Pathogenesis of IgA Nephropathy: The 4-Hit Cascade, A Proliferation-Inducing Ligand (APRIL), and cytokines

EP: 1.Advancing IgA Nephropathy Care: Emerging Therapies, Unmet Needs, and Economic Considerations

EP: 2.Introduction to IgA Nephropathy

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EP: 3.Pathogenesis of IgA Nephropathy: The 4-Hit Cascade, A Proliferation-Inducing Ligand (APRIL), and cytokines

EP: 4.Diagnosing IgA Nephropathy

IgA Nephropathy: Pathogenesis and the 4-Hit Cascade

IgA nephropathy (IgAN) is characterized by the deposition of IgA1-containing immune complexes in the glomerular mesangium. The pathogenesis follows a 4-hit cascade:

4-Hit Cascade

1. First hit - Aberrant IgA1 production: Production of galactose-deficient IgA1 (Gd-IgA1) due to abnormal O-glycosylation in the hinge region. This process involves defective activity of specific glycosyltransferases, particularly C1GalT1 and its chaperone Cosmc.
2. Second hit - Anti-glycan antibody production: Formation of autoantibodies (IgG or IgA) against the exposed GalNAc epitopes on Gd-IgA1.
3. Third hit - Immune complex formation: Circulating immune complexes form between Gd-IgA1 and anti-glycan antibodies.
4. Fourth hit - Mesangial deposition and inflammation: Deposition of these immune complexes in the mesangium, activating complement and mesangial cells, leading to inflammation, matrix expansion, and ultimately renal damage.

Role of APRIL and Cytokines

A PRoliferation-Inducing Ligand (APRIL):

• Member of the TNF family that promotes B-cell survival and differentiation
• Upregulated in patients with IgAN
• Stimulates IgA1-producing cells and may contribute to the overproduction of Gd-IgA1
• Binds to receptors TACI and BCMA, promoting plasma cell survival and IgA class switching

Key Cytokines in IgAN Pathogenesis:

• IL-6: Enhances IgA production and may affect glycosylation of IgA1
• TGF-β: Drives mesangial cell proliferation, extracellular matrix production, and fibrosis
• TNF-α: Promotes inflammation and mesangial cell activation
• BAFF: Works synergistically with APRIL to support B-cell survival and antibody production
• IL-4 and IL-5: Contribute to B-cell differentiation and IgA synthesis
• MCP-1/CCL2: Recruits inflammatory cells to the glomeruli

These cytokines create a proinflammatory environment that perpetuates kidney injury and progressive loss of renal function in patients with IgAN.