to facilitate their uptake by phagocytes, or mediate inflammation. The complement system can be activated through three pathways—classic, alternative, or lectin—that involve a cascade-like, sequential activation of complement factors resulting in an amplified response (Fig. 75-1). Disorders of the complement system predispose to recurrent infection, autoimmunity, and angioedema (Table 75-1).
The three pathways for complement activation are initiated by different mechanisms. The classic pathway is activated by antigen-antibody complexes or by C-reactive protein. The alternative pathway may be activated by C3b generated through classic complement activation or by spontaneous hydrolysis of C3 on microbial surfaces. The lectin pathwayis initiated by the interaction of mannose-binding lectin with microbial carbohydrate. Activation of the classic pathway by an antigen-antibody complex is initiated by the binding of C1q to the Fc portion of an antibody molecule in the immune complex. C1r auto-activates and cleaves C1s, which cleaves C4 and then C2, forming the C3 convertase, C4b2a. C4b2a is activated by the lectin pathway when mannose-binding protein binds to sugar residues on the surface of pathogens, and mannose-binding protein–associated proteases (MASP) cleave C4 and C2. The alternative pathway is always active at a low level and is amplified when active C3 binds to a surface that lacks regulatory proteins. C3b generated from C3 binds to factor B, which is cleaved by factor D to form the alternative pathway C3 convertase, C3bBb. Properdin binds to and stabilizes the C3 convertase (see Fig. 75-1). The C3 convertase can cleave C3 resulting in further C3b deposition and activation of the alternative pathway that acts as an amplification loop by generating more C3b, or it can form the C5 convertase which initiates the formation of a membrane attack complex (MAC). The MAC is a complex of C5b, C6, C7, C8, and several C9 molecules that is common to all three pathways (see Fig. 75-1). The MAC generates pores in the cell membrane, leading to lysis of the cells. C3a and C5a, produced by cleavage of C3 and C5 respectively, can release histamine from mast cells and basophils, leading to increased vascular permeability and smooth muscle contraction. In addition, C5a has chemotactic
C1q, C1r SLE, glomerulonephritis; encapsulated
C2 SLE, glomerulonephritis; encapsulated bacterial infections
C3 Recurrent bacterial infections, rare glomerulonephritis, or SLE
C4 SLE, glomerulonephritis; encapsulated bacterial infections
Properdin Recurrent infections, severe meningococcal infection
MBL Increased susceptibility to infections
Factor H Glomerulonephritis, atypical HUS
Factor I Recurrent infections, glomerulonephritis
MCP Glomerulonephritis, atypical HUS
HUS, hemolytic uremic syndrome; MBL, mannose binding lectin; MCP, membrane cofactor protein; SLE, systemic lupus erythematosus.
activity, attracting phagocytes to the site of complement activation, and it can cause degranulation of phagocytic cells. C3b acts as an opsonin when attached to the surface of a pathogen by binding to phagocytes via complement receptor 1 (CR1). Its degradation product, iC3b, can bind to CR3 on the surface of phagocytes leading to the ingestion of the C3b-coated or iC3b-coated pathogen. iC3b and its breakdown product C3dg can bind complement receptor 2 (CR2) on B cells leading to activation and differentiation.