Chapter 6 The Complement System

Complement System Major effector branch of humoral immune system in vertebrates However, invertebrates possess proteins related to complement system Even sea urchins have complement

Functions of Complement

7 Functional Categories: Initiate complement components Enzymatic mediators Membrane binding (opsonins) Inflammatory mediators Membrane attack proteins Complement receptor proteins Regulatory proteins

Components of Complement Soluble proteins and glycoproteins Synthesized mainly by liver hepatocytes and other cell types 5% of serum globulins Circulate as inactive proenzymes – 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 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

Classical Pathway Antibody Dependent Activated by Ag-Ab complex (most commonly IgM and IgG) Early stages involve C1, C2, C3, and C4

Classical Pathway What C1 looks like

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

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

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 carbs on surface of microorganisms

Membrane Attack Complex (MAC) Forms pores in cell membrane Ions and small molecules can freely pass through pores Cell cannot maintain osmotic stability

Regulation Components are capable of attacking host cells 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 and 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

Introduction to Complement https://www.youtube.com/watch?v=_5bj0oUrqDQ