Complement System Study Notes

Overview of the Complement System

  • Date & Presenter: 16.10.2025, Dr. Eleni Beli

  • Institution: Queen's University Belfast

  • Focus: Activation pathways, effector functions, and regulation of the complement system.

Learning Outcomes

  • Describe the basic structure and components of the complement system.

  • Differentiate between classical, lectin, and alternative activation pathways.

  • Understand the process of C3 and C5 convertase formation and how they lead to downstream effector functions.

  • Know the major functions of complement, including opsonization, cell lysis, inflammation, and their major mediators.

  • Identify key regulatory mechanisms that prevent complement-mediated damage to host tissues.

  • Recognize the clinical consequences of complement deficiencies or overactivation.

Background of the Complement System

  • Discovery: Discovered by Jules Bordet at the Pasteur Institute in Paris, 1895.

  • Importance: Essential component of the innate humoral immunity.

  • Composition: Consists of approximately 30 proteins, synthesized mainly by the liver, with contributions from circulating myeloid cells.

  • Functionality: Enhances the ability of antibodies and phagocytic cells to clear microbes; does not require antibodies for activation.

  • Activation Mechanism: Triggered by various stimuli leading to proteolytic cleavage of proteins, releasing cytokines and initiating an amplification cascade.

  • Outcome of Activation: Resulting processes include stimulation of phagocytes, inflammation, and formation of the membrane attack complex (MAC) for cell lysis.

Functional Roles of the Complement System

  • Regulation: The complement activation is highly regulated to prevent tissue damage.

  • Role in Immunity:

    • Induces Acute Inflammation

    • Opsonizes Microbes: Enhancing phagocytosis.

    • Killing Mechanism: Some microbes are killed by osmotic lysis through the MAC.

    • Facilitates Clearance: Removal of dead and apoptotic cells.

Nomenclature of the Complement System

  • All complement components are prefixed with 'C'.

  • Classical and lectin pathways consist of proteins named in the order of discovery: C1, C2, C3, C4, C5, C6, C7, C8, and C9.

  • C1 consists of three components: C1q, C1r, and C1s. These are distinct proteins but not cleaved.

  • Proteins are cleaved into one larger (typically 'b') and one smaller (typically 'a') fragment, with C2a and C2b being exceptions.

  • Components of the alternative pathway include Factor B and D.

Complement Activation Pathways

General Overview

  • Types of Pathways:

    • Classical Pathway

    • Lectin Pathway

    • Alternative Pathway

Classical Pathway

  • Initiated when the C1 complex is activated upon binding that occurs due to:

    • Antigen-antibody complexes (1 IgM or several IgGs).

    • Direct binding to pathogen surfaces.

    • Recruitment by C-reactive protein on damaged cells.

  • C1 Complex Structure:

    • C1q (pathogen sensor), C1r, C1s (proteases).

    • Upon activation, C1 complex cleaves C4 and opsonizes the pathogen with C4b.

    • C4b subsequently binds to C2, which is also cleaved to form the C4b2a complex (C3 convertase), resulting in the cleavage of C3 into C3a and C3b.

Lectin Pathway

  • Does not require antibodies; instead utilizes soluble receptors (e.g., Mannose-binding lectin [MBL]) that bind molecular structures present on pathogen surfaces.

  • MBL activates MBL-associated serine proteases (MASP-1 and MASP-2) similar to the classical pathway's C1r and C1s.

  • The pathway cleaves C4 and C2 to produce C4b2a (C3 convertase) which then cleaves C3 into C3a and C3b.

Alternative Pathway

  • Can be initiated spontaneously; C3 can hydrolyze to C3(H2O), which deposits on bacterial surfaces.

  • Factor B binds to C3b triggering the formation of the C3bBb complex (alternative C3 convertase) that cleaves additional C3 molecules.

  • This pathway may account for 80-90% of all complement activation.

Complement Convertases

Formation of C3 Convertases

  • Classical Pathway: C4b2a

  • Alternative Pathway: C3bBb

  • Role: Both convertases are crucial for the cleavage of C3, resulting in significant progressive amplification effects via C3b and C3a.

Formation of C5 Convertases

  • Both pathways eventually lead to the formation of C5 convertases, which generate C5b, a critical component necessary for the formation of the MAC.

Membrane Attack Complex (MAC)

Formation Process

  1. C5b binds to C6 and C7.

  2. C5b, C6, and C7 complex binds to the membrane via C7.

  3. C8 then binds to this complex and integrates into the cell membrane.

  4. C9 molecules bind to the complex, polymerizing to form a pore in the membrane (10-16 molecules per pore).

Mediators of Inflammation

  • Anaphylatoxins: C3a, C4a, C5a collectively stimulate acute inflammation.

  • C3a: Induces mast cell degranulation, promoting leukocyte migration from the bloodstream.

  • C5a: Acts as a potent chemoattractant, binding to neutrophils and mast cells.

Complement Regulation

Importance of Regulation

  • Need for Regulation: To prevent destructive effects on host tissues.

  • Characteristics of Regulation:

    • Activation occurs on pathogen surfaces.

    • Activated fragments typically bind to nearby surfaces or are rapidly inactivated.

Key Regulatory Proteins

  • C1 Inhibitor (C1INH): Inactivates the C1 complex by dissociating activated enzymes from C1q.

  • C4-binding protein (C4BP): Binds to C4b, facilitating the cleavage by Factor I.

  • Factor H: Helps displace C3b.

  • Decay-accelerating factor (DAF): Displaces Bb from C3b, and C2a from C4b.

  • Membrane cofactor protein (MCP): Aids in the inactivation of C3b and C4b.

  • CD59: Prevents MAC formation on host cells by inhibiting its assembly.

Clinical Implications of Complement Deficiencies

Early Complement Deficiencies

  • Mutations/deficiencies in C1q, C2, and C4 lead to:

    • Increased risk of inflammation and autoimmune diseases.

    • Impaired immune complex clearance.

    • Increased susceptibility to infections (bacterial and yeast).

Central and Late Complement Deficiencies

  • Deficiencies of C3 lead to serious recurrent pyogenic infections.

  • Regulatory protein deficiencies lead to severe recurrent infections (Factor I deficiency, hereditary angioedema, and atypical hemolytic uremic syndrome).

  • Deficiencies in proteins for the lytic pathway (C5-C9) are less critical but may increase susceptibility to Neisseria infections (e.g., meningitis and gonorrhea).

Further Reading