Plasmacytoid dendritic cells modulate the production of mucosal IgA in IgA nephropathy

BACKGROUND AND HYPOTHESIS: Aberrantly glycosylated immunoglobulin A (IgA) plays a central role in the pathogenesis of IgA nephropathy (IgAN). The activation of Toll-like receptor 9 (TLR9) has been shown to induce aberrant glycosylation of IgA via the a proliferation-inducing ligand (APRIL)-mediated pathway. TLR9 is known to be highly expressed in B cells and plasmacytoid dendritic cells (pDCs). Although the stimulation of TLR9 in B cells has been reported to promote the production of aberrantly glycosylated IgA, the effects of TLR9 stimulation on pDCs remain unclear. Therefore, in this study, we focused on the role of mucosal pDCs in the synthesis of aberrantly glycosylated IgA in patients with IgAN. METHODS: We evaluated the distribution of the DC subsets in tonsillar mononuclear cells (MNCs). The synthesis of aberrantly glycosylated IgA in MNCs cultured with or without pDCs was analyzed. We also evaluated the effects of pDC depletion on the production of aberrantly glycosylated IgA in ddY mice, a spontaneous murine model of IgAN, nasally immunized with CpG-oligonucleotide, a ligand for TLR9. RESULTS: The percentage of DCs, especially pDCs, was significantly higher in the palatine tonsils of patients with IgAN than in those of patients with chronic tonsillitis. In patients with IgAN, the abundance of pDCs was significantly correlated with the APRIL and TLR9 expressions in tonsillar MNCs. The levels of aberrantly glycosylated IgA in culture supernatants of tonsillar MNCs were found to be increased in the presence of pDCs. The pDC-depleted ddY mice exhibited significantly lower serum levels of aberrantly glycosylated IgA in vivo. CONCLUSION: Mucosal pDCs contribute to the pathogenesis of IgAN by facilitating the production of aberrantly glycosylated IgA via TLR9 signaling. Our findings demonstrated that pDC may be a novel therapeutic target for IgAN.