New Insights and Future Perspectives of APRIL in IgA Nephropathy

Abstract

IgA nephropathy (IgAN) is characterized by immune-mediated glomerulonephritis, with the accumulation of galactose-deficient IgA1 (Gd-IgA1) in the glomeruli and increased levels of circulating Gd-IgA1 and Gd-IgA1-containing immune complexes. An incomplete understanding of the underlying mechanisms and differences in clinical and pathological features between individuals and ethnicities has contributed to the lack of established treatments for IgAN. A tumor necrosis factor (TNF) family member, a proliferation-inducing ligand (APRIL), is a crucial cytokine essential for the generation and survival of plasma cells. Recent studies demonstrated that APRIL is a pivotal mediator in the production of Gd-IgA1 in IgAN. As our understanding of the autoimmune pathogenesis underlying IgAN has improved, various pharmacological therapeutic targets, including APRIL antagonists, have emerged. Preliminary results showed that APRIL-targeting agents effectively reduced proteinuria and Gd-IgA1 levels without significantly increasing adverse events, indicating their potential as novel therapeutic agents for IgAN. In the present review, we discuss the current understanding of the role of APRIL in the pathogenesis of IgAN and novel therapeutic strategies focusing on APRIL-targeting agents for IgAN. APRIL inhibitors may offer new hope to patients with IgAN.

Keywords: B cell-activating factor (BAFF); IgA nephropathy; a proliferation-inducing ligand (APRIL); galactose-deficient IgA1 (Gd-IgA1).

Figure 1

The proposed pathogenesis of IgA nephropathy and APRIL/BAFF-targeting therapy. After mucosal infection, class switching and recombination (CSR) of naïve B cells to IgA1 + B cells occurs via T-cell-dependent (TD) (cytokine-mediated) and T-cell-independent mechanisms (TID) (Toll-like receptor (TLR) ligation). A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) play key roles in driving both TD and TID CSR, resulting in the generation of IgA + B cells. The upregulation of these cytokines contributes to the production of aberrantly O–glycosylated IgA1 (Gd-IgA1) and the subsequent synthesis of autoantibodies directed against Gd-IgA1. During lymphocyte trafficking, some IgA antibody-secreting cells (ASCs) do not enter the systemic compartment. These displaced IgA ASCs migrate to systemic sites and produce Gd-IgA1, which is released into the systemic circulation. IgA1 secretion by the displaced mucosal ASCs is enhanced by TLR activation through mucosal-derived pathogen-associated molecular patterns that enter the systemic circulation. Some of the Gd-IgA1-containing immune complexes formed in circulation are deposited in the kidneys, where they activate mesangial cells, and induce glomerular injury.

Figure 2

APRIL and BAFF signaling, their main physiological functions, and specifically targeted immunomodulatory agents. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) both interact with two receptors: B-cell maturation antigen (BCMA) and transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI). BCMA is predominantly expressed on plasma cells, whereas TACI is expressed on both mature B cells and plasma cells. BAFF is distinct from APRIL due to its unique capacity to bind to the BAFF receptor (BAFF-R), which is predominantly found on both immature and mature naïve B cells. The heparan sulfate proteoglycan (HSPG), which serves as a receptor for APRIL, allows APRIL to interact with target cells, facilitating efficient signaling through TACI. Atacicept, telitacicept, and povetacicept are dual APRIL/BAFF antagonists, whereas sibeprenlimab and zigakibart exclusively inhibit APRIL signaling.