Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Fonseka, Chamith Y.; Rao, Deepak A.; Raychaudhuri, Soumya

doi:10.1016/j.coi.2017.08.005

Cited by 17 publications

(14 citation statements)

References 112 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The stratifying naive CD4 T cells and classical monocytes (i.e., subsets with increased p-STAT1 and/ or p-STAT3 in patients compared with controls) were heterogeneous with varying expression levels of different surface markers. This is reminiscent of recent work using mass cytometry that demonstrated that synovial T cell infiltrates in rheumatoid arthritis were highly heterogeneous and that characterization of the CD4 T cell diversity facilitated potential discrimination of pathogenic and nonpathogenic variants of known T cell subsets (37,38). Similarly, NK cell heterogeneity identified with mass cytometry was shown to contribute to West Nile virus susceptibility (39,40).…”

Section: Discussionmentioning

confidence: 84%

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Throm¹,

Moncrieffe²,

Orandi³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 84%

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Throm¹,

Moncrieffe²,

Orandi³

et al. 2018

JCI Insight

View full text Add to dashboard Cite

“…Abnormal proliferation of a large number of RA synovial fibroblast (RASF)-like cells, infiltration of inflammatory cells, abnormal secretion of inflammatory factors, thickening of the synovial lining layer and the destruction of articular cartilage and bone are observed 3 in diseased joints [1]. Currently, the pathogenesis of RA is not entirely clear.Dysregulation of the naїve T cell (Tn) subset is an important step in RA pathogenesis [2]. Due to the influence of cytokines, Tn cells differentiate into a variety of cell subsets with different functions.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Effect of Exogenous Treg Cells on Collagen-Induced Arthritis and Rheumatoid Arthritis

Wang

et al. 2019

Preprint

View full text Add to dashboard Cite

Background Regulatory T (Treg) cells have anti-inflammatory and anti-autoimmune functions. The proportion and functions of Treg cells are perturbed in rheumatoid arthritis (RA) patients. Methods Human Treg cells were induced to amplify in vitro and cocultured with RA synovial fibroblast cells (RASFs). The proliferation and apoptosis of RASFs were determined by the cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. Human Treg cells were also injected to collagen-induced arthritis (CIA) rats via the tail vein. Changes in lymphocyte subtypes and cytokines in the peripheral blood and spleen were observed by flow cytometry. Results After coculture with the Treg cells, the proliferation of RA synovial fibroblast cells decreased (p<0.01), and the rate of apoptosis increased (p=0.037). The human Treg cells were injected into the tail veins of collagen-induced arthritis (CIA) rats. The severity of the CIA was reduced (p<0.01) following the injection, the percentages of rat endogenous Treg cells in the peripheral blood and spleen increased significantly (p=0.007 and p<0.01, respectively), and the proportion of B cells decreased (p=0.031). The levels of interleukin IL-5 and IL-6 and the Th1/Th2 ratio in the peripheral blood were significantly decreased (p=0.013, 0.009 and 0.012, respectively). The number of NK cells and the levels of IL-4, IL-13, TNF-α, IFN-γ and GM-CSF in the peripheral blood and spleen did not change significantly. Conclusion These results suggest that exogenous Treg cells play a therapeutic role in RA and CIA. Treg cell treatment could serve as a therapy for RA.

show abstract

“…Flow cytometric studies have identified alterations in specific circulating T cell subsets in RA patients, including an increased frequency of CD28-CD4+ T cells (14)(15)(16); however, the expansion of CD28-T cells represents one of the relatively few T cell alterations that has been reproducibly detected by multiple groups. Limited reproducibility may be the consequence of differences in clinical cohorts, small sample sizes, methodologic variability, and use of limited, idiosyncratic combinations of phenotypic markers (17).…”

Section: Introductionmentioning

confidence: 99%

Mixed Effects Association of Single Cells Identifies an Expanded Th1-Skewed Cytotoxic Effector CD4+ T Cell Subset in Rheumatoid Arthritis

Fonseka

Rao

Teslovich

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

High dimensional single-cell analyses have dramatically 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 novel 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 confounds and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from 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 respond to immunosuppressive therapy. 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. We find that CD27- HLA-DR+ cells are abundant producers of IFN-γ and also express perforin and granzyme A at elevated levels. Thus MASC identified the expansion of a unique Th1 skewed effector T cell population with cytotoxic capacity in RA. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data.One Sentence SummaryMixed-effects regression of single cells identifies a cytotoxic Th1-like CD4+ T cell subset while accounting for inter-individual and technical variation.

show abstract

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Cited by 17 publications

References 112 publications

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

Therapeutic Effect of Exogenous Treg Cells on Collagen-Induced Arthritis and Rheumatoid Arthritis

Mixed Effects Association of Single Cells Identifies an Expanded Th1-Skewed Cytotoxic Effector CD4+ T Cell Subset in Rheumatoid Arthritis

Contact Info

Product

Resources

About