Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces
Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces
复制标题
放线菌肽诱导的实验性抗肾小球基底膜肾小球肾炎
DOI：
10.1681/asn.2019060619
复制
发表时间：
2020-06-01
影响因子：
13.6
通讯作者：
Zhao, Ming-hui
中科院分区：
文献类型：
--
作者：
Gu, Qiu-hua;Huynh, Megan;Zhao, Ming-hui
抗肾小球基底膜（anti-GBM）疾病与HLA-DRB1*1501（该疾病的主要易感遗传因素）相关，与？3(127？148)作为肾源性T和B细胞表位。长期以来，人们一直怀疑感染与抗gbm疾病有关。在这项研究中，作者使用生物信息学工具从微生物中寻找模仿good牧草病病原表位关键基序的肽（3(127?148)）。他们发现了一种来自放线菌的致病肽，该肽被抗GBM患者的血清识别，并通过淋巴细胞的交叉反应在WKY大鼠和人源化HLA-DR15转基因小鼠中诱导蛋白尿、GBM上线性IgG沉积和新月形成。这些发现暗示了感染和分子模拟在抗gbm疾病发病机制中的作用。背景：抗肾小球基底膜（anti-GBM）疾病与HLA-DRB1*1501（该疾病的主要易感遗传因素）相关，与？3(127？148)作为肾源性T和B细胞表位。虽然疾病的原因尚不清楚，但长期以来人们一直怀疑感染与抗gbm疾病有关。方法利用BLAST、SYFPEITHI、ABCpred等生物信息学工具进行多肽搜索和表位预测，探讨微生物在抗gbm过程中是否可能通过分子模拟激活自身反应性T淋巴细胞和B淋巴细胞。我们使用抗gbm患者的血清来评估抗体识别的肽，并用每种候选肽免疫WKY大鼠和人源化小鼠模型（HLA-DR15转基因小鼠）来评估致病性。结果在关键基序的基础上，生物信息学方法鉴定出36个模仿人的微生物肽（127 ~ 148）。抗gbm患者血清中的循环抗体识别了其中的9种。一种从放线菌中提取的肽B7注射到WKY大鼠体内后，可引起蛋白尿、GBM上线状IgG沉积和新月形成。B7抗体也能靶向人和大鼠（127和148）。B7诱导人3(127)T细胞活化148)免疫老鼠。用放线菌裂解蛋白或重组蛋白免疫大鼠，检测T细胞对B7的应答。我们确认B7了吗？在HLA-DR15转基因小鼠中发生肾损伤的致病性与在3(135？145)免疫小鼠。结论抗gbm患者血清可识别生物信息学方法鉴定的微生物肽，放线菌肽可通过T细胞和B细胞交叉反应诱导实验性抗gbm GN。这些研究表明，抗gbm疾病可能是由微生物肽免疫引起的。
Significance Statement Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with ?3(127?148) as a nephritogenic T and B cell epitope. Association of infections with anti-GBM disease has been long suspected. In this study, the authors used bioinformatic tools to search for peptides from microbes mimicking the critical motif of a pathogenic epitope for Goodpasture disease (?3(127?148)). They identified a pathogenic peptide derived from Actinomyces, which was recognized by sera from patients with anti-GBM disease and that induced proteinuria, linear IgG deposition on GBM, and crescent formation in both WKY rats and humanized HLA-DR15 transgenic mice via crossreactivity of lymphocytes. These findings implicate a role for infection and molecular mimicry in the pathogenesis of anti-GBM disease.Background Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with ?3(127?148) as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected.Methods To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity.Results On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human ?3(127?148). Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat ?3(127?148). B7 induced T cell activation from human ?3(127?148)-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7?s pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in ?3(135?145)-immunized mice.Conclusions Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.