C3 glomerulopathy (C3G) is characterized by C3-dominant glomerular deposits by immunofluorescence with absent or trace immunoglobulin. Which pathogenetic mechanism most accurately explains C3G?

• A Antibodies against the GBM activate the classical complement pathway, depositing C3 selectively without immunoglobulins
• B C3G is caused exclusively by hereditary C3 deficiency, with paradoxical glomerular C3 deposition from alternative pathway feedback
• C T-cell mediated injury activates local complement within the mesangium, depositing C3 independent of systemic complement dysregulation
• D Dysregulation of the alternative complement pathway — through gain-of-function mutations in C3, CFB, or CFH, or acquired anti-complement factor H antibodies — causes uncontrolled C3 convertase activity with glomerular C3 deposition without immune complex formation ✓

Explanation

C3 glomerulopathy results from dysregulation of the alternative complement pathway rather than immune complex formation. Mechanisms include: genetic mutations causing gain-of-function in C3 or factor B (stabilizing the C3 convertase C3bBb), or loss-of-function in factor H (the major inhibitor of the alternative pathway), or acquired autoantibodies against factor H (anti-FH antibodies) or C3 nephritic factor (C3NeF, which stabilizes the convertase). The net result is uncontrolled alternative pathway activation with excessive C3 deposition in the glomerulus. The pathognomonic IF pattern is C3-only or C3-dominant staining (≥2+ above immunoglobulins). C3 deficiency causes immune complex disease, not C3G.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.