Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis.
Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis.
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DOI：
10.1002/art.22059
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发表时间：
2006-09
影响因子：
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通讯作者：
Minako Yoshida;K. Saiga;T. Hato;Shoko Iwaki;T. Niiya;N. Arita;H. Komori;T. Tsubaki;H. Furukawa;M. Terada;K. Maeyama;K. Nemoto;M. Nose;M. Ono
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文献类型：
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作者：
Minako Yoshida;K. Saiga;T. Hato;Shoko Iwaki;T. Niiya;N. Arita;H. Komori;T. Tsubaki;H. Furukawa;M. Terada;K. Maeyama;K. Nemoto;M. Nose;M. Ono
目的肾小球新月体形成是进展性肾小球病伴致死性肾功能衰竭的典型表现，因此，预防新月体形成具有重要的临床意义。关于新月体形成的致病机制知之甚少。本研究试图通过分析一种新的突变小鼠品系来鉴定免疫复合物新月体肾小球肾炎（CGN）中新月体形成的关键事件。方法从自身免疫易感株EOD中分离出一种自发突变株小鼠，该株小鼠稳定地发展致命性CGN。组织病理学，血液学和免疫学的突变表型进行了评估。利用微卫星标记定位克隆寻找突变。结果与野生型EOD小鼠相比，突变型EOD小鼠的CGN明显改善，自发死亡率明显降低。在WT-EOD小鼠中，血液尿素氮浓度和血小板计数之间的负相关性以及血小板在肾小球中的大量积累是明显的，这表明血小板在肾小球中的积累有助于CGN的进展。突变体血小板对胶原蛋白和凝血酶的反应显示出异常聚集，并与突变体EOD小鼠的出血倾向相关。基因分析揭示了卡布奇诺基因（cno）的一个有害突变，cno编码的蛋白质属于一种称为溶酶体相关细胞器复合体1生物发生的复合体，并与血小板功能密切相关。形态学检查显示血小板δ颗粒致密体形成部分缺陷。结论血小板功能在自身免疫性肾炎新月体形成中起重要作用。
OBJECTIVE Crescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice. METHODS A spontaneous mutant strain of mice was isolated from the autoimmune-prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers. RESULTS Compared with wild-type EOD (WT-EOD) mice, mutant EOD (mut-EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT-EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut-EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (cno), which encodes a protein that belongs to a complex called the biogenesis of lysosome-related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the delta-granule of platelets. CONCLUSION The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.