Based on single-cell sequencing analysis of CD4+ T cells and B cells in patients with lupus nephritis, the heterogeneity of these cells was investigated.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE306378 | GEO | 2026/01/01
REPOSITORIES: GEO
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Project description:Lupus nephritis (LN) is one of the more severe systemic lupus erythematosus manifestations with the potential of developing into end stage kidney disease. Mycophenolate mofetil (MMF) and Azathioprine (AZA) are widely used for both induction and maintenance therapy for LN, but the one year complete renal response ranges from 30-40% in most trials. Reasons for non-response are still unknown. Thus, anticipating lack of drug efficacy in a patient could lead to early introduction of advanced therapies. A longitudinal cohort comprising gene-expression and clinical data of responder and non-responder samples to MMF, AZA and standar of care drugs (hidroxicloroquine (HC) and HC + glococorticoids (GC) (SOC)) was retrospectively analyzed. Response to drugs was defined over time using SRI-4 scores. Differential gene expression and functional analysis were performed. Response rate was measured based on blood cell proportions. Single-cell RNA sequencing data was analyzed to identify the cell subtypes influencing non-response and their contributing genes. SLE: Systemic Lupus Erythematosus; MMF: Mycophenolate mofetil; AZA: Azathioprine; HC: Hydroxychloroquine; PHC: Prednisone (Glucocorticoid (GC)) + HC; SOC: Standard Of Care drugs (HC and HC + PHC)
2023-05-01 | GSE224705 | GEO
Project description:Purpose:We previously found that kidney-infiltrating T cells (KITs) in murine lupus nephritis (LN) resembled dysfunctional T cells that infiltrate tumors. This unexpected finding raised the question of how to reconcile the “exhausted” phenotype of KITs with ongoing tissue destruction in LN. Methods: we performed scRNA-seq and TCR-seq of KITs in murine lupus models using 10X Genomics Chromium system . Results: We found that CD8 KITs exist first in a transitional state, before clonally expanding and evolving toward exhaustion. On the other hand, CD4 KITs did not fit into current differentiation paradigms, but included both hypoxic and cytotoxic subsets with a pervasive exhaustion signature. Thus, autoimmune nephritis is unlike acute pathogen immunity; rather the kidney microenvironment suppresses T cells by progressively inducing exhausted states. Our findings suggest that lupus nephritis, a chronic condition, results from slow evolution of damage caused by dysfunctional T cells and their precursors on the way to exhaustion. These findings have implications for both autoimmunity and tumor immunology.
2022-02-24 | GSE197339 | GEO
Project description:Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4+ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4+ T cell Ezh2 conditional knockout mouse on the MRL/lpr lupus-prone background. We demonstrate that Ezh2 deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programed cell death pathways in EZH2-deficient mice. Ezh2 deletion in CD4+ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4+ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.
2024-11-13 | GSE278393 | GEO
Project description:To identify factors that influence the progression of lupus nephritis (LN), we performed RNA sequencing on renal biopsy samples obtained from patients with active LN. The renal biopsy pathology followed the classification of the International Society of Nephrology and Renal Pathology Society (ISN/RPS) for 21 lupus nephritis patients: 2 in Class II, 3 in Class III, 10 in Class IV, 5 in Class V, and 1 patient with mixed type LN. The duration of disease from onset of systemic lupus erythematosus (SLE) to the onset of lupus nephritis was 26 months. Proteinuria was 2.5 (g/gCr or g/24hr), estimated Glomerular Filtration Rate (eGFR) was 72.9 (ml/min/1.73 m2), Index of activity was 5, and Index of chronicity was 3. Among different gene expression variations, the type I interferon (IFN) signature showed high expression in patients with shorter disease duration, preserved eGFR, and lower Index of chronicity. The type I IFN signature contributes to fibrosis in the tubulointerstitial space and worsens chronic lesions. Early control of the type I IFN signature may limit disease progression. Our results reveal a potential molecular mechanism for active LN and the link between functional and structural changes and differential gene expression observed in patients with early-stage LN.
2025-12-31 | GSE239576 | GEO
Project description:Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. T cell from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). Here we evaluated the functional role of CaMKIV in lupus nephritis (LN) using kidney biopsy specimens and human podocyte cell line (AB8/13). We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. CaMKIV expression was found to be increased in podocytes of LN kidney biopsy specimens and exposure to IgG from LN patients. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkivM-bM-^HM-^R/M-bM-^HM-^R mice. IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. These findings may indicate that inhibition of CaMKIV may prove of clinical use in patients with LN. IgG Purification Kits (Dojindo Molecular Technologies, Inc.) are used for isolation and purification of immunoglobulin G of healthy and normal individual according to the manufacturerM-bM-^@M-^Ys protocol. Flow through the column was used for non IgG binding samples. Cultured human podocytes with IgG purified from sera of normal individuals and LN patient for 24 hr were collected for RNA.
2014-08-01 | E-GEOD-55768 | biostudies-arrayexpress
Project description:Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from Lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody positive mice and the structures were organized as interconnected large networks with distinct T and B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS and LyN revealed a similar gene signature of TLS and LyN. The upregulated genes within the kidneys of lupus-prone mice during the development of LN reflected the TLS formation, while the downregulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar upregulated genes as observed during the development of murine LN and TLS. We conclude that kidney TLS have a similar cell composition, structure and gene signature as LyN, and therefore may function as a kidney specific type of LyN.
2020-07-30 | GSE155405 | GEO
Project description:<p>Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) and it occurs at a much higher rate in patients that are not of European descent. The purpose of this study is to identify genetic variants contributing to the risk of LN in a multi-ethnic cohort of SLE patients. We used a comprehensive genome-wide screen and 1244 SLE patients from 5 different ethnic groups. In genome-wide gene-based and candidate SNP analyses, we found distinct genes and pathways, and established risk SNPs associated with lupus nephritis for each ethnic group. This study represents progress in elucidating the genetic underpinnings driving LN among SLE patients of different ethnic groups.</p>
| phs001609 | dbGaP
Project description:Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. T cell from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). Here we evaluated the functional role of CaMKIV in lupus nephritis (LN) using kidney biopsy specimens and human podocyte cell line (AB8/13). We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. CaMKIV expression was found to be increased in podocytes of LN kidney biopsy specimens and exposure to IgG from LN patients. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv−/− mice. IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. These findings may indicate that inhibition of CaMKIV may prove of clinical use in patients with LN.
2014-08-01 | GSE55768 | GEO
Project description:Expansion of different CD4+ CXCR5+ and CXCR5- memory T helper cells has been reported in human systemic lupus erythematosus (SLE) blood. To understand their complexity, we profiled blood CD4+ T cells from heathy donors (HD) and pediatric SLE patients at the single cell level and identified naïve, memory, regulatory (Treg) and proliferative clusters, as well as a cluster defined by high expression of interferon-stimulated genes (ISGs). Within the memory compartment, we mapped follicular (Tfh) and peripheral (Tph and Th10) helper cells and confirmed their expansion in patients with lupus nephritis (LN) and/or high disease activity. Cytotoxic programs mapped to effector memory T cells re-expressing CD45RA (TEMRA), as well as to two memory subclusters, one of which overlapped with Th10 cells. Importantly, we identified an expansion of dysfunctional Tregs in patients with LN, and an upregulation of TLR5 and FCRL3 in naïve SLE Tregs, potentially linking their dysfunction with mucosal microbial dysbiosis. Our studies shed light into CD4+ T cell subsets that may contribute to dysfunctional B cell help and T cell suppression in SLE.
2025-09-05 | GSE285773 | GEO
Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (pâ¤0.05,SI>orâ¤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with pâ¤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN. We analyzed blood from 11 female subjects (5 lupus, 3 lupus nephritis and 3 healthy control) using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Alt Analyze and Genespring software. No techinical replicates were performed. One of the outiler sample (HC2) was excluded from further analysis.
2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress