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HONG XIAO; DAIRAGHI, Daniel J; BAO LU; GERARD, Norma P; GERARD, Craig; SCHALL, Thomas J; JAEN, Juan C; FALK, Ronald J; JENNETTE, J. Charles; POWERS, Jay P; ERTL, Linda S; BAUMGART, Trageen; YU WANG; SEITZ, Lisa C; PENFOLD, Mark E. T; LIN GAN; PEIQI HU
Journal of the American Society of Nephrology, 02/2014, Letnik: 25, Številka: 2Journal Article
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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