Division of Rheumatology, University of Texas Health Science Center Houston, McGovern Medical School, Houston, Texas, USA
Division of Rheumatology, University of Texas Health Science Center Houston, McGovern Medical School, Houston, Texas, USA.
Ann Rheum Dis. 2022 Apr;81(4):516-523. doi: 10.1136/annrheumdis-2021-221352. Epub 2021 Dec 22.
Determine relationships between skin gene expression and systemic sclerosis (SSc) clinical disease features, and changes in skin gene expression over time.
A total of 339 forearm skin biopsies were obtained from 113 SSc patients and 44 matched healthy controls. 105 SSc patients had a second biopsy, and 76 had a third biopsy. Global gene expression profiling was performed, and differentially expressed genes and cell type-specific signatures in SSc were evaluated for relationships to modified Rodnan Skin Score (mRSS) and other clinical variables. Changes in skin gene expression over time were analysed by mixed effects models and principal component analysis. Immunohistochemical staining was performed to validate conclusions.
Gene expression dysregulation was greater in SSc patients with affected skin than in those with unaffected skin. Immune cell and fibroblast signatures positively correlated with mRSS. High baseline immune cell and fibroblast signatures predicted higher mRSS over time, but were not independently predictive of longitudinal mRSS after adjustment for baseline mRSS. In early diffuse cutaneous SSc, immune cell and fibroblast signatures declined over time, and overall skin gene expression trended towards normalisation. On immunohistochemical staining, most early diffuse cutaneous SSc patients with high baseline T cell and macrophage numbers had declines in these numbers at follow-up.
Skin thickness in SSc is related to dysregulated immune cell and fibroblast gene expression. Skin gene expression changes over time in early diffuse SSc, with a tendency towards normalisation. These observations are relevant for understanding SSc pathogenesis and could inform treatment strategies and clinical trial design.
确定皮肤基因表达与系统性硬化症 (SSc) 临床疾病特征之间的关系，以及皮肤基因表达随时间的变化。
共从 113 例 SSc 患者和 44 例匹配的健康对照者中获得了 339 例前臂皮肤活检。105 例 SSc 患者进行了第二次活检，76 例进行了第三次活检。进行了全基因表达谱分析，并评估了 SSc 中差异表达的基因和细胞类型特异性特征与改良 Rodnan 皮肤评分 (mRSS) 和其他临床变量的关系。通过混合效应模型和主成分分析分析皮肤基因表达随时间的变化。进行免疫组织化学染色以验证结论。
与无病变皮肤的 SSc 患者相比，有病变皮肤的 SSc 患者的基因表达失调更为严重。免疫细胞和成纤维细胞特征与 mRSS 呈正相关。高基线免疫细胞和成纤维细胞特征预示着更高的 mRSS 随时间的推移，但在调整基线 mRSS 后，它们并不是纵向 mRSS 的独立预测因素。在早期弥漫性皮肤 SSc 中，免疫细胞和成纤维细胞特征随时间下降，整体皮肤基因表达趋于正常化。在免疫组织化学染色上，大多数基线 T 细胞和巨噬细胞数量较高的早期弥漫性皮肤 SSc 患者在随访时这些细胞数量下降。
SSc 皮肤厚度与失调的免疫细胞和成纤维细胞基因表达有关。早期弥漫性 SSc 皮肤基因表达随时间变化，有趋于正常化的趋势。这些观察结果与理解 SSc 的发病机制有关，并可能为治疗策略和临床试验设计提供信息。
