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Article ; Online: The lupus nephritis management renaissance.

Mejia-Vilet, Juan M / Malvar, Ana / Arazi, Arnon / Rovin, Brad H

2021 Volume 101, Issue 2, Page(s) 242–255

Abstract: Over the past year, and for the first time ever, the US Food and Drug Administration approved 2 drugs specifically for the treatment of lupus nephritis (LN). As the lupus community works toward understanding how to best use these new therapies, it is ... ...

Abstract	Over the past year, and for the first time ever, the US Food and Drug Administration approved 2 drugs specifically for the treatment of lupus nephritis (LN). As the lupus community works toward understanding how to best use these new therapies, it is also an ideal time to begin to rethink the overall management strategy of LN. In addition to new drugs, this must include how to use kidney biopsies for management and not just diagnosis, how molecular technologies can be applied to interrogate biopsies and how such data can impact management, and how to incorporate LN biomarkers into management paradigms. Herein, we will review new developments in these areas of LN and put them into perspective for disease management now and in the future.
MeSH term(s)	Biomarkers ; Biopsy ; Humans ; Kidney/pathology ; Lupus Erythematosus, Systemic ; Lupus Nephritis/diagnosis ; Lupus Nephritis/drug therapy
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2021.09.012
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Article ; Online: Design and application of single-cell RNA sequencing to study kidney immune cells in lupus nephritis.

Rao, Deepak A / Arazi, Arnon / Wofsy, David / Diamond, Betty

Nature reviews. Nephrology

2019 Volume 16, Issue 4, Page(s) 238–250

Abstract: The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present ...

Abstract	The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.
MeSH term(s)	Biopsy, Needle ; Epithelial Cells/immunology ; Epithelial Cells/pathology ; Female ; Humans ; Immunohistochemistry ; Lupus Nephritis/genetics ; Lupus Nephritis/immunology ; Lupus Nephritis/pathology ; Male ; Molecular Biology/methods ; Sensitivity and Specificity ; Sequence Analysis, RNA ; Whole Exome Sequencing/methods
Language	English
Publishing date	2019-12-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2490366-8
ISSN	1759-507X ; 1759-5061
ISSN (online)	1759-507X
ISSN	1759-5061
DOI	10.1038/s41581-019-0232-6
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Article: Associations between circulating interferon and kynurenine/tryptophan pathway metabolites: support for a novel potential mechanism for cognitive dysfunction in SLE.

Anderson, Erik W / Jin, Ying / Shih, Andrew / Arazi, Arnon / Goodwin, Sara / Roeser, Julien / Furie, Richard A / Aranow, Cynthia / Volpe, Bruce / Diamond, Betty / Mackay, Meggan

Lupus science & medicine

2022 Volume 9, Issue 1

Abstract: Objective: Quinolinic acid (QA), a kynurenine (KYN)/tryptophan (TRP) pathway metabolite, is an N-methyl-D-aspartate receptor agonist that can produce excitotoxic neuron damage. Type I and II interferons (IFNs) stimulate the KYN/TRP pathway, producing ... ...

Abstract	Objective: Quinolinic acid (QA), a kynurenine (KYN)/tryptophan (TRP) pathway metabolite, is an N-methyl-D-aspartate receptor agonist that can produce excitotoxic neuron damage. Type I and II interferons (IFNs) stimulate the KYN/TRP pathway, producing elevated QA/kynurenic acid (KA), a potential neurotoxic imbalance that may contribute to SLE-mediated cognitive dysfunction. We determined whether peripheral blood interferon-stimulated gene (ISG) expression associates with elevated serum KYN:TRP and QA:KA ratios in SLE. Methods: ISG expression (whole-blood RNA sequencing) and serum metabolite ratios (high-performance liquid chromatography) were measured in 72 subjects with SLE and 73 healthy controls (HCs). ISG were identified from published gene sets and individual IFN scores were derived to analyse associations with metabolite ratios, clinical parameters and neuropsychological assessments. SLE analyses were grouped by level of ISG expression ('IFN high', 'IFN low' and 'IFN similar to HC') and level of monocyte-associated gene expression (using CIBERSORTx). Results: Serum KYN:TRP and QA:KA ratios were higher in SLE than in HC (p<0.01). 933 genes were differentially expressed ≥2-fold in SLE versus HC (p<0.05). 70 of the top 100 most highly variant genes were ISG. Approximately half of overexpressed genes that correlated with KYN:TRP and QA:KA ratios (p<0.05) were ISG. In 36 IFN-high subjects with SLE, IFN scores correlated with KYN:TRP ratios (p<0.01), but not with QA:KA ratios. Of these 36 subjects, 23 had high monocyte-associated gene expression, and in this subgroup, the IFN scores correlated with both KY:NTRP and QA:KA ratios (p<0.05). Conclusions: High ISG expression correlated with elevated KYN:TRP ratios in subjects with SLE, suggesting IFN-mediated KYN/TRP pathway activation, and with QA:KA ratios in a subset with high monocyte-associated gene expression, suggesting that KYN/TRP pathway activation may be particularly important in monocytes. These results need validation, which may aid in determining which patient subset may benefit from therapeutics directed at the IFN or KYN/TRP pathways to ameliorate a potentially neurotoxic QA/KA imbalance.
MeSH term(s)	Humans ; Kynurenine/metabolism ; Tryptophan/metabolism ; Interferons ; Lupus Erythematosus, Systemic/complications ; Kynurenic Acid/metabolism ; Quinolinic Acid/metabolism ; Cognitive Dysfunction/etiology
Chemical Substances	Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Interferons (9008-11-1) ; Kynurenic Acid (H030S2S85J) ; Quinolinic Acid (F6F0HK1URN)
Language	English
Publishing date	2022-11-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2779620-6
ISSN	2053-8790
ISSN	2053-8790
DOI	10.1136/lupus-2022-000808
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Article ; Online: β Cells that Resist Immunological Attack Develop during Progression of Autoimmune Diabetes in NOD Mice.

Rui, Jinxiu / Deng, Songyan / Arazi, Arnon / Perdigoto, Ana Luisa / Liu, Zongzhi / Herold, Kevan C

Cell metabolism

2017 Volume 25, Issue 3, Page(s) 727–738

Abstract: Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells during the progression of T1D in non-obese diabetic (NOD) ... ...

Abstract	Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal β cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of β cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclophosphamide. Human β cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long-term survival of β cells in some patients.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; CD3 Complex/metabolism ; Cell Survival/drug effects ; Cell Survival/immunology ; Cells, Cultured ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/pathology ; Disease Progression ; Female ; Humans ; Immunotherapy ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/immunology ; Insulin-Secreting Cells/pathology ; Lymphocytes/drug effects ; Lymphocytes/pathology ; Mice, Inbred NOD ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, RNA ; Transcription, Genetic/drug effects ; Transcriptome/drug effects ; Transcriptome/genetics
Chemical Substances	Antibodies, Monoclonal ; CD3 Complex
Language	English
Publishing date	2017-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2017.01.005
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Article ; Online: Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis.

Fava, Andrea / Buyon, Jill / Magder, Laurence / Hodgin, Jeff / Rosenberg, Avi / Demeke, Dawit S / Rao, Deepak A / Arazi, Arnon / Celia, Alessandra Ida / Putterman, Chaim / Anolik, Jennifer H / Barnas, Jennifer / Dall'Era, Maria / Wofsy, David / Furie, Richard / Kamen, Diane / Kalunian, Kenneth / James, Judith A / Guthridge, Joel /

Atta, Mohamed G / Monroy Trujillo, Jose / Fine, Derek / Clancy, Robert / Belmont, H Michael / Izmirly, Peter / Apruzzese, William / Goldman, Daniel / Berthier, Celine C / Hoover, Paul / Hacohen, Nir / Raychaudhuri, Soumya / Davidson, Anne / Diamond, Betty / Petri, Michelle

JCI insight

2024 Volume 9, Issue 2

Abstract: Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of ... ...

Abstract	Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.
MeSH term(s)	Humans ; Lupus Nephritis/drug therapy ; Proteomics ; Proteinuria ; Inflammation ; Aggression
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.172569
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Article ; Online: Accelerating Medicines Partnership: Organizational Structure and Preliminary Data From the Phase 1 Studies of Lupus Nephritis.

Hoover, Paul / Der, Evan / Berthier, Celine C / Arazi, Arnon / Lederer, James A / James, Judith A / Buyon, Jill / Petri, Michelle / Belmont, H Michael / Izmirly, Peter / Wofsy, David / Hacohen, Nir / Diamond, Betty / Putterman, Chaim / Davidson, Anne

Arthritis care & research

2020 Volume 72, Issue 2, Page(s) 233–242

Abstract: The Accelerating Medicines Partnership (AMP) Lupus Network was established as a partnership between the National Institutes of Health, pharmaceutical companies, nonprofit stakeholders, and lupus investigators across multiple academic centers to apply ... ...

Abstract	The Accelerating Medicines Partnership (AMP) Lupus Network was established as a partnership between the National Institutes of Health, pharmaceutical companies, nonprofit stakeholders, and lupus investigators across multiple academic centers to apply high-throughput technologies to the analysis of renal tissue, urine, and blood from patients with lupus nephritis (LN). The AMP network provides publicly accessible data to the community with the goal of generating new scientific hypotheses and improving diagnostic and therapeutic tools so as to improve disease outcomes. We present here a description of the structure of the AMP Lupus Network and a summary of the preliminary results from the phase 1 studies. The successful completion of phase 1 sets the stage for analysis of a large cohort of LN samples in phase 2 and provides a model for establishing similar discovery cohorts.
MeSH term(s)	Academic Medical Centers/organization & administration ; Biomarkers/metabolism ; Clinical Trials, Phase I as Topic/methods ; Drug Industry/organization & administration ; Humans ; Lupus Nephritis/epidemiology ; Lupus Nephritis/genetics ; Lupus Nephritis/metabolism ; National Institutes of Health (U.S.)/organization & administration ; Preliminary Data ; Public-Private Sector Partnerships/organization & administration ; Sequence Analysis, RNA/methods ; United States/epidemiology
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	645059-3
ISSN	2151-4658 ; 0893-7524 ; 2151-464X
ISSN (online)	2151-4658
ISSN	0893-7524 ; 2151-464X
DOI	10.1002/acr.24066
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Article ; Online: Urine Proteomics and Renal Single-Cell Transcriptomics Implicate Interleukin-16 in Lupus Nephritis.

Arthritis & rheumatology (Hoboken, N.J.)

2022 Volume 74, Issue 5, Page(s) 829–839

Abstract: Objective: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the ... ...

Abstract	Objective: Current lupus nephritis (LN) treatments are effective in only 30% of patients, emphasizing the need for novel therapeutic strategies. We undertook this study to develop mechanistic hypotheses and explore novel biomarkers by analyzing the longitudinal urinary proteomic profiles in LN patients undergoing treatment. Methods: We quantified 1,000 urinary proteins in 30 patients with LN at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single-cell transcriptomics of renal biopsy sections from LN patients. Results: Our analysis revealed multiple biologic pathways, including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization, which could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with LN, as compared to controls without systemic lupus erythematosus. Interleukin-16 (IL-16), CD163, and transforming growth factor β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction in urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single-cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in LN kidneys. IL-16-producing cells were found at key sites of kidney injury. Conclusion: Urine proteomics may profoundly change the diagnosis and management of LN by noninvasively monitoring active intrarenal biologic pathways. These findings implicate IL-16 in LN pathogenesis, designating it as a potentially treatable target and biomarker.
MeSH term(s)	Biological Products ; Biomarkers/metabolism ; Female ; Humans ; Interleukin-16/genetics ; Interleukin-16/metabolism ; Kidney/pathology ; Lupus Nephritis/pathology ; Male ; Proteomics/methods ; Single-Cell Analysis ; Transcriptome
Chemical Substances	Biological Products ; Biomarkers ; Il16 protein, human ; Interleukin-16
Language	English
Publishing date	2022-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.42023
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Article: Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.

Horisberger, Alice / Griffith, Alec / Keegan, Joshua / Arazi, Arnon / Pulford, John / Murzin, Ekaterina / Howard, Kaitlyn / Hancock, Brandon / Fava, Andrea / Sasaki, Takanori / Ghosh, Tusharkanti / Inamo, Jun / Beuschel, Rebecca / Cao, Ye / Preisinger, Katie / Gutierrez-Arcelus, Maria / Eisenhaure, Thomas M / Guthridge, Joel / Hoover, Paul J /

Dall'Era, Maria / Wofsy, David / Kamen, Diane L / Kalunian, Kenneth C / Furie, Richard / Belmont, Michael / Izmirly, Peter / Clancy, Robert / Hildeman, David / Woodle, E Steve / Apruzzese, William / McMahon, Maureen A / Grossman, Jennifer / Barnas, Jennifer L / Payan-Schober, Fernanda / Ishimori, Mariko / Weisman, Michael / Kretzler, Matthias / Berthier, Celine C / Hodgin, Jeffrey B / Demeke, Dawit S / Putterman, Chaim / Brenner, Michael B / Anolik, Jennifer H / Raychaudhuri, Soumya / Hacohen, Nir / James, Judith A / Davidson, Anne / Petri, Michelle A / Buyon, Jill P / Diamond, Betty / Zhang, Fan / Lederer, James A / Rao, Deepak A

bioRxiv : the preprint server for biology

2024

Abstract: Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations ... ...

Abstract	Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
Language	English
Publishing date	2024-03-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.14.575609
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Article: Human systems immunology: Hypothesis-based modeling and unbiased data-driven approaches

Arazi, Arnon / Pendergraft, William F., III / Ribeiro, Ruy M / Perelson, Alan S / Hacohen, Nir

Seminars in immunology. 2013 Oct. 31, v. 25, no. 3

2013

Abstract: Systems immunology is an emerging paradigm that aims at a more systematic and quantitative understanding of the immune system. Two major approaches have been utilized to date in this field: unbiased data-driven modeling to comprehensively identify ... ...

Abstract	Systems immunology is an emerging paradigm that aims at a more systematic and quantitative understanding of the immune system. Two major approaches have been utilized to date in this field: unbiased data-driven modeling to comprehensively identify molecular and cellular components of a system and their interactions; and hypothesis-based quantitative modeling to understand the operating principles of a system by extracting a minimal set of variables and rules underlying them. In this review, we describe applications of the two approaches to the study of viral infections and autoimmune diseases in humans, and discuss possible ways by which these two approaches can synergize when applied to human immunology.
Keywords	autoimmune diseases ; humans ; immune system ; immunology ; models
Language	English
Dates of publication	2013-1031
Size	p. 193-200.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2012.11.003
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Article ; Online: Human systems immunology: hypothesis-based modeling and unbiased data-driven approaches.

Arazi, Arnon / Pendergraft, William F / Ribeiro, Ruy M / Perelson, Alan S / Hacohen, Nir

Seminars in immunology

2013 Volume 25, Issue 3, Page(s) 193–200

Abstract	Systems immunology is an emerging paradigm that aims at a more systematic and quantitative understanding of the immune system. Two major approaches have been utilized to date in this field: unbiased data-driven modeling to comprehensively identify molecular and cellular components of a system and their interactions; and hypothesis-based quantitative modeling to understand the operating principles of a system by extracting a minimal set of variables and rules underlying them. In this review, we describe applications of the two approaches to the study of viral infections and autoimmune diseases in humans, and discuss possible ways by which these two approaches can synergize when applied to human immunology.
MeSH term(s)	Allergy and Immunology ; Autoimmune Diseases/immunology ; Evidence-Based Medicine ; Humans ; Immune System ; Models, Biological ; Systems Biology ; Virus Diseases/immunology
Language	English
Publishing date	2013-01-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2012.11.003
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