Abstract
The complement system (CS) has recently been recognized as a bridge between innate and adaptive immunity that constitutes a very complex mechanism controlling the clearance of pathogens, cellular debris, and immune complexes. Out of three known pathways of complement activation, the alternative pathway (AP) plays a critical role in host defense by amplifying the complement response, independently of initiation pathway and continuously maintaining low-level activity in a process called ‘thick-over.’ A key molecule of the CS is C3, in which the AP is constantly activated. To prevent host cell destruction, a group of the AP regulators tightly controls this pathway of the CS activation. Acquired and genetic abnormalities of the CS may alter the delicate balance between enhancing and inhibiting the AP cascade. These can lead to the uncontrolled CS activation, inflammatory response, and subsequent tissue damage. Since complement components are locally produced and activated in the kidney, the abnormalities targeting the AP may cause glomerular injury. C3 glomerulopathy is a new entity, in which the AP dysregulation has been well established. However, recent studies indicate that the AP may also contribute to a wide range of kidney pathologies, including immune-complex-mediated glomerulonephritis (GN), pauci-immune GN, and primary membranous nephropathy (PMN). This article provides insight into current knowledge on the role of the AP in the pathogenesis of glomerular diseases, focusing mainly on various types of primary and secondary GN and PMN.
Highlights
The alternative pathway regulating proteinsSince the AP is constantly activated in plasma, to prevent host cells and tissue destruction, it has to be tightly regulated
The alternative pathway of complement activation and the glomerular diseases The complement system (CS), discovered in 1896 by Bordet, is the key element combining innate and adaptive immune system
In the light of recent studies, systemic lupus erythematosus (SLE) is characterized by the excessive complement system activation, and the C3b present in immune complexes in glomeruli activates the alternative pathway (AP) via amplification loop
Summary
Since the AP is constantly activated in plasma, to prevent host cells and tissue destruction, it has to be tightly regulated. The complement FH-related proteins (CFHR1-5) are the members of the RCA gene cluster, encoded by five genes on chromosome 1q32 They exhibit high sequence homology with the surfacebinding domains of CFH, none of them possesses the regulatory SCRs 1-4 domains (Fig. 3). CFHRs may compete with CFH for the same binding site on C3b, but because of lack of the regulatory domains, they do not exhibit both cofactor and decay acceleration activity. This process was called complement deregulation, and so far, CFHR1, CFHR2, and CFHR5 have been described to be a competitive antagonist of CFH [37–40]. These dimers are not supposed to compete efficiently with CFH [42]
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