Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis
Arna Katewa, … , Michael J. Townsend, Karin Reif
Arna Katewa, … , Michael J. Townsend, Karin Reif
Published April 6, 2017
Citation Information: JCI Insight. 2017;2(7):e90111. https://doi.org/10.1172/jci.insight.90111.
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Categories: Research Article Immunology

Btk-specific inhibition blocks pathogenic plasma cell signatures and myeloid cell–associated damage in IFNα-driven lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton’s tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens. Selective Btk inhibition ablated plasmablast generation, reduced autoantibodies, and — similar to cyclophosphamide — improved renal pathology in IFNα-accelerated lupus. Employing global transcriptional profiling of spleen and kidney coupled with cross-species human modular repertoire analyses, we identify similarities in the inflammatory process between mice and humans, and we demonstrate that G-744 reduced gene expression signatures essential for splenic B cell terminal differentiation, particularly the secretory pathway, as well as renal transcriptional profiles coupled with myeloid cell–mediated pathology and glomerular plus tubulointerstitial disease in human glomerulonephritis patients. These findings reveal the mechanism through which a selective Btk inhibitor blocks murine autoimmune kidney disease, highlighting pathway activity that may translate to human SLE.

Authors

Arna Katewa, Yugang Wang, Jason A. Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D. Austin, Meire Bremer, Jacob Zhi Chen, James J. Crawford, Kevin S. Currie, Peter Blomgren, Jason DeVoss, Julie A. DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E. DeForge, Zhonghua Lin, Marya Liimatta, Joseph W. Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P. Lee, Harvey Wong, Wendy B. Young, Michael J. Townsend, Karin Reif

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Figure 1

G-744 inhibits Btk signaling and B cell receptor–mediated (BCR-mediated) responses in murine B cells.

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G-744 inhibits Btk signaling and B cell receptor–mediated (BCR-mediated)...
(A) Chemical structure of G-744. (B–F) B cell signaling readouts in presence of indicated concentrations of G-744 or P505-15 following anti-IgM F(ab′)2 stimulation of primary murine splenic B cells. (B) Phosphorylation of Btk-Y223 in presence of G-744. The triangle indicates pBtk-Y223 phosphorylation in unstimulated B cells without G-744. (C) Phosphorylation of Akt-S473 in presence of G-744. (D and E) Induction of [Ca2+] in presence of (D) G-744 or (E) P505-15. Arrows indicate stimuli added. (F) Proliferation in presence of G-744. The triangle and square indicate B cell proliferation without G-744 in un- and anti-IgM F(ab′)2-stimulated B cells, respectively. (G) Inhibition of anti-IgD–induced CD86 induction in C57BL/6 mice by G-744. CD86 expression on splenic B220+ B cells was quantified by flow cytometry 6 h after anti-IgD stimulation. Mice were dosed orally with vehicle or G-744 as indicated prior to anti-IgD injection. Mean fluorescence intensity (MFI) is indicated for individual mice (represented by symbols), and data is expressed as mean ± SEM for each group (n = 5). Percent inhibition by G-744 treatment compared with stimulated vehicle control is indicated. *P < 0.05, **P < 0.0001, one-way ANOVA with Dunnett’s correction. (B–G) Graphs are representative of at least 3 experiments.