Complement

Related Subjects: |Major Histocompatibility complex |Immune response |Complement |Opsonisation |Toll-like Receptors (TLRs) |Immunoglobulins |Immunology |X linked Agammaglobulinaemia (Bruton) |X-linked lymphoproliferative disease (Children) |Chediak Higashi syndrome |Common variable immunodeficiency |Severe combined immunodeficiency disorders |DiGeorge syndrome (thymic aplasia) |Selective IgA deficiency |Wiskott-Aldrich syndrome (Children) |T lymphocytes

🛡️ The complement system is a tightly regulated cascade of plasma proteins that forms a central bridge between innate and adaptive immunity. It amplifies antibody function, enhances phagocytosis, recruits inflammatory cells, and can directly destroy pathogens through membrane pore formation. Physiologically, complement acts as a “biological alarm system” - rapidly triggered by microbes, immune complexes, or damaged tissue.

🔑 Core Principles

• System Architecture
  • ⚙️ Comprises >30 circulating and membrane-bound proteins.
  • Main effector components: C1–C9.
  • Includes regulators (Factor H, CD55, CD59) and receptors (CR1–CR4).
  • Proteins circulate in inactive pro-enzyme form → rapid amplification when triggered.
• Cascade Logic
  • Each activation step cleaves the next component → exponential signal amplification.
  • Small triggers generate large inflammatory and opsonic responses.
  • Unchecked activation risks host tissue injury.

🛣️ Pathways of Complement Activation

• 📘 Classical Pathway (Antibody-Dependent)
  • Triggered by IgG or IgM bound to antigen.
  • C1q binds Fc region → activates C1r and C1s.
  • C4 and C2 cleavage → C3 convertase (C4b2a).
  • Links adaptive immunity to innate effector mechanisms.
• 📗 Lectin Pathway (Pattern Recognition)
  • Triggered by mannose-binding lectin (MBL) or ficolins.
  • Recognises microbial carbohydrates.
  • MASP activation → C4b2a formation.
  • Functions independently of antibodies.
• 📙 Alternative Pathway (Spontaneous Surveillance)
  • Continuous low-level C3 hydrolysis (“tick-over”).
  • C3b binds microbial surfaces.
  • Forms C3bBb convertase.
  • Stabilised by properdin.
  • Key first-line defence mechanism.

⚔️ Effector Functions

• 🖇️ Opsonisation
  • C3b/iC3b coat pathogens.
  • Bind CR1/CR3 on phagocytes.
  • Greatly enhances phagocytosis.
• 💥 Membrane Attack Complex (MAC)
  • C5b–C9 assemble into transmembrane pores.
  • Causes osmotic lysis.
  • Especially effective against Neisseria species.
• 🔥 Inflammatory Signalling
  • Anaphylatoxins: C3a, C4a, C5a.
  • C5a is the most potent chemoattractant.
  • Promotes mast cell degranulation and vascular permeability.
• 🧹 Immune Complex Clearance
  • Complexes bind CR1 on erythrocytes.
  • Transported to liver and spleen.
  • Removed by macrophages.
  • Prevents immune complex deposition.

🧯 Regulation and Host Protection

• Key Regulatory Proteins
  • 🧩 Factor H → inhibits alternative pathway on host cells.
  • 🚫 CD55 (DAF) → accelerates convertase decay.
  • 🛑 CD59 (Protectin) → blocks MAC insertion.
  • 🔒 C1 Inhibitor (C1-INH) → suppresses classical/lectin pathways.

🏥 Clinical Relevance

• 🧬 Complement Deficiencies
  • C3 deficiency → severe recurrent infections.
  • C5–C9 deficiency → Neisseria susceptibility.
  • Early component deficiency → SLE risk.
• 🌙 Paroxysmal Nocturnal Haemoglobinuria (PNH)
  • PIGA mutation → loss of CD55/CD59.
  • Uncontrolled MAC-mediated haemolysis.
  • High thrombotic risk.
• 🤒 Immune-Mediated Injury
  • SLE, vasculitis, RA, glomerulonephritis.
  • Driven by immune complex–complement activation.
• 💊 Targeted Therapy
  • Eculizumab/ravulizumab → C5 inhibition.
  • Used in PNH, aHUS, C3 glomerulopathy.

📌 Summary

🧩 The complement system integrates innate surveillance with adaptive immunity.
Its core actions are opsonisation, inflammation, cytolysis, and immune complex clearance.
Clinical disease reflects imbalance: deficiency → infection; excess → autoimmunity and tissue damage.
Understanding regulation is central to modern immunotherapy.