A patient develops episodic destruction of their own red blood cells with no evidence of infection. Lab workup reveals a somatic mutation that eliminates complement regulatory proteins CD55 and CD59 on red blood cells. What best explains this pathophysiology?
AActivated T cells are targeting red blood cells as a bystander effect of chronic inflammation
BAbsence of CD55 and CD59 allows the membrane attack complex to lyse the patient's own red blood cells, which can no longer be distinguished from pathogens
CC3b opsonizes the red blood cells, triggering antibody-dependent cellular cytotoxicity
DThe alternative pathway is continuously activated by a hidden pathogen residing in erythrocytes
This is paroxysmal nocturnal hemoglobinuria (PNH). CD55 and CD59 are regulatory proteins that protect host cells from complement deposition. Without them, MAC (C5b-9) assembles on the red cell surface and lyses it by osmotic disruption — with no infection involved. The common misconception is that complement only acts in response to pathogens; in fact, complement is always primed and host cells require continuous regulatory protection to avoid self-attack.
Question 2 Multiple Choice
In sepsis, massive systemic complement activation leads to worse patient outcomes despite active pathogen clearance. Which mechanism best explains this paradox?
AComplement depletion leaves bacteria unopsonized, allowing them to proliferate unchecked
BC5a floods the circulation, driving neutrophil activation, endothelial damage, and cytokine release that causes widespread tissue injury beyond the infection site
CMAC formed in the bloodstream lyses bacteria too slowly, allowing them to release toxins first
DClassical pathway activation is suppressed during sepsis, impairing antibody-mediated killing
The paradox arises from complement's double-edged nature. C5a is a potent anaphylatoxin: locally it recruits neutrophils appropriately, but when generated systemically it activates neutrophils throughout the body, damages endothelial cells in the lung, kidney, and liver, and triggers cytokine cascades that amplify injury far beyond the infection site. The harm comes not from the pathogen but from the complement-driven inflammatory response directed against the host's own tissues — the 'friendly fire' of SIRS.
Question 3 True / False
Deficiency of early complement components such as C1q or C4 protects patients from autoimmune disease by reducing the overall inflammatory drive of the complement system.
TTrue
FFalse
Answer: False
This is the opposite of what occurs. C1q and C4 are required for clearance of apoptotic cells and immune complexes. When these components are absent, immune complexes accumulate and apoptotic debris goes uncleared — both of which trigger autoimmune responses. C1q deficiency is one of the strongest known genetic risk factors for systemic lupus erythematosus. The misconception conflates 'less complement activation' with 'less inflammation,' ignoring complement's essential housekeeping role in preventing immune complex disease.
Question 4 True / False
In ischemia-reperfusion injury, complement can attack viable host cells in tissue that survived the initial ischemia, extending the zone of tissue damage beyond the original infarct.
TTrue
FFalse
Answer: True
During ischemia, stressed cells may express neoantigens or downregulate complement regulatory proteins. When blood flow is restored, complement activated in the newly oxygenated tissue deposits MAC on these stressed but viable cells, killing them. The total zone of destruction after reperfusion therefore exceeds the zone caused by ischemia alone — a clinically important mechanism in myocardial infarction that helps explain the paradox of 'reperfusion injury.'
Question 5 Short Answer
Why does complement dysregulation produce two seemingly opposite clinical outcomes — increased infection susceptibility in some deficiencies and autoimmune disease in others?
Think about your answer, then reveal below.
Model answer: Which outcome depends on which component is deficient and what function it serves. Terminal components (C5-C9) form the MAC needed to lyse encapsulated bacteria like Neisseria; deficiencies here remove a killing mechanism and increase infection risk. Early components (C1q, C3, C4) opsonize pathogens and clear immune complexes and apoptotic debris; deficiencies here impair immune housekeeping, allowing complexes to accumulate and trigger autoimmunity. Complement is not a single-purpose attack system — it performs surveillance, tagging, and clearance functions that serve different goals at different stages of the cascade.
The key insight is that 'complement deficiency' describes many different conditions with different consequences. MAC is primarily for killing; C3b is for opsonization and clearance; C3a/C5a are inflammatory signals. Removing different effectors produces predictably different defects. Understanding this requires treating complement as a system with distinct roles rather than as a monolithic attack mechanism whose absence is uniformly protective or harmful.