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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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Research Article Immunology

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

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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 5

Effect on renal IgM and IgG deposition after short-term treatment with G-744, P505-15, or cyclophosphamide in IFNα-accelerated LN.

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Effect on renal IgM and IgG deposition after short-term treatment with G...
Kidney sections were examined for IgM and IgG staining for each group derived from the experiment in Figure 4. (A) Representative immunofluorescence images of kidney sections showing IgM-rich deposits in glomeruli. Images are magnified 100×. Scale bars: 50 μm. (B–E) Intensity scores of the (B) glomerular IgM signal (representative images shown in A), (C) tubular IgM signal, (D) glomerular IgG signal, and (E) tubular IgG signal from kidney sections for the groups indicated (n = 10, except Ig control [n = 6], BR3-Fc [n = 8]). Statistical significance was determined using Fisher’s exact test between naive and vehicle groups; between vehicle and G-744, P505-15, and cyclophosphamide groups; and between Ig control and BR3-Fc groups (*P < 0.05, **P < 0.005, ***P < 0.0005).

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