Department of Pulmonology, Leiden University Medical Center (LUMC), Leiden, Netherlands.
Front Immunol. 2020 Sep 4;11:1990. doi: 10.3389/fimmu.2020.01990. eCollection 2020.
Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by immune dysregulation and progressive fibrosis. Interstitial lung disease (ILD) is the most common cause of death among SSc patients and there are currently very limited approved disease-modifying treatment options for systemic sclerosis-related interstitial lung disease (SSc-ILD). The mechanisms underlying pulmonary fibrosis in SSc-ILD are not completely unraveled, and knowledge on fibrotic processes has been acquired mostly from studies in idiopathic pulmonary fibrosis (IPF). The incomplete knowledge of SSc-ILD pathogenesis partly explains the limited options for disease-modifying therapy for SSc-ILD. Fibrosis in IPF appears to be related to aberrant repair following injury, but whether this also holds for SSc-ILD is less evident. Furthermore, immune dysregulation appears to contribute to pro-fibrotic responses in SSc-ILD, perhaps more than in IPF. In addition, SSc-ILD patient heterogeneity complicates the understanding of the underlying mechanisms of disease development, and more importantly, limits correct clinical diagnosis and treatment effectivity. Therefore, there is an unmet need for patient-relevant () models to examine patient-specific disease pathogenesis, predict disease progression, screen appropriate treatment regimens and identify new targets for treatment. Technological advances in patient-relevant disease modeling, including (human induced pluripotent stem cell (hiPSC)-derived) lung epithelial cells, organoids and organ-on-chip technology offer a platform that has the potential to contribute to unravel the underlying mechanisms of SSc-ILD development. Combining these models with state-of-the-art analysis platforms, including (single cell) RNA sequencing and (imaging) mass cytometry, may help to delineate pathogenic mechanisms and define new treatment targets of SSc-ILD.
系统性硬化症 (SSc) 是一种自身免疫性结缔组织疾病，其特征为免疫失调和进行性纤维化。间质性肺病 (ILD) 是 SSc 患者死亡的最常见原因，目前针对系统性硬化症相关间质性肺病 (SSc-ILD) ，获批的治疗方法非常有限。SSc-ILD 中的肺纤维化机制尚未完全阐明，纤维化过程的知识主要来自特发性肺纤维化 (IPF) 的研究。对 SSc-ILD 发病机制的不完全了解部分解释了 SSc-ILD 疾病修饰治疗选择有限的原因。IPF 中的纤维化似乎与损伤后的异常修复有关，但这是否也适用于 SSc-ILD 尚不清楚。此外，免疫失调似乎有助于 SSc-ILD 中的促纤维化反应，其作用可能比在 IPF 中更为明显。此外，SSc-ILD 患者异质性使疾病发展的潜在机制难以理解，更重要的是，限制了正确的临床诊断和治疗效果。因此，需要建立与患者相关的模型来研究患者特异性疾病发病机制、预测疾病进展、筛选适当的治疗方案，并确定新的治疗靶点。与患者相关的疾病建模技术的进步，包括（人诱导多能干细胞 (hiPSC) 衍生的）肺上皮细胞、类器官和器官芯片技术，为阐明 SSc-ILD 发展的潜在机制提供了一个平台。将这些模型与最先进的分析平台（包括单细胞 RNA 测序和（成像）质谱流式细胞术）相结合，可能有助于描绘发病机制并确定 SSc-ILD 的新治疗靶点。
