Complement System Activation: Mechanisms, Diseases, and Innovative Therapies

The complement system is a crucial part of the innate immune response, orchestrating a series of reactions to identify and eliminate pathogens while promoting inflammation. However, excessive activation of this system can result in inflammatory and autoimmune conditions.

The complement system consists of serum proteins activated through three pathways: classical, alternative, and lectin. These pathways converge to produce C3 convertase, which cleaves C3 into C3a and C3b. C3a, an anaphylatoxin, enhances inflammation by increasing vascular permeability and drawing immune cells to infection sites. In contrast, C3b functions as an opsonin, marking pathogens for destruction by phagocytes. C3b also combines with other complement components to form C5 convertase, which perpetuates the cascade and leads to the creation of the membrane attack complex (MAC). The MAC induces cell lysis by forming pores in the target cell membrane. C3 is essential in activating and amplifying the complement system, linking innate and adaptive immune responses to effectively address infections.

Tools like the C3a ELISA are critical for studying these pathways and components. This assay measures C3a levels in biological samples, offering valuable insights into complement system activation and regulation, especially in disease contexts.

The MAC, a final product of the complement system, creates pores in target cell membranes, causing cell lysis and death. It represents the common endpoint of the complement cascade, involving protein cleavage and activation through the classical, alternative, or lectin pathways. Specifically, C5 is cleaved into C5a and C5b by C5 convertase. C5b binds with C6 and then C7 to form the C5b67 complex, which embeds into the cell membrane. The binding of C8 forms the C5b678 complex, and multiple C9 molecules then polymerize on C5b678 to create a ring structure, forming the complete MAC (C5b6789). The MAC directly damages the membranes of various pathogens, including bacteria, virus-infected cells, and certain tumor cells.

Despite its vital role in immune defense, an imbalanced complement system can lead to diseases like Paroxysmal Nocturnal Hemoglobinuria (PNH), Atypical Hemolytic Uremic Syndrome (aHUS), and complement-mediated kidney disorders such as membranous nephropathy and IgA nephropathy. PNH is characterized by the lack of protective proteins (e.g., CD55 and CD59) on red blood cells, making them susceptible 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. Complement-mediated kidney diseases can involve MAC deposition on the glomerular basement membrane, leading to glomerular injury and reduced kidney function.

To address the detrimental effects of activation, complement inhibitors have been developed, such as Eculizumab (Soliris) and Ravulizumab (Ultomiris), which are C5 inhibitors that prevent MAC formation by blocking C5 cleavage. These drugs are commonly used to treat PNH and aHUS. Other medications, like Avacopan, act as C5aR1 antagonists and are primarily used for treating ANCA-associated vasculitis and related conditions.

Ongoing research into the complement system and its inhibitors holds promise for developing safer and more effective therapies for a wider range of patients. Emerging studies on the roles of C5a and MAC in the tumor microenvironment offer potential new avenues for cancer treatment. Overall, understanding the complement system's functions and related therapies is crucial for better managing various immune-related diseases.