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Open Access 01-12-2012 | Research article

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

Authors: Jack Hutcheson, Kamala Vanarsa, Anna Bashmakov, Simer Grewal, Deena Sajitharan, Betty Y Chang, Joseph J Buggy, Xin J Zhou, Yong Du, Anne B Satterthwaite, Chandra Mohan

Published in: Arthritis Research & Therapy | Issue 6/2012

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

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Title: Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus
Authors: Jack Hutcheson
Kamala Vanarsa
Anna Bashmakov
Simer Grewal
Deena Sajitharan
Betty Y Chang
Joseph J Buggy
Xin J Zhou
Yong Du
Anne B Satterthwaite
Chandra Mohan
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 6/2012
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/ar4086

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Abstract

Introduction

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