IgA nephropathy is pathogenetically linked to defective galactosylation of IgA1 hinge-region O-glycans. The resultant poorly galactosylated IgA1 (Gd-IgA1) promotes glomerular injury via:
- A Formation of Gd-IgA1 immune complexes with IgG autoantibodies targeting the glycan defect, depositing in the mesangium ✓
- B Direct complement activation through the lectin pathway at the podocyte surface
- C Gd-IgA1 binding to mesangial FcαRI triggering TGF-β independent fibrosis
- D Gd-IgA1 cross-reacting with type IV collagen in the GBM
Explanation
Oxford (MEST-C) pathogenesis model: aberrantly glycosylated Gd-IgA1 is recognized as a neoantigen by IgG autoantibodies; the resulting IgG–Gd-IgA1 immune complexes deposit in the mesangium, activating complement (especially the alternative pathway) and mesangial cells to release cytokines and matrix proteins. The four-hit hypothesis describes this sequence: (1) Gd-IgA1 overproduction; (2) IgG autoantibody formation; (3) immune complex formation; (4) mesangial deposition and inflammation. Lectin pathway activation occurs as a secondary event but is not the primary step. GBM cross-reactivity characterizes Goodpasture disease (anti-GBM nephritis).
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.