Questions: Complement Regulation and Disease Associated with Deficiency

Question 1

A patient has recurrent Neisseria meningitidis infections despite normal complement activity through C3. Testing reveals absent activity at the C5 level. What explains the specific susceptibility to this pathogen?

• A. C5 deficiency impairs opsonization, preventing neutrophils from engulfing the bacteria
• B. C5 deficiency impairs the classical pathway initiation, so antibody-antigen complexes cannot activate complement
• C. C5 deficiency prevents membrane attack complex formation; Neisseria is specifically vulnerable to MAC-mediated lysis because its thin Gram-negative outer membrane is accessible
• D. C5 deficiency reduces cytokine production, impairing T cell responses needed to control encapsulated bacteria

Answer: (C)

C5 is the first component of the terminal MAC-forming pathway (C5–C9). Without C5, the MAC cannot assemble and bacteria cannot be lysed. Neisseria meningitidis and N. gonorrhoeae are particularly vulnerable to MAC-mediated killing because they are Gram-negative with accessible outer membranes — unlike Gram-positive bacteria with thick peptidoglycan walls or encapsulated bacteria that resist MAC. This is why terminal complement deficiencies (C5–C9) produce a highly specific phenotype: recurrent Neisseria infections rather than general susceptibility to all pathogens.

Question 2

A patient with C2 deficiency is found to have systemic lupus erythematosus. Which mechanism best explains this association?

• A. C2 normally suppresses T cell activation; without it, autoreactive T cells escape deletion
• B. C2 deficiency causes overactivation of the alternative pathway, which generates inflammatory mediators that damage joint tissue
• C. Classical pathway components are needed to clear immune complexes and apoptotic debris; when they accumulate, they provide self-antigens that drive autoimmune responses
• D. C2 deficiency leads to low IgG levels, so immune complexes are not cleared by Fc receptors

Answer: (C)

Early classical pathway components (C1q, C2, C4) have a critical clearance function: they tag immune complexes and apoptotic debris for phagocytosis. When this clearance fails, debris accumulates. Uncleared apoptotic cells release nuclear antigens (DNA, histones, ribonucleoproteins) that are normally hidden from immune surveillance. These become a persistent source of self-antigens that can trigger and sustain autoimmune responses. C1q deficiency is the strongest known genetic risk factor for SLE — not because complement directly prevents autoimmunity, but because its clearance function prevents self-antigen exposure.

Question 3

Complement deficiency generally increases susceptibility to bacterial infections, because complement is a central component of innate immune defense.

• T. True
• F. False

Answer: False

The direction of clinical consequence depends entirely on where in the cascade the deficiency falls. Early classical pathway deficiencies (C1, C2, C4) are primarily associated with autoimmune disease — particularly SLE — because these components are essential for clearing immune complexes and apoptotic debris, not primarily for killing bacteria. Terminal component deficiencies (C5–C9) do impair MAC formation and increase bacterial infection risk (especially Neisseria). Alternative pathway deficiencies increase susceptibility to encapsulated organisms. The clinical phenotype is specific to the component's function, not a generic 'immunosuppression.'

Question 4

Factor H mutations cause disease not by reducing complement activity, but by allowing uncontrolled complement activation against host tissues.

• T. True
• F. False

Answer: True

This is the key insight about dysregulation vs. deficiency. Factor H normally binds C3b on host cell surfaces (recognizing sialic acid markers of self) and serves as a cofactor for Factor I to inactivate C3b. Without functional Factor H, complement cannot distinguish host cells from pathogens — the alternative pathway amplification loop proceeds unchecked on self surfaces. In atypical HUS (aHUS), Factor H mutations allow the alternative pathway to attack kidney endothelium, causing thrombotic microangiopathy and renal failure. More complement activation is worse here, not better: the disease is caused by losing the brake, not losing the engine.

Question 5

Why does early classical pathway complement deficiency (C1, C2, C4) predispose to autoimmune disease rather than to infection, and how does this differ mechanistically from terminal complement deficiency?

Model answer: Early classical pathway components (C1q, C2, C4) play a crucial role in clearing immune complexes and apoptotic debris. When cells die by apoptosis, their nuclear contents (DNA, histones) are normally packaged and cleared rapidly by complement-opsonized phagocytosis. Without early complement components, this clearance fails, debris accumulates, and nuclear self-antigens become chronically exposed to immune cells — driving autoimmune responses, particularly SLE. Terminal complement components (C5–C9) form the MAC, which lyses Gram-negative bacteria. Deficiency there impairs bacterial killing specifically, without disrupting clearance, producing recurrent Neisseria infections rather than autoimmunity.

This clinical logic flows directly from understanding the distinct functions of different complement components: opsonization and clearance vs. direct lysis. Knowing the function of each component predicts the disease associated with its deficiency — a major organizing principle for clinical immunology.