Makindo Medical Notes

Overview of the Complement System

The complement system is a crucial part of the innate immune system, consisting of a series of small proteins found in the blood plasma. These proteins work together to enhance the ability of antibodies and phagocytic cells to clear pathogens from an organism, promote inflammation, and attack the pathogen's plasma membrane.

Key Concepts

• Components of the Complement System:
  • Consists of over 30 proteins and protein fragments.
  • Includes complement proteins (C1-C9), regulators, and receptors.

Pathways of Complement Activation

• Classical Pathway:
  • Triggered by antibodies bound to antigens on the pathogen surface.
  • Involves the recognition of antigen-antibody complexes by C1q, leading to the activation of C1r and C1s.
  • Results in the formation of the C3 convertase (C4b2a) that cleaves C3 into C3a and C3b.
• Lectin Pathway:
  • Triggered by mannose-binding lectin (MBL) or ficolins binding to carbohydrates on the pathogen surface.
  • Involves the activation of MBL-associated serine proteases (MASPs), which cleave C4 and C2 to form C3 convertase (C4b2a).
• Alternative Pathway:
  • Triggered by the presence of pathogen surfaces directly.
  • Involves the spontaneous hydrolysis of C3 and the formation of C3 convertase (C3bBb) stabilized by properdin.

Functions of the Complement System

• Opsonization:
  • C3b binds to the surface of pathogens, tagging them for recognition and phagocytosis by immune cells (e.g., macrophages, neutrophils).
• Cell Lysis:
  • Formation of the membrane attack complex (MAC) (C5b6789) creates pores in the pathogen membrane, leading to cell lysis and death.
• Inflammation:
  • Anaphylatoxins (C3a, C4a, C5a) act as chemoattractants and inflammatory mediators, recruiting immune cells to the site of infection and enhancing the inflammatory response.
• Immune Complex Clearance:
  • Facilitates the removal of immune complexes from the circulation by binding to erythrocytes, which transport them to the liver and spleen for clearance by macrophages.

Regulation of the Complement System

• Regulatory Proteins:
  • Factor H: Regulates the alternative pathway by promoting the decay of C3 convertase (C3bBb) and inactivating C3b.
  • CD55 (DAF, Decay-Accelerating Factor): Accelerates the decay of C3/C5 convertases in all pathways.
  • CD59 (Protectin): Inhibits the formation of the membrane attack complex (MAC) on host cells.
  • C1 Inhibitor (C1-INH): Inhibits the classical and lectin pathways by inactivating C1r, C1s, and MASPs.

Clinical Relevance

• Complement Deficiencies:
  • Inherited deficiencies can lead to increased susceptibility to infections and autoimmune diseases (e.g., C3 deficiency, C5-C9 deficiencies).
• Paroxysmal Nocturnal Haemoglobinuria (PNH):
  • Caused by a deficiency of GPI-anchored proteins, including CD55 and CD59, leading to unregulated complement activation and red blood cell lysis.
  • Symptoms: Haemolysis, haemoglobinuria, fatigue, and thrombosis.
• Autoimmune Diseases:
  • Complement activation can contribute to tissue damage in autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis).
• Therapeutic Targeting:
  • Complement inhibitors are being developed to treat diseases involving excessive or inappropriate complement activation (e.g., eculizumab for PNH and atypical haemolytic uremic syndrome).

Summary

The complement system is a key component of the innate immune response, playing essential roles in pathogen recognition, opsonization, cell lysis, and inflammation. Proper regulation is crucial to prevent tissue damage and autoimmune reactions. Understanding its mechanisms and clinical relevance is vital for developing therapeutic interventions for complement-related disorders.