Functional and molecular diversity of skin fibroblasts in systemic sclerosis.

系统性硬化症（SSc），也称为硬皮病，是一种罕见的自身免疫性风湿病，导致皮肤增厚（硬化症），皮肤和重要器官（如肺、心脏、肾脏和肠道）出现纤维化或疤痕。这些并发症导致该病对日常生活的几乎所有方面产生重大影响，在最严重的情况下可导致死亡。皮肤增厚的模式和严重程度可用于识别严重脏器受累和降低长期生存风险的病例。然而，由于硬皮病发病的基本机制尚不清楚，皮肤病与总体预后之间的关系尚不明确。皮肤受累程度有助于对患者进行分类，不同的皮肤受累轨迹与不同的预后和生存有关。因此，硬皮病仍然是一种具有挑战性的疾病，其造成的死亡人数超过任何其他风湿病。虽然硬皮病是罕见的，但发生故障的过程和决定疾病严重程度的过程可能与许多常见疾病有关，如肺和肝纤维化，或手术后过度疤痕，烧伤或皮肤损伤。通过这种方式，硬皮病为了解并最终预防或治疗这些其他重要疾病提供了可能的途径。以前在硬皮病方面的研究表明，皮肤和内脏器官中一种叫做成纤维细胞的关键细胞类型在皮肤病中起着纤维化的驱动作用。成纤维细胞可以从硬皮病患者局部麻醉下的小片皮肤（活检）中生长。然而，只有一些成纤维细胞从活检中生长出来，最近的研究表明，这些细胞可能不是决定皮肤纤维化最重要的细胞。这限制了以前的研究，因为可能有许多不同类型的成纤维细胞，在正常健康的皮肤和硬皮病等疾病中有不同的作用。新的实验室技术为区分皮肤中不同群体的成纤维细胞提供了令人兴奋的工具，我们已经开发了一种从硬皮病皮肤活检中分离不同群体成纤维细胞的新方法。这是向前迈出的重要一步，因为与其他细胞类型（如免疫细胞或血细胞）不同，使用传统方法和实验室工具检测的成纤维细胞通常彼此无法区分。目前的应用将使用现代科学方法来检查基因和蛋白质表达，并定义皮肤中不同类型的成纤维细胞，并进一步了解它们在硬皮病疾病过程中的潜在重要性。我们将要求到我们常规诊所就诊的硬皮病患者捐献小块皮肤样本，并对活检中的每个细胞进行单独分析，以确定存在的细胞类型。我们期望在活检中发现表达类似蛋白质的小群细胞。我们建议使用的技术已经应用于类风湿关节炎，另一种影响关节的自身免疫性疾病，以及健康皮肤。我们完全期望会有不同的成纤维细胞群，并且这些成纤维细胞在硬皮病的不同阶段具有不同的特性。这些细胞的详细特性和功能的定义将对未来的治疗目标产生影响，并确定哪种新的硬皮病治疗方法对个体患者最有效。考虑到硬皮病非常高的临床负担和目前对现有药物的反应变化，这一点至关重要。除了提供有关疤痕和纤维化的重要信息外，这项工作还将对影响皮肤的其他常见自身免疫性疾病（如牛皮癣）产生更广泛的影响，在这些疾病中，驱动疾病的细胞类型可能存在重叠，类似的治疗方法可能适用。

Systemic sclerosis (SSc), also called scleroderma, is an uncommon autoimmune rheumatic condition leading to thickened skin (sclerosis) with fibrosis, or scarring, in the skin and vital organs such as the lungs and heart, kidneys and bowel. These complications are responsible for major impact of the disease on almost all aspects of everyday life and in the most severe cases can lead to death. The pattern and severity of skin thickening can be used to identify cases most at risk of severe internal organ involvement and reduced long-term survival. However, the relationship between skin disease and overall outcome is imprecise because the basic mechanisms of disease in scleroderma remain poorly understood. The extent of skin involvement helps to classify patients, and distinct trajectories of skin involvement are associated with differing prognosis and survival. As a result, scleroderma remains a challenging disease to treat and is responsible for more deaths than any other rheumatic disease.Although scleroderma is rare, the processes that have malfunctioned and that determine severity of the disease are likely to be relevant to many commoner conditions such as lung and liver fibrosis, or excessive scarring after surgery, burns or skin wounding. In this way scleroderma offers a possible route to understand and ultimately prevent or treat these other important disorders.Previous work in scleroderma has suggested that a key type of cell in the skin and internal organs called the fibroblast acts as a driver of fibrosis in skin disease. Fibroblasts can be grown from small pieces of skin (biopsies) taken under local anaesthetic from scleroderma patients. However only some of the fibroblasts grow out of the biopsy and recent research suggests that these may not be the most important cells determining skin fibrosis. This has limited previous studies because there are likely to be many different types of fibroblasts that have different roles in normal healthy skin and in diseases such as scleroderma.New laboratory techniques provide exciting tools to distinguish between the different populations of fibroblasts in skin and we have developed a new method to isolate different populations of fibroblasts from skin biopsies in scleroderma. This is a major step forward because unlike other cell types, such as immune cells or blood cells, fibroblasts examined using traditional methods and laboratory tools are often indistinguishable from each other. The present application will use modern scientific approaches to examine gene and protein expression and to define the distinct types of fibroblasts in the skin, and further understand their potential importance in the scleroderma disease process. We will ask patients with scleroderma attending our routine clinic to donate small samples of skin and will analyse each cell in the biopsy individually to identify the types of cells present. We expect to find small groups of cells within the biopsy expressing similar proteins. The technique we propose to use has already been applied in rheumatoid arthritis, another autoimmune disease affecting the joints, as well as in healthy skin.We fully expect that there will be different fibroblast populations, and that these will have distinct properties at different stages of scleroderma. Definition of the detailed properties and function of these cells will have implications on future treatment targets and determine which of the emerging therapies for scleroderma will work best for an individual patient. This is vital considering the very high clinical burden of scleroderma and current variation in response to available drugs.As well as providing important information about scarring and fibrosis, this work will also have wider implications on other common autoimmune diseases affecting the skin, such as psoriasis, where there may be overlap in the types of cells driving the disease, and similar treatments may be applicable.