Lecture Notes on the Complement System

Introduction to the Complement System

• Definition: Part of the natural immunity or innate immunity; bridges gap between innate and acquired immunity.
• Components: Collection of complement proteins present in blood plasma or serum.
• Function: Proteins increase in concentration with inflammation; 30+ circulating and membrane-bound proteins.

Synthesis and Structure

• Production: Synthesized by hepatocytes, intestinal epithelial cells, adipocytes, monocytes, macrophages, neutrophils, and T cells.
• Cascade Mechanism: Activation of one component triggers the next, similar to the coagulation pathway.

Historical Context

• Key Contributors: Erlich discovered complement role in antibody-mediated bacterial killing; other scientists expanded on functions.
• Properties: Heat-labile, destroyed by heat, different complement components discovered over time.

Nomenclature

• Naming: Capital letter C followed by numbers (C1, C2, etc.).
• Subunits & Complexes: C1 comprised of C1q, C1r, and C1s; Activation units include C4, C2, and C3; MAC unit includes C5-9.
• Zymogens: Inactive complement proteins, cleave into active components (e.g., C2a, C2b).

Functions of the Complement System

• Cytolysis: Target cell destruction or bursting.
• Opsonization: Facilitated phagocytosis.
• Inflammatory Response: Triggers inflammation and anaphylaxis.
• Clearance of Immune Complexes: Removes excess antigen-antibody complexes to prevent tissue damage.

Pathways of Activation

• Classical Pathway: Initiated by antigen-antibody complexes; bridges innate and acquired immunity.
• Alternative Pathway: Antibody-independent; starts with C3 activation.
• Lectin Pathway: Initiated by mannose-binding lectin on microbial surfaces.
• Common Pathway: Despite different initiation, all pathways converge on a common terminal sequence.

Classical Pathway Details

• Initiation: Antigen-antibody complex binds C1 leading to activation of C4 and C2 forming C3 convertase.
• Progression: C3 convertase leads to C5 convertase and subsequently the formation of the MAC.

Alternative Pathway Details

• Initiation: Starts with spontaneous hydrolysis of C3; involves factor B, factor D, and properdin.
• Role of Properdin: Stabilizes C3 convertase.

Lectin Pathway Details

• Initiation: Mannose-binding lectin binds microbial mannose; involves MASP-1 and MASP-2.
• Mechanism: Similar to classical pathway, activates C4 and C2.

Regulation of the Complement System

• Regulatory Proteins: Prevent overactivation and collateral damage.
• Mechanisms: Control assembly of convertase activity and MAC formation.

Associated Diseases

• Deficiency Effects: Can lead to increased susceptibility to infections and autoimmune conditions.
• Examples: C2 deficiency linked to recurrent infections, C3 deficiency is severe, C5-9 deficiency linked to neisserial infections.

Laboratory Testing

• Tests: Measurement of components and functional activity, including radial immunodiffusion, hemolytic titration (CH50), and ELISA.
• Complement Fixation Test: Detects antibodies through bacterial and hemolytic phases.

Conclusion

• The complement system plays a crucial role in immunity, linking innate and acquired responses, but requires tight regulation to prevent tissue damage.