The Complement System

• Jules Bordet in 1980s working on V. cholerae
• Paul Ehrlich carried similar experiment.

Complement System

• Complement now includes more than 30 soluble and cell-bound proteins.
• Affect both innate and acquired immunity.
• Major effector branch is humoral immune system in vertebrates
• However, invertebrates possess proteins related to complement system

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Functions of Complement

Components of Complement

• Soluble proteins and glycoproteins
• Synthesized mainly by liver hepatocytes and other cell types (blood monocytes, tissue macrophages, and epithelial cells of the GIT and GUT)
• 5% of serum globulins
• Circulate as inactive proenzymes (or zymogens) – proteolytic cleavage removes inhibitory fragment and exposes active site

Components of Complement

• Designated by numerals, letter symbols, or trivial names
• Examples: C1-C9, factor D, homologous restriction factor
• Peptide fragments made by activation
• “a” for smaller fragment – C3a
• “b” for larger fragment – C3b
• Except C2- “a” is larger
• Complexes with enzymatic activity have bar on top – C4b2a

Complement Activation

• Early steps – resulting in C5
• Can occur by 3 pathways:
• Classical
• Alternative
• Lectin
• Final steps leading to membrane-attack complex (MAC) are identical in all 3 pathways

1. Classical Pathway

• Antibody Dependent
• Activated by Ag-Ab complex (most commonly IgM and IgG)
• Early stages involve C1, C2, C3, and C4
• antigen-antibody complex induces conformational changes in the Fc portion of the IgM molecule that expose a binding site for the C1 component of the complement system.

Classical Pathway

• What C1 looks like

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

2. Alternative Pathway

• Antibody-Independent
• Component of innate immune system
• Early stages involve C3, factor B, factor D, and properdin
• Initiated by cell surface constituents foreign to host
• For example – Gram- and Gram+ bacteria

Alternative �Pathway

3. Lectin Pathway

• Antibody-Independent
• However, proceeds more like classical pathway
• Uses C4 and C2
• Activated by binding of mannose-binding lectin (MBL) to mannose residues on glycoproteins or carbohydrates on surface of microorganisms.
• MBL is an acute phase protein produced in inflammatory responses.
• Function similar to C1q

Membrane Attack Complex (MAC)

• Forms pores in cell membrane
• Ions and small molecules can freely pass through pores
• Cell cannot maintain osmotic stability

Regulation of Complement System

• Components are capable of attacking host cells (Sialic acid causes inactivation)
• Components undergo spontaneous inactivation if they are not stabilized with other components
• C3 convertase is major amplification step in all 3 pathways
• Regulatory proteins are present that control C3 convertase

Biological Consequences of Complement Activation

• Amplifies humoral response and causes it to be an effector response
• Lyse cells
• Participate in inflammatory response
• Opsonization of antigen
• Clearance of immune complexes

Cell Lysis

• MAC can lyse broad spectrum of cells
• Gram+ bacteria generally more resistant because of thick peptidoglycan
• Some have developed ways to evade MAC

Mediating Inflammation

• Cleavage products of complement components mediate inflammation
• Smaller fragments bind to basophils and mast cells
• C3a and C5a (anaphylatoxins) induce smooth muscle contraction and increase vascular permeability

Opsonization

• C3b and C4b have opsonizing activity – cause phagocytosis

Viral Neutralization

• Binding of antibody and complement to viruses blocks attachment to susceptible host cells

Clearing of Immune Complexes

• Tissue damage can result from build up of immune complexes
• C3b coats immune complexes
• RBC have capability of binding C3b coated complexes and carrying them to liver and spleen to be cleared
• Deficiencies with any of complement may result in improper binding of C3b and loss of clearing may occur