C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

Abstract

IntroductionThe complement system is crucial for the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In particular, C5a plays a central role. In this study, plasma and urinary levels of C5a as well as renal C5a receptors (CD88 and C5L2) expression were investigated in patients with AAV.MethodsTwenty-four patients with AAV in the active phase, 19 patients with AAV in the remission phase, and 20 patients with lupus nephritis (LN) were included. Plasma and urinary levels of C5a were measured with enzyme-linked immunosorbent assay (ELISA). The staining of CD88 and C5L2 in renal specimens was detected with immunohistochemistry.ResultsThe level of plasma C5a was significantly higher in patients with AAV in the active phase than that in patients in remission, that in patients with LN, and that in normal controls. The urinary C5a level was significantly higher in patients with AAV in the active phase than that in patients in remission and that in normal controls, but not significantly different between patients with active AAV and patients with LN. The mean optical density of CD88 staining in the tubulointerstitium was significantly lower in AAV patients than that in normal controls (0.0052 ± 0.0011 versus 0.029 ± 0.0042; P = 0.005). The mean optical density of C5L2 in glomeruli was significantly higher in AAV patients than that in normal controls (0.013 ± 0.0027 versus 0.0032 ± 0.0006; P < 0.001). The mean optical density of CD88 staining closely correlated with the initial eGFR (r = 0.835; P < 0.001) in AAV patients. Double-labeling immunofluorescence assay suggested that CD88 did not express on neutrophils, monocytes, or macrophages, but C5L2 expressed on neutrophils (or monocytes) and macrophages.ConclusionThe elevated plasma and urinary C5a levels indicated complement activation in human AAV. The level of renal CD88 expression could reflect the disease severity of ANCA-associated glomerulonephritis. CD88 expression was downregulated, and C5L2 was upregulated in ANCA-associated glomerulonephritis.

Alternative Complement Pathway Activation Products in Urine and Kidneys of Patients with ANCA-Associated GN

“…Recently, increasing evidences have suggested an important role of complement activation in the pathogenesis of AAV (6)(7)(8)(9)(10)(11)(12)(13). In the animal study by Xiao et al (7), it was found that activation of the alternative complement pathway, but not the classic or lectin pathway, was required for induction of GN with anti-MPO IgG.…”

With Complements from ANCA Mice

“…Recent mouse studies have added support to the hypothesis that M1-type, clodronate-sensitive macrophages do participate in initial injury, 11,16 but have also revealed that macrophages are critical for the normal repair processes that inhibit the progression of fibrosis and CKD. [10][11][12] Using several sophisticated mouse models, Lin et al demonstrated that macrophages responding to renal injury produce and release the Wnt ligand Wnt7b that acts on injured and regenerating TECs to promote their continuation through the cell cycle and regeneration of the tubule basement membrane, thus re-establishing renal function and reducing fibrosis. 12 Importantly, it was demonstrated that the M1 macrophages that traffic to the postischemic kidney change their phenotype in situ to the anti-inflammatory M2 phenotype.…”

“…[10][11][12] Using several sophisticated mouse models, Lin et al demonstrated that macrophages responding to renal injury produce and release the Wnt ligand Wnt7b that acts on injured and regenerating TECs to promote their continuation through the cell cycle and regeneration of the tubule basement membrane, thus re-establishing renal function and reducing fibrosis. 12 Importantly, it was demonstrated that the M1 macrophages that traffic to the postischemic kidney change their phenotype in situ to the anti-inflammatory M2 phenotype. 11 Collectively, these studies have greatly enhanced our understanding of the role of macrophages in the normal and abnormal injury and reparative response of the kidney after AKI.…”

“…Macrophages are among the innate leukocytes that rapidly accumulate in the kidney and promote inflammation in the acute phase of AKI, 9,10 yet macrophages also have a critical role in wound healing as scavengers of proinflammatory cell debris and as promoters of regeneration. 7,[10][11][12][13] It should be mentioned here that the study of renal resident and/or infiltrating monocytes, macrophages, and dendritic cells is complicated by the overlapping phenotypes and surface marker expression by these different cell types in the kidney during health and injury, 7 and use of the term macrophage to describe the cell types discussed herein is for simplicity.…”

“…Renal C5a (CD88) receptor expression was downregulated and the C5L2 receptor was upregulated. 12 Thus inspired by mouse data, increasing evidence from ANCA vasculitis patients has now accumulated, establishing alternative complement activation with increased anaphylatoxin C5a.…”