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The immune cell landscape in kidneys of patients with lupus nephritis.

ABSTRACT: Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

SUBMITTER: Arazi A

PROVIDER: S-EPMC6726437 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The immune cell landscape in kidneys of patients with lupus nephritis.

Arazi Arnon A Rao Deepak A DA Berthier Celine C CC Davidson Anne A Liu Yanyan Y Hoover Paul J PJ Chicoine Adam A Eisenhaure Thomas M TM Jonsson A Helena AH Li Shuqiang S Lieb David J DJ Zhang Fan F Slowikowski Kamil K Browne Edward P EP Noma Akiko A Sutherby Danielle D Steelman Scott S Smilek Dawn E DE Tosta Patti P Apruzzese William W Massarotti Elena E Dall'Era Maria M Park Meyeon M Kamen Diane L DL Furie Richard A RA Payan-Schober Fernanda F Pendergraft William F WF McInnis Elizabeth A EA Buyon Jill P JP Petri Michelle A MA Putterman Chaim C Kalunian Kenneth C KC Woodle E Steve ES Lederer James A JA Hildeman David A DA Nusbaum Chad C Raychaudhuri Soumya S Kretzler Matthias M Anolik Jennifer H JH Brenner Michael B MB Wofsy David D Hacohen Nir N Diamond Betty B

Nature immunology 20190617 7

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory respo ...[more]

PMID: 31209404

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Project description:ObjectiveA challenging issue in the clinical management of lupus nephritis (LN) is the resistance to immunosuppressive therapy. We postulated that perturbed intrarenal immune cell landscape affected LN onset and remission induction, and shedding light on the characteristics of intrarenal immune cell infiltration could cultivate more efficient treatment regimens.Materials and methodsGenome-wide expression profiles of microarray datasets were downloaded from the Gene Expression Omnibus database. The CIBERSORT algorithm was used to analyze the intrarenal immune cell landscape, followed by Pearson correlation analysis and principal component analysis. The differentially expressed genes were identified and subjected to Gene Ontology (GO) enrichment analyses and protein-protein interaction network establishment, being visualized by Cytoscape and further analyzed by CytoHubba to extract hub genes. Hub genes were also validated in the genomic dataset from kidney biopsy-proven LN patients.ResultsIn addition to memory B cells, monocytes and M1 macrophages were identified as two predominantly increased intrarenal immune cell types in LN-prone NZB/W mice upon nephritis onset. Most interestingly, apart from memory B cells, monocytes and M1 macrophages proportions in kidney tissue were significantly lower in early remission mice compared with late remission mice. Furthermore, GO analysis showed that intrarenal mononuclear phagocytes triggered nephritis onset mainly via the initiation of adaptive immune response and inflammatory reaction, but this functional involvement was mitigated upon remission induction. Hub genes related to LN onset in NZB/W mice were validated in the genomic dataset from kidney biopsy-proven LN patients.ConclusionLN characterizes aberrant mononuclear phagocytes abundance and signature upon disease onset, of which the reversal is associated with early remission induction in LN-prone NZB/W mice. Mononuclear phagocytes might be an adjunctive histology marker for monitoring disease onset and stratifying LN patients in terms of response to remission induction therapy.

Project description:ObjectiveWe aimed to reveal a spatial proteomic and immune signature of kidney function regions in lupus nephritis (LN).Material and methodsThe laser capture microdissection (LCM) was used to isolate the glomerulus, tubules, and interstitial of the kidney from paraffin samples. The data-independent acquisition (DIA) method was used to collect proteomics data. The bioinformatic analysis was performed.ResultsA total of 49,658 peptides and 4056 proteins were quantitated. Our results first showed that a high proportion of activated NK cells, naive B cells, and neutrophils in the glomerulus, activated NK cells in interstitial, and resting NK cells were accumulated in tubules in LN. The immune-related function analysis of differential expression proteins in different regions indicated that the glomerulus and interstitial were major sites of immune disturbance and regulation connected with immune response activation. Furthermore, we identified 7, 8, and 9 hub genes in LN's glomerulus, renal interstitial, and tubules. These hub genes were significantly correlated with the infiltration of immune cell subsets. We screened out ALB, CTSB, LCN2, A2M, CDC42, VIM, LTF, and CD14, which show higher performance as candidate biomarkers after correlation analysis with clinical indexes. The function within three regions of the kidney was analyzed. The differential expression proteins (DEGs) between interstitial and glomerulus were significantly enriched in the immune-related biological processes, and myeloid leukocyte-mediated immunity and cellular response to hormone stimulus. The DEGs between tubules and glomerulus were significantly enriched in cell activation and leukocyte-mediated immunity. While the DEGs between tubules and interstitial were enriched in response to lipid, antigen processing, and presentation of peptide antigen response to oxygen-containing compound, the results indicated a different function within kidney regions.ConclusionsCollectively, we revealed spatial proteomics and immune signature of LN kidney regions by combined using LCM and DIA.

Project description:ObjectiveTo identify potential diagnostic markers of lupus nephritis (LN) based on bioinformatics and machine learning and to explore the significance of immune cell infiltration in this pathology.MethodsSeven LN gene expression datasets were downloaded from the GEO database, and the larger sample size was used as the training group to obtain differential genes (DEGs) between LN and healthy controls, and to perform gene function, disease ontology (DO), and gene set enrichment analyses (GSEA). Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), were applied to identify candidate biomarkers. The diagnostic value of LN diagnostic gene biomarkers was further evaluated in the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from LN patients and to analyze their correlation with diagnostic markers.ResultsThirty and twenty-one DEGs were screened in kidney tissue and peripheral blood, respectively. Both of which covered macrophages and interferons. The disease enrichment analysis of DEGs in kidney tissues showed that they were mainly involved in immune and renal diseases, and in peripheral blood it was mainly enriched in cardiovascular system, bone marrow, and oral cavity. The machine learning algorithm combined with external dataset validation revealed that C1QA(AUC = 0.741), C1QB(AUC = 0.758), MX1(AUC = 0.865), RORC(AUC = 0.911), CD177(AUC = 0.855), DEFA4(AUC= 0.843)and HERC5(AUC = 0.880) had high diagnostic value and could be used as diagnostic biomarkers of LN. Compared to controls, pathways such as cell adhesion molecule cam, and systemic lupus erythematosus were activated in kidney tissues; cell cycle, cytoplasmic DNA sensing pathways, NOD-like receptor signaling pathways, proteasome, and RIG-1-like receptors were activated in peripheral blood. Immune cell infiltration analysis showed that diagnostic markers in kidney tissue were associated with T cells CD8 and Dendritic cells resting, and in blood were associated with T cells CD4 memory resting, suggesting that CD4 T cells, CD8 T cells and dendritic cells are closely related to the development and progression of LN.ConclusionC1QA, C1QB, MX1, RORC, CD177, DEFA4 and HERC5 could be used as new candidate molecular markers for LN. It may provide new insights into the diagnosis and molecular treatment of LN in the future.

Dataset Information

The immune cell landscape in kidneys of patients with lupus nephritis.

Publications

The immune cell landscape in kidneys of patients with lupus nephritis.

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