As a bridge between innate and adaptive immunity, the complement cascade is required for host protection against invasive pathogens and maintenance of organism’s homeostasis, commonly the system can not only be activated in response to pathogens but also due to the presence of autoantibodies, apoptotic, necrotic or ischemic cells/tissues. The complement system is an intricate network that integrates the interactions of leukocytes, platelets, and tissues in the inflammatory response. There are three activation pathways: the classical, lectin and alternative pathway, in which more than 40 zymogens, receptors, and regulators play coordinating roles to avoid excessive or insufficient activation.
In recent decades, the complement system has been evaluated as a mediator of various disease, e.g. nephropathy, also known as kidney disease or renal disease. In the pathogenesis of nephropathy verified by a number of clinical researches, inappropriate activation of the complement pathways shows a deleterious influence. Many kidney disorders have been linked to abnormal complement activation, including autoantibody mediated glomerulonephritis (lupus nephritis, membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, etc.
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Glomerulonephritis
Glomerulonephritis is one of the most common reasons of chronic kidney disease and end-stage renal failure in the world. It is generally caused by the presence of autoantibodies and the autoantibody-mediated involvement of classical pathway. Lupus nephritis is one representative symptom of glomerulonephritis, which develops due to an impaired clearance of apoptotic cells, and thus leads to immune complex deposition in glomeruli. So the immune system is constantly exposed to autoantigens and subsequent development of autoimmunity. The complement component C1q is a key regulating factor in the clearance of immune complexes, and C3, C4 are associated with lupus development and activity. The MBL (initiator of lectin-pathway) deficiency may also be predisposed to lupus nephritis development.
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Hemolytic Uremic Syndrome
The hemolytic uremic syndrome (HUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is a heterogeneous disease of the microvasculature and the main cause in the pathogenesis is the deficiency in the regulation of the alternative complement pathway. In the HUS patients, multiple mutations of complement component have been identified, including regulatory proteins [factor H, factor I, MCP (CD46)] and complement activators (CFB and C3), which reveals the central role in the pathogenesis of HUS.
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C3 Glomerulopathy
C3 glomerulopathy is demonstrated to be associated with the uncontrolled systemic activation of the alternative pathway. The disease-causing mutations in alternative pathway inhibitors, such as factor H and factor I, can lead to C3 glomerulopathy, additionally, some autoantibodies leading to the activation or blockage of alternative pathway proteins have also been identified as a pathogenic cause.
Fig 1. The main links between the complement and aHUS. (Jokiranta. 2017)
Because of the close connection between complement and nephropathy, studies evaluating the precise roles of the complement system in nephropathy will still be useful for the development of new therapeutic strategies.
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Reference
1. Jokiranta, T. S. (2017). HUS and atypical HUS. Blood. 129(21), 2847-2856.
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Questions & Answer
A: Techniques such as ELISA, immunofluorescence, and flow cytometry are used to measure markers of complement activation, such as C3a and C5b-9, in renal tissues and biological samples.
A: Yes, a variety of animal models and cell culture systems are available that mimic nephropathy and allow researchers to study the effects of complementary therapies. These include animal models of induced nephrogenic injury and cultured nephrocytes.
A: Complement therapies can target specific complement proteins, such as C3, C5, or complement regulatory proteins, in order to modulate their activity and prevent complement overactivation in nephropathy.
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