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- Nie, M, et al.
(author)
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PD-1/PD-L Pathway Potentially Involved in ITP Immunopathogenesis
- 2019
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In: Thrombosis and haemostasis. - : Georg Thieme Verlag KG. - 2567-689X .- 0340-6245. ; 119:5, s. 758-765
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Journal article (peer-reviewed)abstract
- The binding of programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2 on antigen-presenting cells turns off autoreactive T cells and induces peripheral tolerance. Aberrant PD-1/PD-L signalling could result in a breakdown of peripheral tolerance and lead to autoimmune diseases. In this study, we detected PD-1 and PD-L expression on T cells and dendritic cells (DCs) in immune thrombocytopenia (ITP) patients with active disease by flow cytometry. The effects of PD-L1-Fc fusion protein (PD-L1-Fc) on T cells and on secretion of interferon-γ (IFN-γ) and interleukin-2 (IL-2) were detected by flow cytometry and enzyme-linked immunosorbent assay, respectively. Compared with healthy controls, PD-1 expression was significantly increased in CD4+ T cells and CD8+ T cells from patients with active ITP. However, PD-L1 expression on monocyte-derived DCs was lower in patients with active ITP than in healthy controls. In vitro assays revealed that PD-L1-Fc increased T cell apoptosis, inhibited activation and proliferation of CD4+ T cells and CD8+ T cells and decreased IFN-γ and IL-2 secretion in patients with active ITP. These results suggest that the aberrant PD-1/PD-L negative co-stimulatory pathway may play a role in ITP. Enhancing PD-1/PD-L signalling might be a promising therapeutic approach for ITP patients by enhancing T cell apoptosis, inhibiting T cell activation and proliferation and reducing secretion of inflammatory factors.
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- Schlosser, P, et al.
(author)
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Meta-analyses identify DNA methylation associated with kidney function and damage
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7174-
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Journal article (peer-reviewed)abstract
- Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
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- Tin, A, et al.
(author)
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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 7173-
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Journal article (peer-reviewed)abstract
- Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
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