Gd-IgA1-targeting therapy in IgA nephropathy ~what is pathogenic Gd-IgA1?~.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and galactose-deficient IgA1 (Gd-IgA1) is widely recognized as the central pathogenic molecule in the current multi-hit model of IgAN. Over the past few decades, advances in our understanding of IgAN pathogenesis have driven the development of mechanism-based therapies targeting Gd-IgA1-producing cells and the pathways that regulate their differentiation and survival. Recent clinical trials have demonstrated marked reductions in circulating Gd-IgA1, accompanied by significant improvements in proteinuria and preservation of kidney function, highlighting the transition from non-specific disease-modifying therapies toward mechanism-based therapies in IgAN. However, optimizing the use of these emerging therapies requires a deeper understanding of the immune mechanisms responsible for pathogenic Gd-IgA1 production. In this review, we summarize current knowledge regarding the cellular sources and molecular pathways responsible for the production of Gd-IgA1, review recent advances in therapies targeting these cells, and discuss the emerging concept that specific Gd-IgA1 fractions, including IgA-type anti-mesangial cell autoantibodies (IgA-MESCA), may contribute to the disease pathogenesis.