Momenta Pharmaceuticals Inc, Cambridge, MA, USA.
Janssen Pharmaceutical Companies of Johnson & Johnson, 301 Binney St, Cambridge, MA, 02142, USA.
Arthritis Res Ther. 2021 Oct 15;23(1):259. doi: 10.1186/s13075-021-02633-5.
Serum proteins can be readily assessed during routine clinical care. However, it is unclear to what extent serum proteins reflect the molecular dysregulations of peripheral blood cells (PBCs) or affected end-organs in systemic sclerosis (SSc). We conducted a multiomic comparative analysis of SSc serum profile, PBC, and skin gene expression in concurrently collected samples.
Global gene expression profiling was carried out in skin and PBC samples obtained from 49 SSc patients enrolled in the GENISOS observational cohort and 25 unaffected controls. Levels of 911 proteins were determined by Olink Proximity Extension Assay in concurrently collected serum samples.
Both SSc PBC and skin transcriptomes showed a prominent type I interferon signature. The examination of SSc serum profile revealed an upregulation of proteins involved in pro-fibrotic homing and extravasation, as well as extracellular matrix components/modulators. Notably, several soluble receptor proteins such as EGFR, ERBB2, ERBB3, VEGFR2, TGFBR3, and PDGF-Rα were downregulated. Thirty-nine proteins correlated with severity of SSc skin disease. The differential expression of serum protein in SSc vs. control comparison significantly correlated with the differential expression of corresponding transcripts in skin but not in PBCs. Moreover, the differentially expressed serum proteins were significantly more connected to the Well-Associated-Proteins in the skin than PBC gene expression dataset. The assessment of the concordance of between-sample similarities revealed that the molecular profile of serum proteins and skin gene expression data were significantly concordant in patients with SSc but not in healthy controls.
SSc serum protein profile shows an upregulation of profibrotic cytokines and a downregulation of soluble EGF and other key receptors. Our multilevel comparative analysis indicates that the serum protein profile in SSc correlates more closely with molecular dysregulations of skin than PBCs and might serve as a reflection of disease severity at the end-organ level.
血清蛋白在常规临床护理中可轻易被评估。然而，目前尚不清楚血清蛋白在多大程度上反映了系统性硬化症（SSc）患者外周血细胞（PBC）或受影响的靶器官的分子失调。我们对同时采集的 SSc 血清谱、PBC 和皮肤基因表达进行了多组学比较分析。
对 GENISOS 观察队列中 49 例 SSc 患者和 25 例未受影响的对照者同时采集的皮肤和 PBC 样本进行了全基因组表达谱分析。在同时采集的血清样本中通过 Olink Proximity Extension Assay 测定了 911 种蛋白的水平。
SSc 的 PBC 和皮肤转录组均表现出明显的 I 型干扰素特征。对 SSc 血清谱的研究发现，参与促纤维化归巢和渗出的蛋白以及细胞外基质成分/调节剂呈上调表达。值得注意的是，几种可溶性受体蛋白如 EGFR、ERBB2、ERBB3、VEGFR2、TGFBR3 和 PDGF-Rα 呈下调表达。39 种蛋白与 SSc 皮肤疾病的严重程度相关。SSc 与对照组比较中血清蛋白的差异表达与皮肤中相应转录物的差异表达显著相关，但与 PBC 中无明显相关性。此外，差异表达的血清蛋白与皮肤基因表达数据集的关联蛋白的相关性明显高于 PBC。样本间相似性一致性评估表明，SSc 患者的血清蛋白分子谱与皮肤基因表达数据具有显著的一致性，但在健康对照组中则无明显相关性。
SSc 血清蛋白谱表现出促纤维化细胞因子的上调和可溶性 EGF 及其他关键受体的下调。我们的多层次比较分析表明，SSc 血清蛋白谱与皮肤的分子失调相关性更密切，而与 PBC 相关性较弱，它可能反映了终末器官水平的疾病严重程度。
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