In-Depth Notes on the Complement System

Complement System Overview

  • Definition: The complement system is a biochemical cascade that enhances the ability of antibodies to eliminate pathogens.

  • Components:

    • Composed of over 30 serum and cell surface proteins.
    • Functions through interactions among immune molecules in a regulatory manner.
    • Synthesized primarily in hepatocytes, monocytes, macrophages, and various other cells.
    • Most proteins circulate in inactive form, activated through proteolytic cleavage.

Complement Functions

  • Beneficial Functions:

    • Opsonization: Enhances phagocytosis by marking pathogens for ingestion by phagocytes.
    • Phagocyte Attraction: Attracts and activates phagocytes to the site of infection.
    • Lysis: Destroys bacteria and infected cells through membrane disruption.
    • Regulates Antibody Responses: Helps modulate immune responses.
    • Clearance: Removes immune complexes and apoptotic cells.

  • Potential Detrimental Effects:

    • Can contribute to inflammation and anaphylactic reactions.

Complement Protein Nomenclature

  • Designations:
    • “C”: Indicates complement proteins (e.g., C1, C2).
    • “Factor”: Refers to alternative pathway components.
    • Overbar/Asterisk: Indicates an active form (e.g., *C3).
    • Lowercase Letters: Indicate cleavage fragments (e.g., C3a, C5b).
    • “b” and “a”: Denote larger and smaller biologically active peptides, respectively (e.g., C3b and C3a).

Pathways of Complement Activation

  • Pathways:
    1. Classical Pathway: Activated by antigen-antibody complexes.
    2. Alternative Pathway: Spontaneous activation that does not require antibodies.
    3. Lectin Pathway: Initiated by mannose-binding lectin interacting with specific carbohydrates on pathogens.

Classical Pathway Details

  • Activation Process:
    • Begins with antibody binding to antigens, particularly IgG or IgM.
    • C1 complex (C1q, C1r, C1s) cleaves C4 into C4a and C4b.
    • C4b binds to the membrane and participates in forming a C3 convertase (C4bC2a).
    • Generates C3a and C3b, leading to the formation of C5 convertase (C4bC2aC3b).

C3 and C5 Convertases

  • C3 Convertase:

    • Classical pathway: C4b2a
    • Alternative pathway: C3bBb

  • C5 Convertase:

    • Classical/Lectin pathway: C4b2a3b
    • Alternative pathway: C3bBb3b

Regulation of the Classical Pathway

  • Inhibitors:
    • C1 inhibitor (C1-Inh) regulates C1r and C1s, preventing excessive activation.
    • C4b-binding proteins (C4bBP) and complement receptor type 1 (CR1) aid in regulation, leading to cleavage by Factor I.

Biological Activities of Classical Pathway Components

  • Components and Effects:
    • C2b: Prokinin, causes edema.
    • C3a: Anaphylatoxin that promotes mast cell degranulation.
    • C3b: Opsonin that enhances phagocytosis.
    • C5a: Strong chemotactic factor that activates neutrophils and induces inflammation.

Lectin Pathway

  • Initiation:
    • Triggered by Mannose-binding lectin (MBL) binding to pathogens.
    • Activates similar to the classical pathway through MASP-1 and MASP-2 proteases.

Alternative Pathway

  • Activation:

    • Does not require antibodies, initiated by foreign cell surfaces.
    • Involves factors B, D, and properdin.

  • Amplification Loop: C3b generated can bind to foreign surfaces, leading to more C3b production and enhancing response.

Regulation of the Alternative Pathway

  • Regulatory Proteins:
    • CR1, DAF, and Factor I help control activation and protect host cells from damage.

Membrane Attack Complex (MAC)

  • Formation:
    • C5 convertase cleaves C5, leading to the assembly of MAC consisting of C5b, C6, C7, C8, and multiple C9s, resulting in cellular lysis through pore formation.

Complement Receptors (CR)

  • Function:
    • Membrane proteins (CR1-CR5, C3aR, C5aR) that bind complement components to facilitate various immune responses, especially opsonization and phagocytosis.

Clinical Significance of Complement Deficiencies

  • Diseases:
    • Deficiency in C1, C2, C4, CR1 leads to systemic lupus erythematosus (SLE).
    • MBL deficits increase susceptibility to bacterial infections.
    • Alternative pathway dysfunctions lead to difficulty in opsonization and increased infection risk.