Ethnicity-specific transcriptomic variation in immune cells and correlation with disease activity in systemic lupus erythematosus

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which outcomes vary among different racial groups. We leverage cell-sorted RNA-seq data (CD14 + monocytes, B cells, CD4 + T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four-tier approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on each cell-type resulted in three clusters for CD4 and CD14, and two for B and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across all cells were involved in SLE or other autoimmune-related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into groups base on their disease activity and ethnicity. Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4 + T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable SLE precision medicine.

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Transcriptomic analysis of immune cells in a multi-ethnic cohort of systemic lupus erythematosus patients identifies ethnicity- and disease-specific expression signatures

Communications Biology ◽

10.1038/s42003-021-02000-9 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Gaia Andreoletti ◽

Cristina M. Lanata ◽

Laura Trupin ◽

Ishan Paranjpe ◽

Tia S. Jain ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Disease Activity ◽

Nk Cells ◽

Differentially Expressed Genes ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Differentially Expressed ◽

Cell Type ◽

Systemic Lupus

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease in which outcomes vary among different racial groups. We leverage cell-sorted RNA-seq data (CD14+ monocytes, B cells, CD4+ T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four-tier approach including unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning to identify SLE subgroups within this multiethnic cohort. K-means clustering on each cell-type resulted in three clusters for CD4 and CD14, and two for B and NK cells. To understand the identified clusters, correlation analysis revealed significant positive associations between the clusters and clinical parameters including disease activity as well as ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across cells were involved in SLE or other autoimmune-related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Finally, random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White individuals. The results from these analyses will help stratify patients based on their gene expression signatures to enable SLE precision medicine.

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Ethnicity-specific transcriptomic variation in immune cells and correlation with disease activity in systemic lupus erythematosus

10.1101/2020.10.30.362715 ◽

2020 ◽

Author(s):

Gaia Andreoletti ◽

Cristina M. Lanata ◽

Ishan Paranjpe ◽

Tia S. Jain ◽

Joanne Nititham ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

B Cells ◽

Disease Activity ◽

Nk Cells ◽

Differentially Expressed Genes ◽

Lupus Erythematosus ◽

Differentially Expressed ◽

Cell Type ◽

Systemic Lupus

AbstractSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. The aim of this study is to leverage large-scale transcriptomic data from diverse populations to better sub-classify SLE patients into more clinically actionable groups. We leverage cell sorted RNA-seq data (CD14+ monocytes, B cells, CD4+T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four tier analytical approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on the individual cell type data resulted in three clusters for CD4 and CD14, and two clusters for B cells and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters of each immune cell and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across the four cell types were involved in SLE or other autoimmune related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into White-high, Asians-high (high disease activity defined by SLEDAI score >=6) and White-low, Asians-low (SLEDAI < 6). Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable precision medicine for SLE.

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Elevated expression of TIGIT on CD3+CD4+ T cells correlates with disease activity in systemic lupus erythematosus

Allergy Asthma & Clinical Immunology ◽

10.1186/s13223-017-0188-7 ◽

2017 ◽

Vol 13 (1) ◽

Cited By ~ 5

Author(s):

Qing Luo ◽

Jianqing Ye ◽

Lulu Zeng ◽

Xue Li ◽

Le Fang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Disease Activity ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Systemic Lupus ◽

Elevated Expression

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Fyn and CD70 Expression in CD4+ T Cells from Patients with Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.090424 ◽

2009 ◽

Vol 37 (1) ◽

pp. 53-59 ◽

Cited By ~ 3

Author(s):

ANNA KOZLOWSKA ◽

PAWEL HRYCAJ ◽

JAN K. LACKI ◽

PAWEL P. JAGODZINSKI

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Disease Activity ◽

Protein Content ◽

Lupus Erythematosus ◽

Cd4 T Cells ◽

Healthy Individuals ◽

Systemic Lupus ◽

Autoantibody Production ◽

Protein Levels

Objective.CD4+ T cells from patients with systemic lupus erythematosus (SLE) display defective function that contributes to abnormal activation of B cells and autoantibody production.Methods.We compared the transcript and protein levels of Fyn and CD70 in CD4+ T cells from patients with SLE (n = 41) and healthy individuals (n = 34). The CD4+ T cells were isolated by positive biomagnetic separation technique. The quantitative analysis of messenger RNA was performed by reverse transcription and real-time quantitative PCR. The protein contents in the CD4+ T cells were determined by Western blotting analysis.Results.We observed significantly higher levels of Fyn (p = 0.03) and CD70 (p = 0.029) transcripts in SLE CD4+ T cells than in controls. There was a significant increase in CD70 protein levels (p < 0.0001), but not Fyn protein levels (p = 0.081) in CD4+ T cells from patients with SLE compared to healthy individuals. In the group with high disease activity [SLE Disease Activity Index (SLEDAI) ≥ 9], we observed a significantly higher Fyn protein content than in controls (p = 0.030). There was no correlation between Fyn and CD70 protein levels in SLE CD4+ T cells and disease activity as expressed in the SLEDAI scale.Conclusion.We confirmed previous observations of higher expression of CD70 in CD4+ T cells from patients with SLE. Our findings suggest that increased Fyn protein content in CD4+ T cells can be associated with high SLE disease activity.

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AB0084 INCREASED LEVEL OF NEUROPILIN-1 IN CD4+ T CELL AND ITS CORRELATION WITH DISEASE ACTIVITY OF SYSTEMIC LUPUS ERYTHEMATOSUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3388 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1072.1-1072

Author(s):

Y. J. Choi ◽

E. K. Lee ◽

M. S. Lee ◽

C. H. Lee ◽

C. H. Chung ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Disease Activity ◽

Lupus Erythematosus ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Critical Role ◽

Vehicle Group ◽

Systemic Lupus ◽

Neuropilin 1

Background:Semaphorin has been found as a neuronal guidance molecule, but has recently been called “immune semaphorin”, as their critical role in immune cell activation, differentiation and migration has been revealed. In particular, class 4 semaphorin has been shown to contribute to lymphocyte activation and immune homeostasis.Objectives:This study was aimed to investigate the expression of neuropilin-1 (NRP-1), the receptor of class 4 semaphorin, in the murine mouse model of systemic lupus erythematosus (SLE) and the patients with SLE and the correlation between the expression of NRP-1 and disease activity of SLE.Methods:The expression of NRP-1 was measured in T cells in spleen and renal tissue in control mouse and TLR-7 agonist-induced lupus mouse by flow cytometry, PCR, and immunofluorescence (IF). CD4+ T cells from human peripheral blood were isolated to investigate the expression of NRP-1 in healthy control and the patients with SLE (n=40).Results:The frequency of NRP-1 positivity in CD4+ T cells in spleen was significantly higher in lupus mouse group (median [interquartile range]: 15.34 [14.84] %) compared to vehicle mouse group (4.0 [2.77]%). The quantitative analysis of fluorescense intensity in kidney stained for NRP-1 revealed the increased level in lupus group compared to vehicle group. The CD4+ T cells from peripheral blood mononuclear cells in the patients with lupus also showed significantly higher frequency of NRP-1 positive CD4+ T cells than those from healthy controls. Comparing the correlation of the expression of NRP-1 and disease activity with SLEDAI, C3, C4, and anti-DNA antibodies, the significant correlation between NRP-1 and disease activity markers were confirmed.Conclusion:Our results demonstrate that higher expression of NRP-1 in CD4+ T cells and its significant correlation with disease activity of SLE. These results indicate that pathologic contribution of NRP-1 in the pathogenesis of SLE and potential of targeting NRP-1 for the treatment of SLE.References:[1]Nishide M, Kumanogoh A. The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nat Rev Rheumatol. 2018 Jan;14(1):19-31.Disclosure of Interests:None declared

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Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.108043 ◽

2009 ◽

Vol 69 (6) ◽

pp. 1208-1213 ◽

Cited By ~ 60

Author(s):

Paul A Lyons ◽

Eoin F McKinney ◽

Tim F Rayner ◽

Alexander Hatton ◽

Hayley B Woffendin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Differentially Expressed Genes ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Differentially Expressed ◽

Transcriptional Analysis ◽

Expression Data ◽

Systemic Lupus ◽

Disease Pathogenesis

ObjectiveTo optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers.Methods44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays.ResultsUsing expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis.ConclusionAnalysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease.

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