Lecture 5 - Innate immunity (the molecules pt2)

• Complement system


  Part of the innate immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promote inflammation, and attack the pathogen's cell membrane
• Components of the complement system


  • Serum proteins
  • Cell membrane receptors
  • About 50 proteins and protein fragments
  • Accounting for about 10% of the globulin fraction of blood serum
• Pathways the complement system


  • Classical complement pathway
  • Alternative complement pathway
  • Lectin pathway
• Components of the complement system


  • Nine central components of the cascade (C1 to C9)
  • Multiple activation products (such as C3a and C3b)
  • Regulators and inhibitors (e.g. Factor H and C4BP)
  • Proteases and newly assembled enzymes (e.g. C4b2a and Factor B)
  • Effector molecule receptors (such as C3aR and C5aR)
• Complement system


  • Has various functions, including cell lysis, opsonisation, inflammation and pathogen lysis
  • Strictly regulated to prevent uncontrolled complement activation, as it has the potential for rapid amplification and the ability to damage host tissue as well as microbes
• Majority of complement proteins

  Synthesized in the liver, but other cells such as immune cells can also produce them
• Classical pathway


  Initiated by the binding of C1q to the pathogen surface or by the binding of C1q to antibody-antigen complexes during an adaptive immune response
• Lectin pathway


  Initiated by the binding of mannose-binding lectin (MBL) to mannose-containing carbohydrates on bacteria or viruses
• Alternative pathway


  1. Initiated when a spontaneously activated complement component binds to the surface of a pathogen

  2. Not specific and does not require antigen recognition

  3. Can act as an amplification loop for all three pathways
• Early events of all three pathways

  1. Involve a series of cleavage reactions that culminate in the formation of C3 convertase

  2. C3 convertase leads to the cleavage of the central component C3 into C3b (opsonin) and C3a (anaphylatoxin)
• Late events of complement activation


  Involve a sequence of polymerisation reactions in which the terminal complement components interact to form a membrane-attack complex (MAC), which creates a pore in the cell membranes of some pathogens that can lead to their death
• Complement activation

  • Can lead to opsonisation, inflammation, and pathogen lysis, as well as the recruitment and activation of cells of the innate immune response
  • Has a series of built-in amplification steps and is subject to tight regulation to prevent inadvertent activation on host cell surfaces
• Implications of the complement system

  • Contributes to inflammation by binding to receptors on mast cells and basophils, leading to degranulation and the release of pharmacologically active mediators, as well as attracting and inducing monocytes and neutrophils to adhere to vascular endothelial cells and extravasate
  • Plays a role in the clearance of immune complexes by depositing C3b on the complexes, which then bind to complement receptor CR1 on erythrocytes for removal by phagocytes in the spleen and liver
• Deficiencies or abnormalities in the complement system can lead to autoimmunity, an imbalance between immune activation and control, inadequate removal of immune complexes, and the generation of auto-antibodies, resulting in localised or general inflammatory responses
• Regulatory mechanisms of the complement system


  • C1-inhibitor (C1Inh)
  • Decay Accelerating Factor (DAF or CD55)
  • Membrane Cofactor Protein (MCP or CD46)
  • Membrane Inhibitor of Reactive Lysis (CD59)
• C1Inh


  Serine-protease inhibitor that helps regulate the activation of the classical pathway
• DAF and MCP


  Membrane proteins that regulate the formation of C3 convertase and the deposition of C3b on cell surfaces
• CD59


  Prevents the formation of the membrane attack complex (MAC) and protects host cells from lysis
• Defective complement activity can lead to an increased susceptibility to infections, as the complement system is a major arm of the innate immune system responsible for providing protection against invading pathogens
• Defective complement activity can result in autoimmunity, as there may be an imbalance between immune activation and control, inadequate removal of immune complexes, persistent inflammatory damage, and immune responses against self-antigens
• Over 30% of patients with C2 deficiency and nearly 80% of patients with either C3 or C4 deficiency present autoimmune manifestations, with SLE being the most common autoimmune disease associated with complement deficiencies
• Defective complement activity can lead to an increased potential for rapid amplification and the ability of activated complement proteins to damage host tissue as well as microbes, highlighting the critical need for strict regulation of the complement system