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J Am Soc Nephrol. 2014 Feb;25(2):225-31. doi: 10.1681/ASN.2013020143. Epub 2013 Oct 31.

C5a receptor (CD88) blockade protects against MPO-ANCA GN.

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1
Department of Pathology and Laboratory Medicine and.

Abstract

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.

Comment in

PMID:
24179165
PMCID:
PMC3904560
DOI:
10.1681/ASN.2013020143
[Indexed for MEDLINE]
Free PMC Article

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