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2018 ; 9
(ä): 1433
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Alternative Pathway Is Essential for Glomerular Complement Activation and
Proteinuria in a Mouse Model of Membranous Nephropathy
#MMPMID29988342
Luo W
; Olaru F
; Miner JH
; Beck LH Jr
; van der Vlag J
; Thurman JM
; Borza DB
Front Immunol
2018[]; 9
(ä): 1433
PMID29988342
show ga
Membranous nephropathy is an immune kidney disease caused by IgG antibodies that
form glomerular subepithelial immune complexes. Proteinuria is mediated by
complement activation, as a result of podocyte injury by C5b-9, but the role of
specific complement pathways is not known. Autoantibodies-mediating primary
membranous nephropathy are predominantly of IgG4 subclass, which cannot activate
the classical pathway. Histologic evidence from kidney biopsies suggests that the
lectin and the alternative pathways may be activated in membranous nephropathy,
but the pathogenic relevance of these pathways remains unclear. In this study, we
evaluated the role of the alternative pathway in a mouse model of membranous
nephropathy. After inducing the formation of subepithelial immune complexes, we
found similar glomerular IgG deposition in wild-type mice and in factor B-null
mice, which lack a functional alternative pathway. Unlike wild-type mice, mice
lacking factor B did not develop albuminuria nor exhibit glomerular deposition of
C3c and C5b-9. Albuminuria was also reduced but not completely abolished in
C5-deficient mice. Our results provide the first direct evidence that the
alternative pathway is necessary for pathogenic complement activation by
glomerular subepithelial immune complexes and is, therefore, a key mediator of
proteinuria in experimental membranous nephropathy. This knowledge is important
for the rational design of new therapies for membranous nephropathy.