title: Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression.
abstract: Spleen tyrosine kinase (SYK) is an important component of the intracellular signaling pathway for various immunoreceptors. Inhibition of SYK has shown promise in preclinical models of autoimmune and glomerular disease. However, the description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is lacking. Here we conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from >120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, antiglomerular basement membrane disease, and acute tubular necrosis. 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, lupus nephritis, ANCA-associated glomerulonephritis, and antiglomerular basement membrane disease. SYK was phosphorylated within pathological lesions, such as areas of extracapillary and endocapillary proliferation, and appeared to localize to both infiltrating leucocytes and to resident renal cells within diseased glomeruli. Thus SYK is associated with the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment.
authors.affiliation: Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: McAdoo
authors.affiliation: Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Bhangal
authors.affiliation: Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Theresa
authors.initials: T
authors.lastname: Page
authors.affiliation: Centre for Complement and Inflammation Research, Imperial College London London, UK.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002196:Capillaries / Q000737:chemistry*; D003404:Creatinine / Q000097:blood; D004847:Epithelial Cells / Q000737:chemistry; D005921:Glomerulonephritis / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology*; D007686:Kidney Tubules, Distal / Q000737:chemistry; D007962:Leukocytes / Q000737:chemistry*; D009389:Neovascularization, Pathologic / Q000097:blood / Q000201:enzymology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis* / Q000378:metabolism; D000072377:Syk Kinase; D015854:Up-Regulation; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003404:Creatinine; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000606896:SYK protein, human