Abstract
Objetive : IgA nephropathy (IgAN) patients show macroscopic hematuria and/or proteinuria after upper respiratory tract infections such as tonsillitis. Toll-like receptors (TLR) are key molecules that trigger innate immune responses and thus contributed to host defenses against infections by production of inflammatory mediators from immune-competent cells including macrophages or dendritic cells (DC). In the present study, we investigated TLR expression in tonsils from subjects with IgAN and determined the cell types expressing TLR. Correlations between the magnitude of TLR expression and therapeutic outcome were also examined.
Materials : Sixteen patients who were considered to have a poor or relatively poor prognosis based on the prognostic criteria for IgAN in Japan and treated by tonsillectomy were examined in this study.
Methods : Clinical data were collected before tonsillectomy or each course of steroid pulse therapy. Real-time PCR for TLR and cytokines (IFN-alpha/gamma) was performed using mRNA isolated from tonsils. Immunohistochemical analysis of tonsils was performed to identify localization of TLR expression and cell types.
Results : Levels of mRNA expression of TLR2 and TLR4 in the tonsils did not differ among the patients, although markedly higher expression of TLR9 was observed in three patients. These three patients also showed markedly higher expression of IFN-α and-γ with a significant correlation among them. We defined these three patients as the high TLR9 group and the remaining patients as the low TLR9 group. Immunohistochemical analysis confirmed markedly higher TLR9 expression in the tonsils of the high TLR9 group. TLR9 expression was mainly localized in BDCA-2 and CD123 positive plasmacytoid dendritic cells (pDC). There were higher numbers of pDC in tonsils of the High TLR9 group than in those of the low TLR9 group. However, there was no significant difference in the serum level of IFN-α and-γ between the two groups. Seven patients (High ; N=3, Low ; N=4) completed the steroid pulse therapy protocol. The high TLR9 group showed a significant improvement in proteinuria (P < 0.05) and hematuria (P< 0.01) just after therapy. Moreover, the serum IgA level and IgA/C3 ratio were also significantly decreased in the high TLR9 group (serum IgA : P<0.05, IgA/C3 ratio : P< 0.01).
Conclusion : It is suggested that tonsillectomy with steroid pulse therapy may provide rapid and good therapeutic outcomes in IgAN patients who show high TLR9 expression in tonsillar pDC. These findings indicated that TLR9 activation in the mucosa may be involved in the pathogenesis of IgAN.
