Makita Y, Suzuki H, Kano T, et al. - Given an important role of galactose-deficient IgA1 (Gd-IgA1) in IgA nephropathy (IgAN) development and the known involvement of innate-immune activation via Toll-like receptor 9 (TLR9) in Gd-IgA1 production as well as enhancement of Gd-IgA1 synthesis induced by proliferation inducing ligand (APRIL) and interleukin-6 (IL-6) in IgAN, researchers determined the mechanism underlying overproduction of nephritogenic IgA via TLR9 activation in IgA secreting cells, using IgAN-prone ddY mouse and human IgA1-secreting cells. Raised serum levels of APRIL were detected in CpG-oligonucleotide-stimulated mice, which showed correlation with those of aberrantly glycosylated IgA and IgG-IgA immune complexes. In vitro, splenocytes of ddY mice and human IgA1-secreting cells exhibited TLR9 activation-induced enhanced generation of the nephritogenic IgA as well as APRIL and IL-6. However, IL-6-induced overproduction of Gd-IgA1 was fully suppressed by siRNA knock-down of APRIL. Overall, the activation of TLR9 was shown to result in enhanced production of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. Therefore, experts concluded that the synthesis of Gd-IgA1 is synergistically as well as independently enhanced by APRIL and IL-6.