Molecules Great and Small

Abstract

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.

The role of the alternative pathway of complement activation in glomerular diseases

“…In case of nucleated cells, it induces activation of inflammatory response and tissue damage (Fig. 2) [1,6,15,[17][18][19][20][21][22][23][24][25].…”

“…In fact, it is the only AP inhibitor present on the GBM in glomeruli. Complement FH-like protein (CFHL1), a splice form of CFH, consisting of 7N-terminal domains of CFH has also been reported [1,20,[24][25][26]32]. Recently described, the complement FH-related proteins (CFHR1-5) are also the members of the RCA gene cluster, encoded by five genes on chromosome 1q32.…”

“…While CFHR3 and CFHR4 were revealed to possess a weak FI cofactor activity, CFHR5 bound C3b in vitro and exhibited both FI cofactor and decay acceleration activity. However, most of these AP-regulating activities of CFHRs are weak, and they were observed in in vitro assays, which used non-physiological CFHRs concentrations [23,24,31,32,[34][35][36].…”

All Things Complement

“…Additional details of the molecular interactions involved in C activation are described in an excellent recent review (2).…”

“…Other diseases, such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), are associated with defective regulation and/or enhanced activation of the alternative pathway (AP). Additional details regarding the role of C in membranous nephropathy, antiglomerular basement membrane (GBM) disease, and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis were discussed in a recent Clinical Journal of the American Society of Nephrology educational review (2). Other glomerular diseases in which C activation likely plays a critical role will be reviewed in subsequent articles in this series.…”