Complement Pathways in Immunology

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 (opsonization, phagocytosis, cell lysis), promoting inflammation and immune responses.
• Heat-sensitive component of serum discovered by Jules Bordet and Paul Ehrlich

Lecture Objectives

• Understand the three complement pathways
• Describe the biological role of complement activation
• Explain the involvement of complement receptors in regulating complement activity
• Explain the role of complement and complement receptors in removing immune complexes

Complement Pathways & Nomenclature

• Classical Pathway: Activation by antigen-antibody complexes (C1q, C4, C2). Amplification stage involves (C3, C5, C6, C7, C8, C9).
• Lectin Pathway: Activation by mannose-binding lectin (MBL) binding to pathogen surfaces (MBL, MASP-1, MASP-2, C4, C2). Amplification occurs involving (C3, C5, C6, C7, C8, C9).
• Alternative Pathway: Activation on pathogen surfaces (factors B, D, properdin, C3). Amplification occurs involving (C3, C5, C6, C7, C8, C9).

Overview of Complement Pathways

• Classical pathway is activated by antigen-antibody complexes
• Lectin pathway is activated by lectin binding to pathogen surfaces
• Alternative pathway is activated by pathogen surfaces
• Result of complement activation: Inflammation, opsonization (enhancing phagocytosis of pathogens), killing of pathogens.

Activation - The Classical Complement Pathway

• C1q binds to two or more immunoglobulin (Ig) molecules (IgM or IgG) bound to an antigen
• C1q activation leads to cleavage of C4 and C2, forming C4bC2a, which is the C3 convertase
• Soluble antigens bound to IgG4 cannot activate complement. The ability of Ig to bind and activate C1q decreases in this order: IgM > IgG3 > IgG1 > IgG2

Activation - The Mannose-Binding Lectin (MBL) Pathway

• MBL is structurally similar to C1q
• MBL binds to mannose residues on bacteria, activating MASP-2
• MASP-2 cleaves C4 and C2, forming C4bC2a, which is the C3 convertase

Activation - The Alternative Pathway

• C3 spontaneously hydrolyses, producing C3(H2O), which binds to factor B
• Factor D cleaves factor B, forming C3bB
• C3bBb forms C3 convertase
• C3bBb is stabilized by properdin

Amplification: Generation of C3 & C5 Convertases

• Formation of C3 convertases (C4b2a or C3bBb) leads to amplification of complement activation
• Amplification steps increase the amount of C3b on the pathogen surface

Formation of C3 Convertase

• C3 convertase is formed from C4bC2a (Classical and Lectin Pathways) or C3bBb (Alternative Pathway)
• Properdin stabilizes the Alternative Pathway C3 convertase
• C3 convertase cleaves C3 into C3a and C3b
• C3b deposits on pathogen surface, leading to amplification

Main Biological Activities of Complement

• Production of opsonins to mediate phagocytosis
• Production of anaphylatoxins to contribute to inflammation
• Direct killing of pathogens by forming membrane attack complex (MAC)

Complement Receptors (CR)

• CR1 (CD35): Found on phagocytic cells, binds to C3b, C4b, and iC3b to enhance phagocytosis, and transports immune complexes to the liver
• CR3 (CD11b): Found on phagocytic cells, binds to iC3b, stimulating phagocytosis
• CR4 (CD11c): Similar to CR3

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

• C3b-containing immune complexes bind to CR1 on red blood cells, transporting them to the liver and spleen for removal
• Immune complexes bind to CR3 and Fc receptors on macrophages, which degrade them
• Deficiencies in complement components result in issues with removing immune complexes and can cause inflammation and pathology.

Complement Regulators

• Plasma and cell membrane proteins prevent excessive complement activation
• Regulation occurs at the initiation & activation, amplification (C3 and C5 convertases), and membrane attack complex stages of the complement cascade

Complement Regulation

• C1 inhibitor (C1-INH) inhibits activated C1r and C1s
• C4 binding protein (C4BP) dissociates C3 convertase subunits
• Factor I cleaves C3b and C4b
• Factor H dissociates C3 convertases

Clinical Relevance

• Deficiencies in complement components can lead to difficulties in clearing infections or immune complexes.
• Recurrent Neisseria infections are linked to deficiencies in some complement components
• Hereditary angioedema (HAE) is caused by a genetic mutation in the C1-INH gene
• Deficiencies in CD55 and C59 disrupt complement regulation which may damage cells.

Complement Receptors (cont'd)

• C5a receptor (CR5a) is found on various cells (smooth muscle, endothelial, mast cells, and basophils)
• Binding of C5a to CR5a on mast cells triggers an anaphylatoxin response and inflammation
• C3a receptor (CR3a) also an anaphylatoxin with similar distribution and function. CR3a and CR5a are involved in inflammatory processes and chemotaxis.

Resource Materials

• Immunology books and websites such as UpToDate and News-Medical provide additional resources for information on the complement system.
• YouTube videos may explain complement pathways more readily.

This quiz explores the complement pathways integral to the innate immune system, detailing their functions and roles in immune responses. Learn about the classical and lectin pathways, their activation mechanisms, and the regulation of complement activity.