complement system
Summary
The complement system is a group of >30 plasma and cell-surface proteins that act as part of the innate immune system to opsonize pathogens, recruit inflammatory cells, and directly lyse target cells via the membrane attack complex (MAC). It is activated via three pathways—classical, alternative, and lectin—that converge on C3 activation.
Detail
The complement system consists of proteins synthesized primarily by the liver that circulate as inactive precursors and become sequentially activated in a proteolytic cascade. Three activation pathways exist: (1) Classical pathway—triggered by antigen-antibody complexes (IgM or IgG) binding C1q; (2) Alternative pathway—triggered by pathogen surfaces (spontaneous C3 hydrolysis, no antibody needed); (3) Lectin pathway—triggered by mannose-binding lectin (MBL) binding mannose residues on microbial surfaces. All three pathways converge at C3 convertase formation, leading to C3b (opsonization), C5a and C3a (anaphylatoxins that mediate inflammation and chemotaxis of neutrophils), and eventually C5b-9 (membrane attack complex), which creates pores in pathogen membranes causing lysis—particularly important against Neisseria species.
Key regulatory proteins include C1 esterase inhibitor (deficiency causes hereditary angioedema), Decay-accelerating factor (DAF/CD55), and CD59 (deficiency causes paroxysmal nocturnal hemoglobinuria due to loss of protection against MAC-mediated RBC lysis).
Clinical correlations: - C1 esterase inhibitor deficiency → hereditary angioedema (unopposed bradykinin activity, recurrent angioedema without urticaria) - C3 deficiency → increased susceptibility to recurrent pyogenic sinus and respiratory infections - C5-C9 (terminal complement) deficiency → recurrent Neisseria infections (gonorrhoeae/meningitidis) due to inability to form MAC - DAF/CD55 or CD59 deficiency → paroxysmal nocturnal hemoglobinuria (PNH), causing complement-mediated hemolysis - Complement also plays a role in immune complex clearance; deficiencies (e.g., C1q, C4) are associated with SLE-like autoimmune disease due to impaired clearance of immune complexes.
Understanding complement is essential for USMLE Step 1 (immunology, biochemistry pathways) and Step 2 (clinical correlations such as angioedema, PNH, and susceptibility to specific infections).
Sources
- First Aid for the USMLE Step 1
- Kuby Immunology
- Robbins Basic Pathology
- UWorld Step 1 Qbank
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.