The initial pathogenic event proposed in IgA nephropathy involves an abnormality of the hinge region O-glycans of IgA1. The sequence that best explains mesangial deposition is:

• A Aberrant IgA1 is produced exclusively by bone marrow plasma cells and deposits alone, without antibody participation
• B Defective IgA1 glycosylation allows direct binding of IgA1 to the GBM alpha3 chain
• C Mucosal plasma cells secrete IgA1 lacking secretory component, which activates the classical complement pathway in the circulation
• D Galactose-deficient IgA1 is recognized by antiglycan autoantibodies, forming circulating immune complexes that deposit in the mesangium ✓

Explanation

The accepted multihit model begins with mucosally produced galactose-deficient IgA1 (Gd-IgA1), which is immunogenic. Circulating antiglycan autoantibodies bind Gd-IgA1, form immune complexes that are too large for hepatic clearance, and deposit in the mesangium where they activate the alternative complement pathway. Mesangial deposits therefore contain both IgA1 and C3, supporting option A being wrong, and the classical pathway is not the main route of injury.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.