Targeting spleen tyrosine kinase-Bruton's tyrosine kinase axis for immunologically mediated glomerulonephritis.

Jin-Shuen Chen,Shyh-Jer Huang,Chao-Wen Cheng,Li-Chien Chang

doi:10.1155/2014/814869

Abstract

The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended.

Highlights

The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized
It plays a critical role in intracellular signal transduction of classical immunoreceptors associated with immunoreceptor tyrosine-based activation motifs (ITAMs), including the B-cell receptor (BcR) and Fc receptor (FcR)
Activation of spleen tyrosine kinase (Syk) appears to be mediated through an ITAM-independent pathway by multiple stimuli, including interleukin-1 (IL-1), integrin, lipopolysaccharide, and tumor necrosis factor- (TNF-) α [9], though the underlying mechanisms are currently unknown

Summary

Introduction

The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. In full-blown disease Improved proteinuria Reduced glomerulosclerosis and immune-complex deposition Inhibited B-cell activation and anti-dsDNA autoantibody secretion Downregulated expressions of inflammatory cytokines Targeting BcR activation and FcR responses by Syk and Btk inhibitors may provide alternative therapeutic regimens for lupus nephritis.

Results

Conclusion