Introduction to the Complement Pathway

Introduction to the Complement Pathway

• The complement system is part of the innate immune system.
• It's a complex cascade of proteins that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from the body.
• It plays a vital role in both inflammation and immune defense.
• The complement system is activated by three major pathways: the classical pathway, the lectin pathway, and the alternative pathway.

Classical Pathway

• Activation is triggered by the binding of antibody (IgG or IgM) to antigens on the surface of a pathogen.
• This binding forms an antigen-antibody complex, acting as a platform for complement protein C1q to bind.
• C1q binding activates a cascade of reactions involving C1r, C1s, and subsequent complement proteins, ultimately leading to the formation of the membrane attack complex (MAC).
• This pathway is antibody-dependent and part of the adaptive immune response.

Lectin Pathway

• Activation is initiated by the binding of mannose-binding lectin (MBL) or ficolins to carbohydrates on the surface of microorganisms.
• MBL or ficolins are pattern recognition molecules, constitutively present in blood and mucus.
• The binding of MBL/ficolin activates a cascade of reactions similar to the classical pathway, resulting in the formation of the MAC.
• This pathway is antibody-independent but part of the innate immune response.

Alternative Pathway

• Activation occurs spontaneously, in the absence of antibodies or previous immune responses, against a microbe or pathogen.
• It's activated by the hydrolysis of C3 to C3(H2O), which then binds to factors B, D, and P.
• The formation of a C3 convertase, C3bBb, amplifies the cascade and leads to the formation of the MAC.
• This pathway is primarily triggered by microbial surfaces or pathogen-associated molecular patterns (PAMPs).

Key Complement Proteins and their Functions

• C3: A crucial component, the 'central hub' of the complement system, cleaved in all three pathways.
• C4: Involved in both the classical and lectin pathways, contributing to C3 convertase formation.
• C5: Key component in the formation of the membrane attack complex (MAC).
• C9: Polymerizes to form the MAC, a pore-forming complex disrupting target cell membranes, causing lysis.
• Factor B: Crucial for alternative pathway C3 convertase formation.
• Factor D: An enzyme that cleaves Factor B.
• Properdin (Factor P): Stabilizes the alternative pathway C3 convertase, leading to MAC formation.

Membrane Attack Complex (MAC)

• The MAC is a complex of complement proteins that inserts into target cell membranes (primarily pathogens).
• The MAC forms a transmembrane pore, disrupting membrane integrity and causing cell lysis.
• Its formation is a critical effector function, helping eliminate foreign invaders.

Regulation of the Complement System

• Tight regulation is essential to prevent host tissue damage.
• Regulatory proteins limit activation to specific target cells.
• These proteins interfere with convertase formation or accelerate component degradation.
• Examples include Factor H, Factor I, and decay-accelerating factor (DAF).

Clinical Significance

• Complement deficiencies increase infection susceptibility.
• Overactivation damages host tissues, contributing to autoimmune diseases and inflammatory disorders.
• Complement activation is implicated in systemic lupus erythematosus, rheumatoid arthritis, and glomerulonephritis.
• Drugs inhibiting complement activation are being developed for inflammatory diseases.

Complement and Disease

• Complement component deficiencies lead to recurrent infections.
• Complement activation contributes to tissue damage in autoimmune disorders.
• Complement activation contributes to inflammatory responses, damaging healthy tissues during hypersensitivity reactions.
• Complement may play a role in cancer development.
• Complement inhibition holds therapeutic potential.

Explore the intricacies of the complement system, a pivotal aspect of the innate immune response. This quiz delves into the three major activation pathways: classical, lectin, and alternative, and their roles in enhancing immune defense mechanisms. Test your knowledge of the complement proteins and their importance in inflammation and pathogen clearance.