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*
Department of Internal Medicine,
Institute for Clinical Immunology and Transfusion Medicine, and
Department of Urology, Justus-Liebig-University, Giessen, Germany; and
First Medical Department, University of Mainz, Mainz, Germany
Among the anti-neutrophil cytoplasmic Abs (ANCA), those
targeting proteinase 3 (PR3) have a high sensitivity and specificity
for Wegener’s granulomatosis (WG). A pathogenetic role for these
autoantibodies has been proposed due to their capacity of activating
neutrophils in vitro. Recently, PR3 was also detected in human renal
tubular epithelial cells (TEC). In the present study, the effect of
murine monoclonal anti-PR3 Abs (anti-PR3) and purified c-ANCA
targeting PR3 from WG serum on isolated human renal tubular cell
signaling and inflammatory mediator release was characterized. Priming
of TEC with TNF-
resulted in surface expression of PR3, as
quantified in immunofluorescence studies and by flow cytometry.
Moreover, PR3 was immunoprecipitated on surface-labeled TEC. Primed TEC
responded to anti-PR3 with a dose- and time-dependent activation of
phosphoinositide hydrolysis, resulting in a remarkable accumulation of
inositolphosphates. Control IgG was entirely ineffective, whereas
PR3-ANCA reproduced the phosphoinositide response. The signaling
response was accompanied by a pronounced release of superoxidanion into
the cell supernatant. Moreover, large amounts of PGE2 and,
to a lesser extent, of thromboxane B2, the stable
metabolite of TxA2, were secreted from
anti-PR3-stimulated TEC. In parallel, a rise in intracellular cAMP
levels was observed, which was blocked by the cyclooxygenase inhibitor
indomethacin. We conclude that anti-PR3 Abs directly target renal
TECs, thereby provoking pronounced activation of the
phosphoinositide-related signal transduction pathway. Associated
metabolic events such as the release of reactive oxygen species and
lipid mediators may directly contribute to the development of renal
lesions and loss of kidney function in WG.
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