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




Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus - Download this document for free, or read online. Document in PDF available to download.

Arthritis Research and Therapy

, 14:R243

First Online: 08 November 2012Received: 01 June 2012Revised: 13 August 2012Accepted: 09 October 2012

Abstract

IntroductionSystemic 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.

MethodsB6.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.

ResultsIn 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.

ConclusionsThese 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.

AbbreviationsAPCantigen presenting cell

BCRB cell receptor

BLysB lymphocyte stimulator

BSAbovine serum albumin

BtkBruton-s tyrosine kinase

CLLchronic lymphocytic leukemia

ELISAenzyme-linked immunosorbent assay

GNglomerular nephritis

HandEhematoxylin and eosin

ILinterleukin

MCLmantle cell lymphoma

PASperiod acid Schiff

ROSreactive oxygen species

SLEsystemic lupus erythematosus

Sykspleen tyrosine kinase

TLRtoll-like receptor

TNP2,4,6-trinitrophenol

xidx-linked immunodeficiency.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4086 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Jack Hutcheson - Kamala Vanarsa - Anna Bashmakov - Simer Grewal - Deena Sajitharan - Betty Y Chang - Joseph J Buggy - Xin

Source: https://link.springer.com/







Related documents