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The complement system is a cascade of serum and membrane proteins activated by three pathways (classical, alternative, lectin) that converge on C3 cleavage, generating C3a and C3b. C3b opsonizes pathogens for phagocytosis, C3a and C5a are potent anaphylatoxins driving inflammation, and the membrane attack complex (MAC) directly lyses cells. Complement dysregulation causes excessive inflammation (sepsis), tissue damage (hemolytic anemia), or inadequate clearance of pathogens and immune complexes (autoimmune disease).
Trace all three activation pathways to the C3 convertase. Understand opsonization and MAC formation as effector mechanisms. Study inherited and acquired complement deficiencies and their clinical consequences (recurrent infections with C5-8 defects; SLE with C1q deficiency).
Complement is not only activated by antibodies—the alternative and lectin pathways provide immediate recognition of pathogens. Complement deficiency is not uniformly protective; some deficiencies increase infection risk while others cause autoimmunity.
The complement system's power comes from amplification: a small initiating signal — a few antibodies bound to a bacterium, or surface molecules recognized by lectins — triggers a cascade that rapidly deposits thousands of effector molecules on the target. You already know from your complement overview that three pathways (classical, alternative, lectin) converge on C3 convertase, the enzyme that cleaves C3 into C3a and C3b. In the context of pathophysiology, the question shifts from "how does complement work?" to "what goes wrong when it is mis-regulated or misdirected?"
Start with C3b. When C3b opsonizes a pathogen, it is a defense success — the bacterium gets tagged for phagocytosis and destroyed. But C3b can also deposit on host cells if regulatory proteins fail. Complement regulation proteins (CD46, CD55, CD59, factor H) continuously protect normal cells from accidental complement deposition. When these regulators are mutated, depleted, or blocked by autoantibodies, the complement system attacks the body's own cells. The clinical example is paroxysmal nocturnal hemoglobinuria (PNH), in which a somatic mutation eliminates CD55 and CD59 on red blood cells, making them vulnerable to complement-mediated lysis. This is not infection — it is the immune system consuming red blood cells it can no longer distinguish from pathogens.
The small cleavage fragments — C3a and C5a — are the inflammatory messengers. As anaphylatoxins, they bind G-protein-coupled receptors on mast cells, basophils, and endothelial cells, triggering histamine release, vasodilation, and increased vascular permeability. This is useful in a localized infection but catastrophic when complement activates systemically. In sepsis, massive complement activation floods the circulation with C5a. C5a drives neutrophil activation, endothelial damage, and cytokine release — contributing to the runaway inflammation of systemic inflammatory response syndrome. The lung, kidney, and liver are particularly vulnerable to complement-mediated endothelial injury under these conditions.
The third effector — the membrane attack complex (MAC) formed by C5b-9 — directly punches holes in lipid bilayers, killing cells by osmotic lysis. MAC is essential for killing encapsulated bacteria like Neisseria meningitidis, which is why patients with C5-C9 deficiencies suffer recurrent meningococcal infections. But MAC inserted into host cells contributes to tissue damage in ischemia-reperfusion injury: after blood flow is restored to ischemic tissue, complement activated during the reperfusion phase deposits MAC on viable but stressed cells, extending the zone of injury beyond the original infarct. Understanding complement pathophysiology therefore means recognizing it as a double-edged system — essential for defense, capable of amplifying any initial inflammatory signal into widespread tissue destruction if not precisely regulated.