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Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus

Jack Hutcheson1, Kamala Vanarsa1, Anna Bashmakov1, Simer Grewal1, Deena Sajitharan1, Betty Y Chang2, Joseph J Buggy2, Xin J Zhou3, Yong Du1, Anne B Satterthwaite1 and Chandra Mohan1*

Author Affiliations

1 University of Texas Southwestern Medical Center, Department of Internal Medicine, Division of Rheumatic Diseases, 5323 Harry Hines Blvd., Dallas, TX 75390-8884, USA

2 Pharmacyclics, Inc., 995 East Arques Avenue, Sunnyvale, California 94085, USA

3 University of Texas Southwestern Medical Center, Department of Pathology, 5323 Harry Hines Blvd., Dallas, TX 75390-8884, USA

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Arthritis Research & Therapy 2012, 14:R243  doi:10.1186/ar4086

Published: 8 November 2012



Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice.


B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated.


In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis.


These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.