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The Complement System: Core of Immune Defense and Regulation


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The complement system is a critical component of the innate immune system, orchestrating a cascade of reactions to recognize and eliminate pathogens, while promoting inflammation. However, overactivation of the complement system can lead to various inflammatory and autoimmune diseases.

 

The complement system comprises a group of serum proteins that can be activated through three pathways: the classical, alternative, and lectin pathways. These pathways converge to generate C3 convertase, which cleaves C3 into C3a and C3b. C3a acts as an anaphylatoxin, promoting inflammation by increasing vascular permeability and attracting immune cells to the site of infection. C3b, on the other hand, acts as an opsonin, tagging pathogens for destruction by phagocytes. Additionally, C3b combines with other complement components to form C5 convertase, further propagating the complement cascade and leading to the formation of the membrane attack complex (MAC), which lyses targeted cells. C3 plays a central role in the activation and amplification of the complement system, bridging innate and adaptive immune responses to effectively combat infections.

 

In studying these pathways and components, tools like the C3a ELISA are invaluable. This assay helps quantify levels of C3a in biological samples, providing insights into the activation and regulation of the complement system, particularly in disease states.

 

One of the final products of the complement system is the membrane attack complex (MAC), which forms pores in the target cell membrane, leading to cell lysis and death. MAC formation represents the common terminal pathway of the complement system, involving a series of protein cleavage and activation reactions via the classical, alternative, or lectin pathways. Specifically, C5 is cleaved into C5a and C5b by C5 convertase. C5b binds with C6, followed by C7, forming the C5b67 complex, which inserts into the cell membrane. Subsequent binding of C8 forms the C5b678 complex, and multiple C9 molecules polymerize on C5b678 to form a ring structure, creating a complete membrane attack complex (C5b6789). Through this mechanism, MAC directly damages the cell membranes of various pathogens, including bacteria, virus-infected cells, and certain tumor cells.

 

While the complement system is pivotal for immune defense, its imbalance can contribute to various diseases, including Paroxysmal Nocturnal Hemoglobinuria (PNH), Atypical Hemolytic Uremic Syndrome (aHUS), and complement-mediated kidney disorders such as membranous nephropathy and IgA nephropathy. PNH involves the absence of protective proteins (e.g., CD55 and CD59) on red blood cell surfaces, rendering them vulnerable to MAC attack, resulting in hemolysis and anemia. In aHUS, deficiencies in complement regulatory proteins lead to excessive complement activation, MAC deposition in glomeruli, endothelial cell damage, and thrombus formation. In complement-mediated kidney diseases, MAC deposition on the glomerular basement membrane can precipitate glomerular injury and decline in kidney function.

 

To mitigate the harmful effects of complement system activation, complement inhibitors have been developed, such as Eculizumab (Soliris) and Ravulizumab (Ultomiris). These are C5 inhibitors that prevent MAC formation by blocking the cleavage of C5, commonly used to treat PNH and aHUS. Other drugs, such as Avacopan, are C5aR1 antagonists primarily used for the treatment of ANCA-associated vasculitis and other diseases.

 

With ongoing research into the complement system and complement inhibitors, there is hope for developing safer and more effective therapies for a broader range of patients. The roles of C5a and MAC in the tumor microenvironment are also emerging areas of research, offering potential new avenues for cancer treatment. Overall, the complement system plays an indispensable role in immune defense and regulation, and deeper insights into its function and related therapeutics will aid in better understanding and treating various immune-related diseases.

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