Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression

摘要

Spleen tyrosine kinase (SYK) is an important component of the intracellular signalling pathway for various immunoreceptors, and SYK inhibition has shown promise in preclinical models of autoimmune and glomerular disease. The description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is however lacking. Here, we have conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from over 120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis (LN), ANCA associated glomerulonephritis (AAGN), anti-glomerular basement membrane (anti-GBM) disease, and acute tubular necrosis (ATN). We found significant SYK expression in proliferative glomerulonephritis, and that glomerular expression levels correlated with presenting serum creatinine and histological features of disease activity that predict outcome in IgA nephropathy, LN, AAGN and anti-GBM disease. SYK is phosphorylated within pathological lesions, such as areas of extra- and endocapillary proliferation, and appeared to localise both to infiltrating leucocytes and resident renal cells within diseased glomeruli. These data strongly implicate SYK in the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment, and our results may inform the development of future clinical studies in this field.