ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1018

Renal Single Cell Genomics Links Type II Interferon and Lupus Nephritis in African-Americans

Andrea Fava1, Yuji Zhang 2, Jill Buyon 3, Chaim Putterman 4, Nir Hacohen 5, Arnon Arazi 5, Celine Berthier 6, Deepak Rao 7, Michael Brenner 8, David Wofsy 9, Anne Davidson 10, Mathias Kretzler 11, David Hildeman 12, E. Steve Woodle 12, Betty Diamond 10, Thomas Tuschl 13, Evan Der 14, Hemant Suryawanshi 13, H. Michael Belmont 15, Peter Izmirly 16, Robert Clancy 16, The Accelerating Medicines Partnership 17 and Michelle Petri 18, 1Johns Hopkins University, Baltimore, 2University of Maryland, Baltimore, 3NYU School of Medicine, New York, 4Albert Einstein College of Medicine, New York, NY, 5Broad Institute, Cambridge, 6University of Michigan, Ann Arbor, MI, 7Brigham and Women's Hospital, Boston, MA, 8Brigham and Women’s Hospital:, Boston, 9UCSF, San Francisco, 10Feinstein Institutes for Medical Research, Manhasset, 11University of Michigan, Ann Arbor, 12University of Cincinnati, Cincinnati, 13Rockefeller Research Laboratories, New York, 14Albert Einstein College of Medicine, New York, 15New York University School of Medicine, Ney York, 16New York University School of Medicine, New York, 17Multiple Organizations, USA, 18Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: , , ,

Session Information

Date: Monday, November 11, 2019

Title: SLE – Etiology & Pathogenesis Poster I

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Compared to Caucasian, African-American ethnicity is associated with a higher risk of developing systemic lupus erythematosus, lupus nephritis, high-risk histological features, resistance to treatment, and mortality. In phase 1 of the Accelerating Medicines Partnership (AMP), we used single-cell genomics to identify ethnicity associated features.

Methods: Single cell RNA sequencing was performed on renal biopsies obtained for clinical purpose; one pipeline applying CEL-Seq2 in a leukocyte enriched sample and the other Fluidigm C1 800 in an agnostic approach to dissociated renal cells. Differential abundance of cell populations was determined using a logistic mixed model. Then, the differential expression profile was determined for each cell cluster and interpreted using pathway enrichment analysis.

Results: Samples from 19 African-American and 20 Caucasian patients were obtained. We identified 30 cell clusters. Type I and II interferon inducible genes were upregulated in most cell populations. A cluster of T cells with exceptionally high interferon signature was found to be increased in African-Americans (OR 4.8). Macrophages and DC4-like dendritic cells were instead less abundant (OR 0.3). In African-Americans, type I and II interferon response pathways were enriched in several cell types including T cells, B cells, plasma cells, and activated monocytes. The majority of the differentially expressed genes was specifically inducible by type II interferon. In addition, while there was no local expression of type I interferons, interferon gamma was abundantly expressed by infiltrating NK and CD8 T cells.

Conclusion: African-American patients with lupus nephritis have a stronger interferon response pathway activation, especially type II. Our findings suggest an intrinsic biological factor underlying the outcome gap and highlight the role of interferon gamma in lupus nephritis, implicating this pathway as a potential therapeutic target in SLE. Further work in Phase 2 of AMP is being pursued to validate and extend these findings.

Disclosure: A. Fava, None; Y. Zhang, None; J. Buyon, Bristol Myers Squibb, 5, Exagen Diagnostics, 2; C. Putterman, Equillium, 5, Equillium, Inc, 2, 5, Exagen, 2; N. Hacohen, Neon Therapeutics, 1, 8; A. Arazi, None; C. Berthier, None; D. Rao, Janssen, 5, Merck, 2, Pfizer, 5; M. Brenner, None; D. Wofsy, Celgene, 5, Genentech, 5, GlaxoSmithKline, Lilly, 5, Novartis, Principia, 5; A. Davidson, None; M. Kretzler, None; D. Hildeman, None; E. Woodle, None; B. Diamond, GSK, 5, Jansen, 5, Lilly, 5; T. Tuschl, None; E. Der, None; H. Suryawanshi, None; H. Belmont, None; P. Izmirly, Glaxosmithkline, 5, GSK, 5; R. Clancy, None; T. Accelerating Medicines Partnership, None; M. Petri, Eli Lilly and Company, 5, Exagen, 2, 5.

To cite this abstract in AMA style:

Fava A, Zhang Y, Buyon J, Putterman C, Hacohen N, Arazi A, Berthier C, Rao D, Brenner M, Wofsy D, Davidson A, Kretzler M, Hildeman D, Woodle E, Diamond B, Tuschl T, Der E, Suryawanshi H, Belmont H, Izmirly P, Clancy R, Accelerating Medicines Partnership T, Petri M. Renal Single Cell Genomics Links Type II Interferon and Lupus Nephritis in African-Americans [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/renal-single-cell-genomics-links-type-ii-interferon-and-lupus-nephritis-in-african-americans/. Accessed .

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