The Complement System Amy Lovett-Racke, PhD Associate Professor Department of Microbial Infection and Immunity Reading: The Immune System, 3 rd Edition, Peter Parham, Chapter 2

Learning Objectives  Compare and contrast the three complement pathways.  Know the role that phagocytic cells play in complement- mediated clearance of a pathogen.

The Complement System Complement is a set of plasma proteins that act in a cascade of reactions to attack extracellular forms of pathogens. Complement proteins are primarily serine proteases. Complement components coat pathogens will either kill the pathogen directly or facilitate its destruction by phagocytes. Complement fixation is the attachment of C3b to the pathogen surface which labels the pathogen for phagocytosis.

The Complement System

Alternative Complement Pathway

C3 convertases – Proteases that cleave and activate C3.

Alternative Complement Pathway C3 convertases – Proteases that cleave and activate C3.

Alternative Complement Pathway

C3bBb Alternative Complement Pathway

Macrophages have complement receptors (CR1) that binds C3b-coated pathogens, resulting in phagocytosis and destruction. Opsonization – the coating of a pathogen with a protein that facilitates phagocytosis. Alternative Complement Pathway

Alternative C5 convertase

Alternative Complement Pathway

Alternative C5 convertase Alternative Complement Pathway

C5b initiates the membrane attack complex. Membrane Attack Complex

C3a and C5a - Anaphylatoxins

Mannose-binding lectin Mannose- associated Serine proteases Lectin Complement Pathway

C2aC4b Classical C3 Convertase Lectin Complement Pathway

Classical Complement Pathway

IgM or IgG antigen Classical Complement Pathway

C2aC4b Classical C3 Convertase In the classical pathway, C1 replaces the role of the mannose-binding lectin in the lectin pathway. Classical/Lectin Complement Pathway

and The Immune System

Summary 1.The complement system is a set of serum proteins that coat the surface of pathogens, making them more readily phagocytosed or inducing lysis via the membrane attack complex. 2.There are three complement pathways that act at different times and are initiated by distinct mechanisms. 3.The cleavage of C3 via C3 convertases into C3a and C3b is critical step in complement fixation. 4.C3b coats pathogens for destruction. 5.Complement receptor 1 (CR1) on macrophages and other phagocytic cells recognizes C3b-coated pathogens and promotes phagocytosis of the pathogens. 6.C3a and C5a can recruit immune cells to the site of infection. They are also anaphylatoxins because they can induce anaphylactic shock when an acute inflammatory response occurs throughout the body.

Terminology Complement - set of plasma proteins that act in a cascade of reactions to attack extracellular forms of pathogens. Complement fixation - the attachment of C3b to the pathogen surface which labels the pathogen for phagocytosis. Classical complement pathway – The complement pathway initiated by antibody or C-reactive protein bound to the pathogen, inducing C1, C4 and C2 to generate C3 and C5 convertases. Alternative complement pathway – The complement pathway initiated by the presence of a pathogen that induces the cleavage of C3. Lectin complement pathway – The complement pathway initiated by the binding of mannose-binding lectin present in plasma to mannose-containing peptidoglycans on the surface of bacteria, inducing C4 and C2 to generate C3 convertases.

Terminology C3 convertase – complexes that cleave complement component 3 (C3) into C3a and C3b. C5 convertase – complexes that cleave complement component 5 (C5) into C5a and C5b. Complement receptors (CR1) – receptor on macrophages and other phagocytic cells that binds C3b-coated pathogens, resulting in phagocytosis and destruction. Opsonization – the coating of a pathogen with a protein that facilitates phagocytosis; this can refer to C3b in the complement system; this term is also used for coating of pathogens with antibodies. Membrane attack complex – A complex of terminal complement components (C5-C9) that forms a pore in the membrane of the target cell or pathogen, damaging the membrane and leading to lysis.

Terminology Antibody – protein secreted from plasma cells (antibody producing B cell) that binds antigen (proteins or peptides recognized by adaptive immune cells). C-reactive protein (CRP) – soluble acute phase protein that binds phosphocholine on bacteria, making them more susceptible to phagocytosis either directly or via the classical complement pathway. Anaphylatoxins – complement components C3a and C5a, which can induce inflammation, recruiting fluid and inflammatory cells to sites of infection. Mannose-binding lectin – soluble acute phase protein in the blood that binds to mannose residues on pathogen surfaces and activate the lectin complement pathway.

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