A 15-year-old boy presents with recurrent macroscopic hematuria following upper respiratory infections. Renal biopsy shows mesangial hypercellularity with mesangial IgA and C3 deposits on immunofluorescence. Electron microscopy confirms mesangial electron-dense deposits. The current pathogenic model of IgA nephropathy involves aberrant glycosylation of which immunoglobulin?

• A Overglycosylated IgA2 that accumulates in the mesangium via Fc receptor
• B Undergalactosylated IgA1 (Gd-IgA1) that serves as an autoantigen for IgG/IgA autoantibodies ✓
• C Desialylated IgA1 that activates the classical complement pathway
• D Hypermannosylated IgM that cross-reacts with mesangial antigens

Explanation

The current four-hit hypothesis of IgA nephropathy (Oxford model): elevated galactose-deficient IgA1 (Gd-IgA1) due to underactivity of beta-1,3-galactosyltransferase (C1GalT1) → Gd-IgA1 is recognized as a neoantigen → IgG and IgA autoantibodies form immune complexes → complexes deposit in the mesangium activating complement and mesangial cells. Serum Gd-IgA1 levels correlate with disease activity and progression. This explains the IgA + C3 pattern on immunofluorescence.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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