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2015 ; 10
(9
): 1636-50
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Molecules Great and Small: The Complement System
#MMPMID25568220
Mathern DR
; Heeger PS
Clin J Am Soc Nephrol
2015[Sep]; 10
(9
): 1636-50
PMID25568220
show ga
The complement cascade, traditionally considered an effector arm of innate
immunity required for host defense against pathogens, is now recognized as a
crucial pathogenic mediator of various kidney diseases. Complement components
produced by the liver and circulating in the plasma undergo activation through
the classical and/or mannose-binding lectin pathways to mediate anti-HLA
antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the
latter including membranous glomerulopathy, antiglomerular basement membrane
disease, and lupus nephritis. Inherited and/or acquired abnormalities of
complement regulators, which requisitely limit restraint on alternative pathway
complement activation, contribute to the pathogenesis of the C3 nephropathies and
atypical hemolytic uremic syndrome. Increasing evidence links complement produced
by endothelial cells and/or tubular cells to the pathogenesis of kidney
ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since
the mid-2000s additionally show that immune cells, including T cells and
antigen-presenting cells, produce alternative pathway complement components
during cognate interactions. The subsequent local complement activation yields
production of the anaphylatoxins C3a and C5a, which bind to their respective
receptors (C3aR and C5aR) on both partners to augment effector T-cell
proliferation and survival, while simultaneously inhibiting regulatory T-cell
induction and function. This immune cell-derived complement enhances pathogenic
alloreactive T-cell immunity that results in transplant rejection and likely
contributes to the pathogenesis of other T cell-mediated kidney diseases.
C5a/C5aR ligations on neutrophils have additionally been shown to contribute to
vascular inflammation in models of ANCA-mediated renal vasculitis. New
translational immunology efforts along with the development of pharmacologic
agents that block human complement components and receptors now permit testing of
the intriguing concept that targeting complement in patients with an assortment
of kidney diseases has the potential to abrogate disease progression and improve
patient health.
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