Antimyeloperoxidase antibodies rapidly induce alpha 4-integrin-dependent glomerular neutrophil adhesion

作者：Kuligowski Michael P; Kwan Rain Y Q; Lo Cecilia; Wong Cyndi; James Will G; Bourges Dorothee; Ooi Joshua D; Abeynaike Latasha D; Hall Pam; Kitching A Richard; Hickey Michael J^*

来源：Blood, 2009, 113(25): 6485-6494.

DOI：10.1182/blood-2008-12-192617

Patients with antineutrophil cytoplasmic antibodies (ANCAs) frequently develop severe vasculitis and glomerulonephritis. Although ANCAs, particularly antimyeloperoxidase (anti-MPO), have been shown to promote leukocyte adhesion in postcapillary venules, their ability to promote adhesion in the glomerular vasculature is less clear. We used intravital microscopy to examine glomerular leukocyte adhesion induced by anti-MPO. In mice pretreated with LPS, 50 mu g anti-MPO induced LFA-1-dependent adhesion in glomeruli. In concert with this finding, in mice pretreated with LPS, more than 80% of circulating neutrophils bound anti-MPO within 5 minutes of intravenous administration. However, even in the absence of LPS, more than 40% of circulating neutrophils bound anti-MPO in vivo, a response not seen in MPO(-/-) mice. In addition, a higher dose of anti-MPO (200 mu g) induced robust glomerular leukocyte adhesion in the absence of LPS. The latter response was beta 2-integrin independent, instead requiring the alpha 4-integrin, which was up-regulated on neutrophils in response to anti-MPO. These data indicate that anti-MPO antibodies bind to circulating neutrophils, and can induce glomerular leukocyte adhesion via multiple pathways. Lower doses induce adhesion only after an infection-related stimulus, whereas higher doses are capable of inducing responses in the absence of an additional inflammatory stimulus, via alternative adhesion mechanisms. (Blood. 2009; 113: 6485-6494)

• 出版日期2009-6-18