy.
Nat Commun. 2021 Apr 8;12(1):2099. doi: 10.1038/s41467-021-22305-x.
In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.
在杜氏肌营养不良症（DMD）中，肌膜脆性和肌纤维坏死产生细胞碎片，吸引炎症细胞。巨噬细胞和 T 淋巴细胞浸润肌肉，以响应损伤相关分子模式信号和 TNF-α、TGF-β 和白细胞介素的释放，从而防止炎症导致骨骼肌改善。这种免疫情况因发现对肌肉抗原的特异性反应以及调节性 T 细胞（Tregs）在肌肉再生中的作用而得到扩展。正常情况下，自身反应性 T 淋巴细胞在胸腺内被删除，从而避免了自身免疫，而在周围，Tregs 监测从中枢调节控制中逃逸的效应 T 细胞。在这里，我们报告 mdx 小鼠的胸腺结构受损，同时生长激素释放肽表达降低，自噬功能障碍和 AIRE 下调。将营养不良的胸腺移植到受体裸鼠中，可导致炎症/纤维化标志物的上调、明显的代谢分解，导致肌肉萎缩和力量丧失。这些结果表明，营养不良的胸腺的退化通过改变中枢免疫耐受而加剧肌肉营养不良。
