Article

Toll-like receptor 9 affects severity of IgA nephropathy

Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Journal of the American Society of Nephrology (Impact Factor: 9.47). 10/2008; 19(12):2384-95. DOI: 10.1681/ASN.2007121311
Source: PubMed

ABSTRACT Environmental pathogens are suspected to aggravate renal injury in IgA nephropathy (IgAN), but neither underlying mechanisms nor specific exogenous antigens have been identified. In this study, a genome-wide scan of ddY mice, which spontaneously develop IgAN, was performed, and myeloid differentiation factor 88 (MyD88) was identified as a candidate gene for progression of renal injury (chi(2) = 21.103, P = 0.00017). For evaluation of the potential influence of environmental pathogens on progression of renal injury, ddY mice were housed in either conventional or specific pathogen-free conditions. Expression of genes encoding toll-like receptors (TLR) and the signaling molecule MyD88 were quantified by real-time reverse transcription-PCR in splenocytes. Although the housing conditions did not affect the prevalence of IgAN, the severity of renal injuries was higher in the conventionally housed group. Mice that had IgAN and were housed in conventional conditions had higher levels of TLR9 and MyD88 transcripts than mice that had IgAN and were housed in specific pathogen-free conditions. Furthermore, nasal challenge with CpG-oligodeoxynucleotides, which are ligands for TLR9, aggravated renal injury, led to strong Th1 polarization, and increased serum and mesangial IgA. For investigation of whether these results may be generalizable to humans, single-nucleotide polymorphisms in the TLR9 and MyD88 genes were analyzed in two cohorts of patients with IgAN; an association was observed between TLR9 polymorphisms and disease progression. In summary, these findings suggest that activation of the TLR9/MyD88 pathway by common antigens may affect the severity of IgAN.

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    • "In particular the T-1237C SNP is associated with an increased risk for asthma in European and American populations (Lazarus et al. 2003) and Crohn's disease in a German population (Torok et al. 2009). TLR-9 G1635A SNP appears to play a role in susceptibility to SLE (Xu et al. 2009) and in relation to renal disease, TLR-9 gene polymorphisms are associated and the histologic severity of disease in Japanese patients with IgA nephropathy (Suzuki et al. 2008). "
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    • "In particular the T-1237C SNP is associated with an increased risk for asthma in European and American populations (Lazarus et al. 2003) and Crohn's disease in a German population (Torok et al. 2009). TLR-9 G1635A SNP appears to play a role in susceptibility to SLE (Xu et al. 2009) and in relation to renal disease, TLR-9 gene polymorphisms are associated and the histologic severity of disease in Japanese patients with IgA nephropathy (Suzuki et al. 2008). "
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