IL-16 Is Linked to Lupus Nephritis Activity

Andrea Fava¹, Deepak Rao², Chandra Mohan³, Ting Zhang³, Avi Rosenberg¹, Paride Fenaroli⁴, H. Michael Belmont⁵, Peter Izmirly⁶, Robert Clancy⁷, Jose Monroy-Trujillo¹, Derek Fine¹, Arnon Arazi⁸, Celine Berthier⁹, Anne Davidson¹⁰, Judith James¹¹, Betty Diamond¹², Nir Hacohen¹³, David Wofsy¹⁴, Soumya Raychaudhuri², Accelerating Medicines Partership (AMP) RA/SLE Network¹⁵, Jill Buyon⁵, Michelle Petri¹⁶ and The Accelerating Medicines Partnership in RA/SLE¹⁷, ¹Johns Hopkins University, Baltimore, MD, ²Brigham and Women's Hospital, Boston, MA, ³University of Houston, Houston, TX, ⁴Universita` degli Studi di Parma, Parma, Italy, ⁵NYU School of Medicine, New York, NY, ⁶New York University School of Medicine, New York, NY, ⁷NYU Grossman School of Medicine, New York, NY, ⁸Feinstein Institutes for Medical Research, Melrose, MA, ⁹University of Michigan, Ann Arbor, MI, ¹⁰Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, ¹¹Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²Northwell Health, Manhasset, NY, ¹³Broad Institute, Cambridge, MA, ¹⁴University of California San Francisco, San Francisco, CA, ¹⁵Brigham and Women's Hospital, Everett, MA, ¹⁶Johns Hopkins University School of Medicine, Baltimore, MD, ¹⁷Multiple Institutions, Multiple

Meeting: ACR Convergence 2021

Keywords: Biomarkers, Genomics and Proteomics, Lupus nephritis, Renal, Systemic lupus erythematosus (SLE)

Session Information

Date: Tuesday, November 9, 2021

Title: Abstracts: Genetics, Genomics & Proteomics (1935–1938)

Session Type: Abstract Session

Session Time: 4:30PM-4:45PM

Background/Purpose: There is a pressing need to identify novel therapeutic targets in lupus nephritis. Multiomic approaches hold great potential for discovery. We integrated urine proteomics and kidney single cell transcriptomics to discover biological processes and biomarkers associated with histologically active LN.

Methods: Urinary proteins (up to 1200) were quantified (RayBiotech Kiloplex) in urine samples from two independent cohorts of SLE patients with lupus nephritis (n=30 and n=144). Samples were collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy in SLE patients with proteinuria > 500mg/d. The NIH Activity Index was determined by a renal pathologist at each site. Intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from patients with active lupus nephritis (n=24).

Results: A total of 174 patients were included: 127 (73%) had a proliferative histological class (III or IV +/- V), 47 (27%) pure membranous (V). Urinary IL-16 showed the strongest positive correlation with histological activity (NIH Activity Index) in two independent cohorts (r=0.69, p=9∙10^-5; r=0.49, p=3∙10^-10; Figure 1). Response to treatment was paralleled by an early reduction of urinary IL-16 (Figure 2). Single cell RNA sequencing independently demonstrated that IL16 is the second most widely expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys (Figure 3).

Conclusion: Urine proteomics can profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16, a proinflammatory chemokine, in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

Figure 1. Urinary biomarkers associated with the LN NIH Activity Index. Volcano plots displaying Spearman correlation coefficient for 1000 (left) and 1200 (right) urinary biomarkers with LN histological activity. FDR = false discovery rate.

Figure 2. Urinary IL_16 declined early in treatment responders. Longitudinal trajectories of urinary IL_16 in patients with class III, IV, or V LN (n=351) according to their response status. Thick lines connect the medians at each time point. Response was defined at 52 weeks from renal biopsy (Complete, urine pr/cr (UPCR) < 0.5, serum creatinine < 125% of baseline, prednisone < 10mg/day; Partial, UPCR < 50% from baseline but >0.5, same creatinine and prednisone requirements; Non responder, not meeting previous definitions).

Figure 3. Intrarenal expression of IL16 based on single cell RNA sequencing of lupus nephritis kidney biopsies. (A) UMAP plot showing IL16 expression by all kidney infiltrating immune cells. (B) Percentage of cytokine positive cells across all kidney infiltrating immune cells. The bar plot shows the top 25 cytokines out of a comprehensive list of 236 obtained from the “Cytokine Registry” (Immport) and the Gene Ontology database.

Disclosures: A. Fava, None; D. Rao, Janssen, 5, 6, Bristol-Myers Squibb, 1, 5, Scipher Medicine, 2, Pfizer, 6, Merck, 6; C. Mohan, None; T. Zhang, None; A. Rosenberg, None; P. Fenaroli, None; H. Belmont, Alexion, 6; P. Izmirly, Momenta/Janssen, 1; R. Clancy, None; J. Monroy-Trujillo, None; D. Fine, None; A. Arazi, None; C. Berthier, None; A. Davidson, None; J. James, Progentec Diagnostics, Inc., 2; B. Diamond, ISD, 2, nextcure, 2, J5J, 2, astlia, 2, dbv, 2, cyxone, 2; N. Hacohen, None; D. Wofsy, None; S. Raychaudhuri, Mestag Therapeutics, 2, 12, Founder, Johnson & Johnson, 1, 2, Pfizer, 1, 2, Biogen, 5, Gilead Sciences, 2; A. (AMP) RA/SLE Network, None; J. Buyon, Bristol Myers Squibb, 1, GlaxoSmithKline, 2, Janssen, 2, Ventus, 2, Equillium, 2; M. Petri, Alexion, 1, Amgen, 1, Astrazeneca, 1, 5, Aurinia, 5, 6, Eli Lilly, 5, Emergent Biosolutions, 1, Exagen, 5, Gilead Biosciences, 2, GSK, 1, 5, IQVIA, 1, Idorsia Pharmaceuticals, 2, Janssen, 1, 5, Merck EMD Serono, 1, Momenta Pharmaceuticals, 2, PPD Development, 1, Sanofi, 2, Thermofisher, 5, UCB Pharmaceuticals, 2; T. Accelerating Medicines Partnership in RA/SLE, None.

To cite this abstract in AMA style:

Fava A, Rao D, Mohan C, Zhang T, Rosenberg A, Fenaroli P, Belmont H, Izmirly P, Clancy R, Monroy-Trujillo J, Fine D, Arazi A, Berthier C, Davidson A, James J, Diamond B, Hacohen N, Wofsy D, Raychaudhuri S, (AMP) RA/SLE Network A, Buyon J, Petri M, Accelerating Medicines Partnership in RA/SLE T. IL-16 Is Linked to Lupus Nephritis Activity [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/il-16-is-linked-to-lupus-nephritis-activity/. Accessed .

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