Toll-Like Receptor 9 Affects Severity of IgA Nephropathy
Toll-Like Receptor 9 Affects Severity of IgA Nephropathy
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DOI：
10.1681/asn.2007121311
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发表时间：
2008-12-01
影响因子：
13.6
通讯作者：
Tomino, Yasuhiko
中科院分区：
文献类型：
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作者：
Suzuki, Hitoshi;Suzuki, Yusuke;Tomino, Yasuhiko
环境病原体被怀疑加重伊加肾病（IgAN）的肾损伤，但既没有潜在的机制，也没有特定的外源性抗原已确定。在这项研究中，对自发发展IgAN的ddY小鼠进行了全基因组扫描，并将髓样分化因子88（MyD 88）鉴定为肾损伤进展的候选基因（chi（2）= 21.103，P = 0.00017）。为了评价环境病原体对肾损伤进展的潜在影响，将ddY小鼠饲养在常规或特定无病原体条件下。通过实时逆转录PCR定量脾细胞中编码toll样受体（TLR）和信号分子MyD 88的基因的表达。虽然住房条件并不影响IgAN的患病率，但肾损伤的严重程度在常规住房组中较高。患有IgAN并在常规条件下饲养的小鼠比患有IgAN并在无特定病原体条件下饲养的小鼠具有更高水平的TLR 9和MyD 88转录物。此外，鼻用CpG-寡脱氧核苷酸，这是TLR 9的配体，加重肾损伤，导致强烈的Th 1极化，并增加血清和系膜伊加。为了研究这些结果是否可以推广到人类，在两个IgAN患者队列中分析了TLR 9和MyD 88基因的单核苷酸多态性;观察到TLR 9多态性与疾病进展之间的关联。总之，这些研究结果表明，TLR 9/MyD 88通路的共同抗原的激活可能会影响IgAN的严重程度。
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.