THU0232 INTERFERON SIGNATURE IN LUPUS KIDNEY IS CORRELATED WITH REMISSION WITHIN 56 WEEKS
Authors: M. Kanda, T. Tsuji, M. Mukai, H. Takahashi, T. Atsumi, N. Hübner
Journal: Annals of the Rheumatic Diseases (2020)

Background: Activation of the type I interferon (IFN) pathway has been implicated in the initiation of systemic lupus erythematosus(SLE) and most SLE patients show increased expression of IFN-regulated genes in peripheral blood mononuclear cells or whole blood. However, the IFN signature in lupus kidney is not well examined especially at single cell resolution. Objectives: To clarify the significance of the IFN signature in lupus kidney at single cell resolution Methods: 18 lupus kidney (LN) and 34 transplanted kidney (KTx) samples were included in the study. Residual frozen kidney biopsies were collected after clinical diagnosis. The tissue from one donor was split into two. One portion was used for total RNA-Seq (tRNA-Seq) by SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara/Clontech). The rest was used for single nucleus RNA-Seq (snRNA-Seq) using Chromium Single Cell 3’ Reagent Kits v3 (10x Genomics) (7 LN and 17 KTx). For the tRNA-Seq, the sequence reads were aligned to Ensembl genome annotation (Ens93) by STAR and the aligned reads were counted by htseq. IFN score of tRNA-Seq was calculated using the reported method [1] per each module (M1.2, M3.4 and M5.12). For the snRNA-Seq, the sequenced reads were processed on the standard pipeline of CellRanger (10x Genomics) and the data was visualized using Seurat. IFN score of snRNA-Seq was computed by the method reported by Arazi A, et al [2]. Clinical outcomes of LN were examined on the medical records retrospectively and the clinical remission in 56 weeks for LN was defined as a urinary protein/creatinine ratio less than 0.5 g/gCr. Results: 11 LN had clinical remission and 7 LN showed non remitted disease within 56 weeks after the biopsy. There were no statistical significance co-variants such as age, gender and WHO class in pathology. IFN score of M1.2, M3.4 and M5.12 were significantly increased in LN with remission within 56 weeks (median 0.773 vs 0.659, 0.595 vs 0.243 and 0.415 vs 0.100: p-value 0.03, 0.01 and 0.02 [Wilcox rank-test]) in tRNA-Seq. In the snRNA-Seq, the lupus kidney with low IFN score showed restricted IFN signature in the endothelial cells mainly, which can be detected even in the controls, but those with high IFN score indicated broadly spread IFN signature among all of the cell types. Conclusion: LN with high IFN score in kidney tissue is correlated with remission within 56 weeks. LN with low IFN score showed IFN signature restricted to endothelial cells but those with a higher IFN score revealed broadly affected cell types with IFN signature. These results suggest that the IFN signature of LN may start from endothelial cells and then spread to the whole kidney. References: [1]Chiche L, Jourde-Chiche N, Whalen E, et al. Modular Transcriptional Repertoire Analyses of Adults With Systemic Lupus Erythematosus Reveal Distinct Type I and Type II Interferon Signatures. Arthritis &amp; Rheumatology 2014; 66 :1583–95. doi: 10.1002/art.38628 [2]Arazi A, Rao DA, Berthier CC, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol 2019; 20 :902–14. doi: 10.1038/s41590-019-0398-x Disclosure of Interests: : Masatoshi Kanda: None declared, Takahiro Tsuji: None declared, Masaya Mukai: None declared, Hiroki Takahashi: None declared, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Norbert Hübner: None declared