Details

Autor(en) / Beteiligte

• Fonseka, Chamith Y
• Rao, Deepak A
• Teslovich, Nikola C
• Korsunsky, Ilya
• Hannes, Susan K
• Slowikowski, Kamil
• Gurish, Michael F
• Donlin, Laura T
• Lederer, James A
• Weinblatt, Michael E
• Massarotti, Elena M
• Coblyn, Jonathan S
• Helfgott, Simon M
• Todd, Derrick J
• Bykerk, Vivian P
• Karlson, Elizabeth W
• Ermann, Joerg
• Lee, Yvonne C
• Brenner, Michael B
• Raychaudhuri, Soumya

Titel

Mixed-effects association of single cells identifies an expanded effector CD4 + T cell subset in rheumatoid arthritis

Ist Teil von

• Science translational medicine, 2018-10, Vol.10 (463)

Ort / Verlag

United States

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 because of technical and interindividual 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 (odds ratio, 1.7; = 1.1 × 10 ). 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 = 2.3 × 10 ). Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained about fivefold 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 T helper 1 (T 1)- and cytotoxicity-associated features and produced abundant interferon-γ (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.