Complement System Overview

Complement System

• The complement system is a series of proteins that work together to kill pathogens.
• It is a key component of the innate immune system and can kill pathogens quickly.
• Complement is a network of proteins, proteases, serum proteins, receptors, and regulators that all work together.
• It is activated by the presence of either pathogen-associated molecular patterns (PAMPs) or by antigen-bound antibodies.
• The system is tightly regulated and disturbances can result in inflammation or autoimmunity.

Functions of the Complement System

• The complement system has many functions including:
  • killing pathogens
  • alerting the immune system to invaders
  • regulating inflammation
  • removing damaged or altered cells
  • regulating adaptive immune responses
  • clearing antigen-antibody complexes
  • blood vessel formation
  • mobilization of stem cells
  • tissue regeneration
  • lipid metabolism

Complement Activation Pathways

• There are three main pathways for complement activation:
  • Alternative Pathway
    • activated by microbial cell walls
    • triggered by C3, the most abundant complement component in serum
    • C3 spontaneously breaks down into C3a and C3b
    • C3b binds to microbes and marks them for destruction
  • Lectin Pathway
    • activated by the binding of soluble pattern-recognition molecules (lectins) to microbial carbohydrates
    • triggered by the presence of bacterial PAMPs
    • lectins bind to microbes and activate proteases that activate complement
    • mannose-binding lectin (MBL) and ficolins are the main lectins
  • Classical Pathway
    • activated by antibodies
    • is an adaptive pathway
    • triggered by antigen-bound IgM or paired, antigen-bound IgG molecules
    • C1 binds to antibody and is then activated, cleaving C4 into C4a and C4b
    • C2 binds to C4b, creating a complex that acts as a protease to cleave C3

Amplification Pathway

• All surface-bound C3 convertases (from the alternative, lectin, or classical pathway) can trigger the amplification pathway.
• C5 binds to C3b and is then cleaved by C3bBb.
• This generates C5b that can bind to C6 and C7, forming a complex that inserts into the microbial cell wall.
• C8 then binds, followed by polymerization of 12-18 C9 molecules to form the terminal complement complex (TCC).
• The TCC forms a pore in the microbial cell membrane, causing osmotic lysis.

Complement Proteins

• Complement proteins are either labeled numerically (e.g., C1, C2, C3) or designated as "factors" by letters of the alphabet (FB, FD, FP, etc.).
• They account for 5% to 10% of the proteins in blood serum.
• Their size varies from 24 kDa for factor D (FD) to 460 kDa for C1q.
• Complement proteins are synthesized at multiple sites, including the liver, macrophages, and mast cells.

Substrate Modulation

• Substrate modulation is one way that the complement system is regulated.
• A target for a protease cannot be cleaved unless it is first bound to another protein.
• Examples include the cleavage of factors C2, B, and C5 only after they have bound to C4, C3, and C3, respectively.

Biological Consequences of Complement Activation

• C5a, a small released peptide, has potent inflammatory effects.
  • It can degranulate mast cells and stimulate platelets to release histamine and serotonin.
  • It attracts neutrophils and macrophages.
  • It increases vascular permeability.
• C3a can kill bacteria by disrupting cell membranes.

Explore the essential functions and activation pathways of the complement system, a crucial component of the innate immune response. This quiz examines the roles and regulation of complement proteins in pathogen elimination and immune system alertness. Test your knowledge on how this network of proteins contributes to various immune functions.