Mixed-effects association of single cells identifies an expanded effector CD4(+) T cell subset in rheumatoid arthritis.
Mixed-effects association of single cells identifies an expanded effector CD4(+) T cell subset in rheumatoid arthritis.
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DOI：
10.1126/scitranslmed.aaq0305
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发表时间：
2018-10-17
影响因子：
17.1
通讯作者：
Raychaudhuri S
中科院分区：
文献类型：
--
作者：
Fonseka CY;Rao DA;Teslovich NC;Korsunsky I;Hannes SK;Slowikowski K;Gurish MF;Donlin LT;Lederer JA;Weinblatt ME;Massarotti EM;Coblyn JS;Helfgott SM;Todd DJ;Bykerk VP;Karlson EW;Ermann J;Lee YC;Brenner MB;Raychaudhuri S
高维单细胞分析提高了从人类疾病样本中分辨复杂混合细胞的能力；然而，由于技术和个体间的差异，识别患者样本中与疾病相关的细胞类型或细胞状态仍然具有挑战性。在这里，我们提出了单细胞关联的混合效应模型(MASC)，这是一种反向单细胞关联策略，用于测试病例对照状态是否影响多个细胞子集中任何一个单细胞的成员资格，同时考虑到技术混杂因素和生物变异。应用MASC对类风湿关节炎(RA)患者和对照组外周血中的CD_4~+T细胞进行分析，结果显示RA患者外周血中CD_4~+T细胞的数量显著增加(OR=1·7；P=1·1×10~(-3)−3)。在第二个RA患者队列的血液样本中，CD27-HLA-DR+细胞的频率也同样升高，而对免疫抑制治疗有反应的RA患者的CD27-HLA-DR+细胞频率降低。MSC和FCM分析显示CD27HLADR+细胞与RA相关(Meta分析p=2.3×10−4)。与外周血相比，RA患者滑液和滑膜组织中CD27-HLA-DR+细胞的比例高约5倍，约占滑膜CD4+T细胞的10%。CD27HLADR+细胞表达一个独特的效应记忆转录程序，具有Th1型和细胞毒性相关的特征，并在刺激下产生丰富的干扰素-γ和颗粒酶A蛋白。我们认为，MASC是在高维单细胞数据中识别疾病相关细胞群的一种广泛适用的方法。单细胞数据的混合效应回归解释了混杂变异，并揭示了类风湿性关节炎中CD4+T细胞群的扩大。
High dimensional single-cell analyses have improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging due to technical and inter-individual variation. Here we present Mixed-effects modeling of Associations of Single Cells (MASC), a reverse single cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounders and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from the blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (OR = 1.7; p = 1.1 × 10−3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who responded to immunosuppressive therapy. Mass cytometry and flow cytometry analyses indicated that CD27- HLA-DR+ cells were associated with RA (meta-analysis p = 2.3 × 10−4). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained ~5-fold higher frequencies of CD27- HLA-DR+ cells, which comprised ~10% of synovial CD4+ T cells. CD27- HLA-DR+ cells expressed a distinctive effector memory transcriptomic program with Th1- and cytotoxicity-associated features, and produced abundant IFN-γ and granzyme A protein upon stimulation. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data. Mixed-effects regression of single-cell data accounts for confounding variation and reveals an expanded CD4+ T cell population in rheumatoid arthritis.
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影响因子：
4.9
作者：
Aletaha D;Nell VP;Stamm T;Uffmann M;Pflugbeil S;Machold K;Smolen JS
通讯作者：
Smolen JS
影响因子：
4.3
作者：
Chen H;Lau MC;Wong MT;Newell EW;Poidinger M;Chen J
通讯作者：
Chen J
影响因子：
10.1
作者：
Hansmann L;Blum L;Ju CH;Liedtke M;Robinson WH;Davis MM
通讯作者：
Davis MM
影响因子：
4.4
作者：
Baecher-Allan, Clare;Wolf, Elizabeth;Haller, David A.
通讯作者：
Haller, David A.
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP