A 12-year-old boy with recurrent gross hematuria following upper respiratory infections has IgA nephropathy. Renal biopsy shows mesangial IgA deposits. The current understanding of IgA nephropathy pathogenesis involves which molecular mechanism as the initiating event?
- A Mucosal IgA1 deficiency causes compensatory systemic IgA2 upregulation with mesangial tropism
- B Toll-like receptor 9 activation by microbial DNA drives polyclonal IgA B-cell activation without structural IgA abnormalities
- C Complement pathway C1q activation by mesangial IgA deposits triggers the classical pathway, causing nephritic syndrome
- D Underglycosylated IgA1 (galactose-deficient IgA1, Gd-IgA1) is recognized by anti-glycan IgG/IgA autoantibodies, forming immune complexes that deposit in the mesangium ✓
Explanation
The multi-hit model of IgA nephropathy proposes: (1) increased production of galactose-deficient IgA1 (Gd-IgA1) by mucosal B cells; (2) autoantibodies (IgG and IgA) recognizing the exposed N-acetylgalactosamine (GalNAc) residues on the hinge region of Gd-IgA1; (3) formation of pathogenic immune complexes that deposit in the mesangium; and (4) mesangial cell activation with complement (lectin pathway) and cytokine-mediated injury. IgA nephropathy activates the alternative and lectin complement pathways, not the classical C1q-mediated pathway. This four-hit model is the current consensus mechanism and explains both primary and secondary IgA nephropathy.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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