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Author Correction: Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways

Der, Evan; Suryawanshi, Hemant; Morozov, Pavel; Kustagi, Manjunath; Goilav, Beatrice; Ranabothu, Saritha; Izmirly, Peter; Clancy, Robert; Belmont, H Michael; Koenigsberg, Mordecai; Mokrzycki, Michele; Rominieki, Helen; Graham, Jay A; Rocca, Juan P; Bornkamp, Nicole; Jordan, Nicole; Schulte, Emma; Wu, Ming; Pullman, James; Slowikowski, Kamil; Raychaudhuri, Soumya; Guthridge, Joel; James, Judith; Buyon, Jill; Tuschl, Thomas; Putterman, Chaim
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 31605099
ISSN: 1529-2916
CID: 4130802

Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways

Der, Evan; Suryawanshi, Hemant; Morozov, Pavel; Kustagi, Manjunath; Goilav, Beatrice; Ranabathou, Saritha; Izmirly, Peter; Clancy, Robert; Belmont, H Michael; Koenigsberg, Mordecai; Mokrzycki, Michele; Rominieki, Helen; Graham, Jay A; Rocca, Juan P; Bornkamp, Nicole; Jordan, Nicole; Schulte, Emma; Wu, Ming; Pullman, James; Slowikowski, Kamil; Raychaudhuri, Soumya; Guthridge, Joel; James, Judith; Buyon, Jill; Tuschl, Thomas; Putterman, Chaim
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.
PMID: 31110316
ISSN: 1529-2916
CID: 3905602

Insights from single-cell RNA sequencing of skin and kidney in lupus nephritis [Meeting Abstract]

Der, E; Suryawanshi, H; Morozov, P; Kustagi, M; Goilav, B; Ranabothu, S; Izmirly, P; Clancy, R; Belmont, M; Koenigsberg, M; Mokrzycki, M; Rominiecki, H; Graham, J; Rocca, J; Bornkamp, N; Jordan, N; Schulte, E; Wu, M; Pullman, J; Slowikowski, K; Raychaudhuri, S; Guthridge, J; James, J A; Buyon, J; Tuschl, T; Putterman, C
Background Classification and treatment decisions in lupus nephritis (LN) are largely based on renal histology. Single-cell RNA sequencing (scRNAseq) analysis may accurately differentiate types of renal involvement at the transcriptomic level, and better inform treatment decisions and prognosis. Methods scRNAseq was performed on kidney and non-lesional skin tissue collected from 20 SLE patients undergoing a clinically indicated renal biopsy. Cell types were determined using principal component analysis and t-distributed stochastic neighbor embedding (tSNE) plotting, resulting in the definitive identification of keratinocytes, tubular cells, mesangial cells, fibroblasts, endothelial cells, and leukocytes. Results LN patients expressed upregulated IFN response genes in both their tubular cells and keratinocytes. This IFN response signature in tubular cells predicted poor response to therapy 6 months post-biopsy. Tubular cells of non-responder patients also expressed upregulated extracellular matrix proteins and fibrotic markers (figure 1A and 1B). Using logistic regression analysis, a 4-gene tubular fibrosis score was created and able to predict response to treatment with an area under curve of 0.9 (figure 1C). Keratinocytes of non-responders also upregulated certain extracellular matrix genes and this response was not observed in peripheral blood mononuclear cells. Differential expression analysis between histology classes indicated an upregulation of IFN and TNF signaling in the tubular cells of patients with proliferative LN compared with membranous. Conclusions scRNAseq from 2-10 mm of renal biopsy tissue in SLE can differentiate between the different classes of LN, and provide important insights into potential pathogenic mechanisms. Further, changes in the skin of LN patients can provide a useful source of biomarkers and may reflect important information concerning concurrent kidney pathological events
EMBASE:627466147
ISSN: 2053-8790
CID: 3861182

10X Genomics-Based Single-Cell RNA-Seq Analysis Identifies a Transcriptional Landscape of Inflammation and Fibrosis in Lupus Nephritis [Meeting Abstract]

Suryawanshi, Hemant; Der, Evan; Morozov, Pavel; Clancy, Robert M.; Goilav, Beatrice; Belmont, H. Michael; Izmirly, Peter M.; Bornkamp, Nicole; Jordan, Nicole; Wu, Ming; James, Judith A.; Guthridge, Joel M.; Raychaudhuri, Soumya; Buyon, Jill P.; Putterman, Chaim; Tuschl, Thomas
ISI:000447268905272
ISSN: 2326-5191
CID: 3726302

Single-cell RNA sequencing of skin and kidney cells in lupus nephritis provides insights into pathogenesis and indicates novel potential biomarkers [Meeting Abstract]

Der, Evan B.; Suryawanshi, Hemant; Ranabothu, Saritha; Goilav, Beatrice; Belmont, H. Michael; Izmirly, Peter; Bornkamp, Nicole; Jordan, Nicole; Wang, Tao; Wu, Ming; James, Judith A.; Guthridge, Joel M.; Raychaudhuri, Soumya; Buyon, Jill; Tuschl, Thomas; Putterman, Chaim
ISI:000459977700114
ISSN: 0022-1767
CID: 3727692

Kidney and Skin Single-Cell RNA Sequencing in Lupus Nephritis Provides Mechanistic Insights and Novel Potential Biomarkers [Meeting Abstract]

Der, Evan; Suryawanshi, Hemant; Ranabothu, Saritha; Goilav, Beatrice; Belmont, HMichael; Izmirly, Peter M; Bornkamp, Nicole; Jordan, Nicole; Wang, Tao; Wu, Ming; James, Judith A; Guthridge, Joel M; Raychaudhuri, Soumya; Tuschl, Thomas; Buyon, Jill P; Putterman, Chaim
ISI:000411824106261
ISSN: 2326-5205
CID: 2766732

Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis

Der, Evan; Ranabothu, Saritha; Suryawanshi, Hemant; Akat, Kemal M; Clancy, Robert; Morozov, Pavel; Kustagi, Manjunath; Czuppa, Mareike; Izmirly, Peter; Belmont, H Michael; Wang, Tao; Jordan, Nicole; Bornkamp, Nicole; Nwaukoni, Janet; Martinez, July; Goilav, Beatrice; Buyon, Jill P; Tuschl, Thomas; Putterman, Chaim
Lupus nephritis is a leading cause of mortality among systemic lupus erythematosus (SLE) patients, and its heterogeneous nature poses a significant challenge to the development of effective diagnostics and treatments. Single cell RNA sequencing (scRNA-seq) offers a potential solution to dissect the heterogeneity of the disease and enables the study of similar cell types distant from the site of renal injury to identify novel biomarkers. We applied scRNA-seq to human renal and skin biopsy tissues and demonstrated that scRNA-seq can be performed on samples obtained during routine care. Chronicity index, IgG deposition, and quantity of proteinuria correlated with a transcriptomic-based score composed of IFN-inducible genes in renal tubular cells. Furthermore, analysis of cumulative expression profiles of single cell keratinocytes dissociated from nonlesional, non-sun-exposed skin of patients with lupus nephritis also revealed upregulation of IFN-inducible genes compared with keratinocytes isolated from healthy controls. This indicates the possible use of scRNA-seq analysis of skin biopsies as a biomarker of renal disease. These data support the potential utility of scRNA-seq to provide new insights into the pathogenesis of lupus nephritis and pave the way for exploiting a readily accessible tissue to reflect injury in the kidney.
PMCID:5414553
PMID: 28469080
ISSN: 2379-3708
CID: 3177502

SLE-KeyTM rule-out serlogic test for SLE using the immunarray ICHIPTM [Meeting Abstract]

Batty, S; Cohen, I; Putterman, C; Jordan, N; Jakobi, K; Sorek, R; Blumenstein, Y
Background. SLE is associated with a broad spectrum of autoantibodies, but currently there is no single adequate serologic test. Lupus diagnosis is based on multiple criteria, and the disease can take years to evolve. Objectives. We developed the previously described iCHIPTM as an effective SLE rule-out diagnostic test by profiling SLE patients compared to healthy controls to rule out a diagnosis of SLE. An initial set of 200 antigens associated with SLE was augmented with sets of proprietary markers developed by ImmunArray. Here we report verification and validation of our SLE-KeyTM Rule-Out Serologic Test. Methods. We collected serum samples from 250 SLE patients and compared them with sera of 250 healthy control samples, all independently sourced. We tested these samples using the ImmunArray iCHIPTM. Training was performed on a subset of 150 SLE patients and 150 healthy controls using 4 independent classification methods. Verification and validation were performed on an additional sets of 50 SLE patients and 50 healthy control samples each. Results. All 4 classification methods differentiated SLE patients from healthy subjects. Validation of the different classification methods was performed on the remaining set of 50 SLE patients and 50 healthy controls showing sensitivity of greater than 90% and specificity of greater than 70% using a selected subset of auto-antigens. Conclusions. The SLE-KeyTM multiplex test can be used to assist physicians in ruling out serologically a diagnosis of SLE with a sensitivity of >90%. Work comparing this testing performance in direct comparison to standard serologic testing is ongoing
EMBASE:71976724
ISSN: 0392-856x
CID: 1749542

Single-Cell RNA Sequencing of Human Podocytes, Endothelial Cells, and Tubular Cells Identifies Markers and Gene Profiles Differentiating Class IV and Class V Renal Disease in Lupus Nephritis [Meeting Abstract]

Der, Even; Akat, Kemal; Clancy, Robert; Goilav, Beatrice; Broder, Anna R; Belmont, HMichael; Izmirly, Peter M; Jordan, Nicole; Wang, Tao; Pullman, James; Schwartz, Daniel; Wu, Ming; Tuschl, Thomas; Buyon, Jill P; Putterman, Chaim
ISI:000370860202335
ISSN: 2326-5205
CID: 2029552

Higher rates and clustering of abnormal lipids, obesity, and diabetes mellitus in psoriatic arthritis compared with rheumatoid arthritis

Labitigan, Monalyn; Bahce-Altuntas, Asena; Kremer, Joel M; Reed, George; Greenberg, Jeff D; Jordan, Nicole; Putterman, Chaim; Broder, Anna
OBJECTIVE: We compared the prevalence and the clustering of the metabolic syndrome (MetS) components (obese body mass index [BMI; >/=30 kg/m(2) ], hypertriglyceridemia, low high-density lipids, hypertension, and diabetes mellitus) in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. METHODS: We included CORRONA participants with a rheumatologist-confirmed clinical diagnosis of PsA or RA with complete data. We used a modified definition of MetS that did not include insulin resistance, waist circumference, or blood pressure measurements. Logistic regression models were adjusted for age, sex, and race. RESULTS: In the overall CORRONA population, the rates of diabetes mellitus and obesity were significantly higher in PsA compared with RA. In 294 PsA and 1,162 RA participants who had lipids measured, the overall prevalence of MetS in PsA versus RA was 27% versus 19%. The odds ratio (OR) of MetS in PsA versus RA was 1.44 (95% confidence interval [95% CI] 1.05-1.96, P = 0.02). The prevalence of hypertriglyceridemia was higher in PsA compared with RA (38% versus 28%; OR 1.51 [95% CI 1.15-1.98], P = 0.003). The prevalence of type 2 diabetes mellitus was also higher in PsA compared with RA (15% versus 11%; OR 1.56 [95% CI 1.07-2.28], P = 0.02) in the adjusted model. Similarly, higher rates of hypertriglyceridemia and diabetes mellitus were observed in the subgroup of PsA and RA patients with obese BMI. CONCLUSION: Compared with RA, PsA is associated with higher rates of obesity, diabetes mellitus, and hypertriglyceridemia.
PMCID:3969762
PMID: 24115739
ISSN: 2151-464x
CID: 883522