What is the role of the complement system?

From the Guidelines

The complement system plays a vital role in the immune system, and its dysregulation can have significant consequences on morbidity, mortality, and quality of life, particularly in patients with COVID-19, where inhibition of complement system activation has been identified as a possible therapeutic target 1. The complement system consists of over 30 proteins that work together in a cascade-like manner to identify and eliminate threats.

• It has three activation pathways: classical (triggered by antibody-antigen complexes), alternative (activated by foreign surfaces), and lectin (initiated by mannose-binding lectin attaching to carbohydrates on microbial surfaces).
• Once activated, these pathways converge to form membrane attack complexes that create holes in target cell membranes, leading to cell lysis.
• Additionally, the complement system enhances phagocytosis through opsonization, where complement proteins coat pathogens to make them more recognizable to immune cells.
• It also triggers inflammation by releasing small fragments called anaphylatoxins (C3a, C4a, C5a) that attract immune cells to infection sites. Complement deficiencies can lead to increased susceptibility to infections, particularly from encapsulated bacteria, while overactivation can contribute to inflammatory conditions like rheumatoid arthritis and age-related macular degeneration. In patients with primary complement deficiencies, vaccination with conjugate meningococcal vaccine is recommended, with a 4-dose series of bivalent meningococcal conjugate vaccine and Haemophilus influenzae type b conjugate vaccine (HibMenCY) or a 2-dose primary series of meningococcal conjugate vaccine, quadrivalent (MCV4) 1. The complement system is regulated by several proteins to prevent damage to healthy host tissues, maintaining a balance between protection and potential harm.
• Inhibition of complement system activation, particularly with C5a inhibitors like vilobelimab, has shown promise in reducing mortality in patients with COVID-19, with a recent meta-analysis demonstrating an overall mortality benefit for complement C5a inhibitor therapy (RR 0.72 [95% CI, 0.55e0.94]) 1.
• The use of vilobelimab has been granted FDA Emergency Use Authorization for hospitalized adults with COVID-19, highlighting the potential of complement system inhibition as a therapeutic strategy in this patient population.

From the FDA Drug Label

Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) thus preventing MAC formation

The complement system is a group of proteins that play a crucial role in the immune system, helping to fight off infections and foreign substances. The terminal complement pathway is a part of this system, and it involves the formation of a membrane attack complex (MAC) that can damage cells.

• The complement system involves several proteins, including C5, which is a key component in the formation of the MAC.
• C5a is a proinflammatory anaphylatoxin that is produced when C5 is cleaved.
• C5b is the initiating subunit of the MAC.
• Inhibition of the terminal complement pathway, such as by ravulizumab-cwvz, can prevent the formation of the MAC and reduce inflammation and cell damage.
• The complement system is involved in various diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD) 2.

From the Research

Overview of the Complement System

• The complement system is a complex innate immune surveillance system that plays a key role in host homeostasis, inflammation, and defense against pathogens 3.
• It is composed of a large number of proteins that are found in the circulation, in tissues, and other body fluids in pro-enzymatic form 4.
• The complement system has multiple functions, including surveillance, pathogen recognition, immune complex trafficking, processing, and pathogen elimination 5.

Role in Immunity and Disease

• The complement system acts as a friend in the defense against pathogens by inducing opsonization and direct killing by C5b-9 membrane attack complex and triggering inflammatory responses with the anaphylatoxins C3a and C5a 3.
• However, it can also be an enemy when pathogens hijack complement regulators to protect themselves from the immune system, or when inadequate complement activation becomes a disease cause, such as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus 3.
• The complement system is also involved in various diseases, including age-related macular degeneration and cancer, and its dysfunction can lead to severe systemic infections or autoimmune disorders 3, 6.

Functions and Location

• The complement system has both canonical and non-canonical functions, including roles in development, differentiation, local homeostasis, and other cellular functions 5.
• Complement proteins are present in both plasma and on membranes, and complement activation occurs both extra- and intracellularly, leading to considerable pleiotropy in their activity 5.
• Understanding the different functions of complement and its location-based and tissue-specific responses is important for designing effective therapies 5.

Clinical Implications and Therapeutic Approaches

• Impairment of the complement system's function, consisting of deficiency or excessive deregulated activation, may lead to severe systemic infections or autoimmune disorders 6.
• Diagnostic tools, ranging from traditional to innovative ones, are available to recognize these diseases, and therapeutic approaches based on targeted drugs are now widespread 6.
• The complement system is a potential therapeutic target, and understanding its pathophysiology and clinical implications is essential for developing effective treatments 3, 6.