Complement Pathways Overview

Complement Pathways

• Complement is a group of circulating and cell membrane proteins part of the innate immune system
• Major functions: assist the immune system in eliminating pathogens or damaged cells, either through opsonization and phagocytosis or cell lysis (killing of cells); promote inflammatory and immune responses
• The heat-sensitive component of serum identified by Jules Bordet and Paul Ehrlich

Lecture Objectives

• Demonstrate understanding of the three complement pathways
• Describe biological role of complement activation
• Explain the involvement of complement receptors in regulation of complement activity
• Explain the role of complement and complement receptors in removal of immune complexes

Complement Pathways & Nomenclature

• Classical Pathway: Complement components (C1, C4, C2, C3, C5, C6, C7, C8, C9) (activation, amplification, terminal)
• Lectin Pathway: Mannose-binding lectin (MBL), C4, C2, C3, C5, C6, C7, C8, C9 (activation, amplification, terminal)
• Alternative Pathway: Factors B, D, Properdin, C3, C5, C6, C7, C8, C9 (activation, amplification, terminal)

Overview of Complement Pathways

• Classical Pathway: Activated by antigen-antibody complexes
• MB-Lectin Pathway: Activated by lectin binding to pathogen surfaces
• Alternative Pathway: Activated by pathogen surfaces

Activation - The Classical Complement Pathway

• C1q has to cross-link the Fc of 2 Ig molecules – IgM or IgG, bonded to an antigen
• Note: soluble antigens bounded to IgG4 cannot activate complement
• Interaction of C1q with Ab-Ag complex activates proteases C1r & C1s
• C1s cleaves C4 and C2, resulting in C4b, C4a, C2a, and C2b
• C4b complexes with C2a on the Ab-Ag complex forming C3 convertase

Activation - The Mannose Binding Lectin (MBL) Pathway

• Terminal mannose residues not found on mammalian cells but expressed on numerous types of bacteria, fungi, and viruses
• MBL is structurally similar to C1q; circulating it is bound to MASP
• MBL binds to mannose residues causing MASP-2 to cleave C4 and C2, forming C4bC2a on the surface of the bacterium. (similar to classical pathway – C4bC2a forms C3 convertase)

Activation - The Alternative Pathway

• Triggered by various foreign substances (endotoxins, necrotic cells, microorganisms, aggregated Ig molecules)
• Hydrolysis of C3 results in small amounts of “preformed” C3b in the serum
• C3b deposited on a particle binds Factor B, forming C3bB
• Factor D cleaves B into Ba and Bb (Ba released into fluid phase); Bb remains associated with C3b
• C3bBb forms the C3 convertase & is stabilized by properdin.

Amplification: Generation of C3 & C5 Convertases

• C3 convertase is made from C4bC2a (classical and lectin pathways) or C3bBb (alternative pathway)
• The alternative pathway has an amplification loop with Properdin binding and cleaving large amounts of C3 to C3b, allowing more C3b to bind to the surface
• C3 convertase cleaves C3 into C3a (fluid phase) and C3b, depositing with C4bC2aC3b (classical/MBL) or C3bBb3b (alternative pathway)
• This forms C5 convertase
• C5 convertase cleaves C5 into C5a (fluid phase) and C5b, which binds to the surface

Main Biological Activities of Complement

• Production of opsonins (mediating phagocytosis)
• Production of anaphylatoxins (contributing to inflammation)
• Direct killing (lysis) of microbes by forming membrane attack complex (MAC)

Complement Receptors (CR)

• CR1 (CD35): found on phagocytic cells and erythrocytes; binds C3b, C4b, iC3b; enhances phagocytosis and transports immune complexes to the liver
• CR3 (CD11b): found on phagocytic cells; binds iC3b; stimulates phagocytosis
• CR4 (CD11c): similar to CR3

The Role of Complement and Complement Receptors in the Removal of Immune Complexes (IC)

• C3b + IC binds to CR1 on RBCs, which transport them to the liver and spleen
• Complexes bind to CR3 & Fc receptors on macrophages for degradation
• Deficiency in clearing IC results in IC deposition in vessels, joints, etc., leading to acute inflammation

Complement Receptors cont'd

• C5a receptor (CR5a): found on various cells (smooth muscle, endothelial, mast cells, basophils); binding of C5a to CR5a promotes anaphylatoxin-like response and inflammation; found on phagocytes (neutrophils); presence of C5a enhances chemotaxis
• C3a receptor (CR3a): binds C3a; similar cell distribution and function as CR5a

Complement Regulators

• Group of plasma and cell membrane proteins preventing excessive complement activation
• Regulation occurs at three steps in the complement pathway: initiation and activation, amplification (C3 and C5 convertases), and membrane attack complex

Complement Regulation - Regulatory Proteins Found in the Plasma

• C1 Inhibitor (C1-INH): binds activated C1r and C1s; removes them from C1q
• C4 binding protein (C4BP): dissociates C3 convertase subunits in classical pathway; cofactor for Factor I-mediated cleavage of C4b
• Factor I: cleaves C3b and C4b
• Factor H: dissociates C3 convertase subunits in the alternative pathway; cofactor for Factor I-mediated cleavage of C3b

Clinical Relevance (C1-INH & Angioedema)

• Genetic mutation in C1NH gene causes Hereditary Angioedema (HAE)
• C1-INH regulates interconnecting pathways (coagulation, fibrinolytic, and kinin)
• Production of large amounts of bradykinin (potent vasodilator) contributes to angioedema

Membrane Proteins that Regulate Complement Activation

• Decay Accelerating Factor (DAF) or CD55: found on many cell types; important in regulating amplification by dissociating C3 convertase subunits; defect affects all three pathways
• CD59: found on many cell types; regulates the membrane attack complex by binding C5b-C8 to block C9 binding & formation of MAC

Resource Material

• Relevant articles and videos for further study on complement pathways, regulators, and their roles in acute inflammation and other health conditions

This quiz covers the three complement pathways involved in the innate immune system. It includes the classical and lectin pathways, their activation, biological role, and regulation through complement receptors. Test your understanding of key components and functions in immune response.