A patient with IgA nephropathy has worsening proteinuria. Galactose-deficient IgA1 (Gd-IgA1) is considered the central pathogenic molecule. Why does Gd-IgA1 lead to glomerular injury?

• A Gd-IgA1 is recognized by naturally occurring IgG autoantibodies forming immune complexes that deposit in mesangium and activate complement ✓
• B Gd-IgA1 directly binds podocyte slit diaphragm proteins causing proteinuria
• C Gd-IgA1 activates the lectin complement pathway via MBL binding to galactose-deficient hinge regions
• D Gd-IgA1 triggers neutrophil NET formation within glomerular capillaries

Explanation

In IgA nephropathy, aberrant O-glycosylation of the IgA1 hinge region creates Gd-IgA1, which is recognized as 'foreign' by anti-glycan IgG and IgA1 autoantibodies (second hit). The resulting Gd-IgA1-containing immune complexes deposit in the mesangium and activate complement (alternative and lectin pathways), leading to mesangial cell proliferation and matrix expansion. This is the 'four-hit hypothesis' of IgA nephropathy pathogenesis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.