Immunology Research, Biogen, Cambridge, Mass.
Faculté de Médecine, Université Paris Sud, Le Kremlin-Bicêtre, France; INSERM, U1184, Center for immunology of viral infections and autoimmune diseases, Le Kremlin-Bicêtre, France.
J Allergy Clin Immunol. 2016 Jun;137(6):1809-1821.e12. doi: 10.1016/j.jaci.2016.01.024. Epub 2016 Apr 1.
Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist.
This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS.
Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry.
In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8(+) T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation.
This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.
液质联用技术最近已成为临床研究的一种有前途的工具。然而，很少有研究表明其有助于患者分层和生物标志物的识别。原发性干燥综合征（pSS）是一种慢性自身免疫性疾病的原型，其发病机制尚不清楚，也没有治疗方法。
本观察性病例对照研究旨在发现 pSS 患者的新细胞生物标志物和治疗靶点。
招募了 49 名 pSS 患者和 45 名对照者进行临床评估和血液中 34 种蛋白标志物的液质联用定量分析。其中三分之一的受试者还进行了配对的唇腺活检标本的液质联用和免疫组织化学分析。
在 pSS 患者的唾液腺活检标本中，我们发现了大量激活的 CD8(+)T 细胞、终末分化的浆细胞和激活的上皮细胞，这为未来的临床干预提供了新的发病机制。在血液中，我们确定了一个由 CD4 和记忆 B 淋巴细胞数量减少、浆细胞样树突状细胞数量减少以及激活的 CD4 和 CD8 T 细胞和浆母细胞数量增加定义的 6 细胞疾病特征。这些血液细胞成分与临床参数相关，当综合考虑时，可将患者聚类为具有不同疾病活动度和腺体炎症的亚组。
这是首次将液质联用技术应用于分层良好的临床队列和小活检组织，证明了这种方法在发现新的生物标志物和治疗靶点方面的益处。类似的高维免疫表型策略可以在该疾病和其他疾病领域的纵向和干预性临床环境中实施。
