Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that has an important role in immunoreceptor signalling, including for the B cell receptor and activatory Fc receptors. SYK inhibition has shown efficacy in animal models of non-renal autoimmune disease. The role of SYK in experimental and clinical renal disease, however, is not well defined.
I have studied the effects of SYK inhibition using a specific small molecule inhibitor (R788; fostamatinib) in two distinct experimental models of glomerulonephritis in the rat. In experimental autoimmune glomerulonephritis (EAG; a model of anti-glomerular basement membrane disease), I have shown that SYK inhibition with fostamatinib both prevents and treats established disease. Significant attenuation of humoral autoimmune responses was observed, and ELISpot and flow cytometric analysis suggests that this was due to a direct inhibitory effect on B cell activity, rather than overall B cell survival. In addition, SYK inhibition appeared to inhibit antibody-dependent, Fc receptor-mediated pro-inflammatory responses, particularly within glomerular macrophages, in EAG. In experimental autoimmune vasculitis (EAV; a model of anti-neutrophil cytoplasm antibody [ANCA] associated vasculitis), SYK inhibition was an effective treatment for life-threatening manifestations of disease, including glomerulonephritis and lung haemorrhage.
I have also examined the pattern of SYK expression by immunohistochemistry in clinical renal biopsy specimens from approximately 100 patients with a spectrum of glomerular pathologies. I found that SYK is expressed and activated in proliferative types of glomerulonephritis, and that expression levels correlate with disease activity in anti-GBM disease, ANCA-associated vasculitis, lupus nephritis and IgA nephropathy.
These data suggest that SYK is important in the pathogenesis of proliferative glomerulonephritis. SYK inhibition is an effective treatment strategy for the organ-threatening manifestations of disease in two experimental models, and SYK inhibition therefore warrants further investigation in human renal disease.Open Acces
