Chapter 6 The Complement System Dr Capers IMMUNOLOGY

Chapter 6 The Complement System Dr. Capers IMMUNOLOGY

Complement System Cooperates with both the innate and adaptive immune 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 – initiate complement ○ ○ ○ cascades Enzymatic mediators – cleave and activate other complement proteins Membrane binding (opsonins) – enhancing phagocytosis Inflammatory mediators – vasodialation and permeability Membrane attack proteins – form MAC Complement receptor proteins – receptors on cell that bind complement proteins Regulatory proteins – help break down unwanted/unneeded complement proteins, protect host cells

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: C 1 -C 9, factor D, homologous restriction factor Peptide fragments made by activation “a” for smaller fragment – C 3 a “b” for larger fragment – C 3 b Complexes with enzymatic activity have bar on top – C 4 b 2 a

Complement Activation Early steps – resulting in C 5 ○ 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 Ig. M and Ig. G) ○ Early stages involve C 1, C 2, C 3, and C 4

Classical Pathway What C 1 looks like

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

Classical Pathway

Alternative Pathway Antibody-Independent Component of innate immune system Early stages involve C 3, 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 C 4 and C 2 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

Watch this video on complement: https: //www. youtube. com/watch? v=vb. W Yz 9 XDt. Lw

Regulation Components are capable of attacking host cells Components undergo spontaneous inactivation if they are not stabilized with other components C 3 convertase is major amplification step in all 3 pathways ○ Regulatory proteins are present that control C 3 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 ○ C 3 a and C 5 a (anaphylatoxins) induce smooth muscle contraction and increase vascular permeability

Opsonization C 3 b and C 4 b 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 C 3 b coats immune complexes ○ RBC have capability of binding C 3 b coated complexes and carrying them to liver and spleen to be cleared ○ Deficiencies with any of complement may result in improper binding of C 3 b and loss of clearing may occur