Complement System _ AD

Complement System Overview

• Definition: A collection of over 30 proteins present in circulation and tissue fluids that complements the action of antibodies.

• Function: Contributes to pathogen destruction and inflammatory responses, operates as a heat-labile component in serum.

Learning Objectives

• Understand the complement system's role in innate immunity.

• Explain the activation pathways: Classical, Lectin, Alternative.

• Recognize how complement proteins assist in pathogen destruction.

• Discuss the involvement of the complement system in hypersensitivity reactions.

Components and Functions of Complement Proteins

Categories of Proteins

• Activation Enzymes: Activate other complement proteins.

• Immune Defence Molecules: Form pores in microbial surfaces.

• Control Proteins: Regulate activation ensuring it stops when no longer needed.

Activation of Complement System

• Mechanism: Triggered by infections and immune responses, operates in a cascade with amplifying effects.

• Key Event: The pivotal step involves the cleavage of C3 into C3a and C3b.

• C3 Convertases: Generated through three pathways.

Classical Activation Pathway

• Initial Discovery: Requires IgM or IgG antibodies and C1 protein.

• Function: These antibodies bind to the target leading to the formation of different C3 convertases.

Lectin Activation Pathway

• Components: MBL (Mannose Binding Lectin) and MASP (Mannose-associated serine protease).

• Process: MBL binds to mannose on microbial surfaces activating MASP enzymes that split C4 and C2, subsequently generating C3 convertase.

Alternative Activation Pathway

• Mechanism: Utilizes complement proteins to initiate their own activation.

• C3 Convertase Generation: Splits C3, which leads to the formation of C5 convertase that eventually splits C5 into C5a and C5b, initiating the membrane attack complex.

Effects of Complement System

Mechanisms of Action

1. Lysis: Formation of the membrane-attack complex results in pores created in microbial membranes leading to cell death.

2. Inflammation: C3a and C5a activate local inflammatory responses, potentially leading to anaphylactic shock when present in large amounts.

   • Induce smooth muscle contraction and increase vascular permeability.

   • Promote the release of inflammatory mediators like histamine from mast cells.

3. Opsonization: Enhances uptake and destruction of pathogens by promoting their recognition by phagocytic cells. C3b is integral as it binds to pathogens, facilitating clearance.

Regulation of Complement Activation

• Necessity: Regulation is crucial to avoid damage to healthy tissue.

Key Regulatory Steps

• Regulation primarily occurs at convertase levels and during MAC assembly.

• Types of Regulators:

  • Soluble Regulators: More specific; control either classical, lectin, or alternative pathways.

  • Membrane-bound Regulators: Relatively non-specific; affect all pathways. Includes factor H and C1 inhibitor.

• Function of Specific Regulators:

  • Factor H: Inhibits C3b and factor B interaction.

  • C1 Inhibitor: Blocks C1 complex formation in the classical pathway.

  • Carboxypeptidase N: Reduces C3a and C5a activity through cleavage.

Hypersensitivity and the Complement System

• Type II Hypersensitivity: Characterized by destruction of incompatible transfused red blood cells.

• Type III Hypersensitivity: Associated with diseases such as Glomerulonephritis, Rheumatoid Arthritis, and Systemic Lupus Erythematosus involving immune-complex mediated inflammation due to complement activation.