The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome
The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome
复制标题
DOI：
10.1093/ndt/gft198
复制
发表时间：
2013-09-01
影响因子：
6.1
通讯作者：
Prohaszka, Zoltan
中科院分区：
文献类型：
--
作者：
Szilagyi, Agnes;Kiss, Nora;Prohaszka, Zoltan
背景溶血性尿毒综合征（阿胡斯）的非典型形式包括由替代补体途径调节缺陷引起的HUS和与产生神经氨酸酶的病原体（如肺炎链球菌）相关的HUS。越来越多的数据支持神经氨酸酶在链球菌的发生发展中的致病作用。肺炎相关溶血尿毒综合征（SP-HUS），但补体的作用从未得到详细阐明。因此，我们的目的是调查是否存在的病理补体谱和遗传危险因素的阿胡斯与SP-HUS患者。入组5例SP-HUS经典途径和旁路途径活动的患者，除C3、C4外，还测定了因子H、B、I和抗因子H自身抗体水平。测定CFH、CFI、CD 46（MCP）、THBD、C3和CFB基因编码区序列，并分析CFI、CD 46、CFH及相关基因的拷贝数。我们发现，在SP-HUS患者的急性期样本中，补体成分C4、C3以及经典和旁路途径的活性降低，表明严重的活化和补体消耗，但这些改变中的大多数在缓解后正常化。其中三名患者在补体介导的阿胡斯相关基因中携带突变和风险单倍型。发现的突变包括一个已发表的CFI变异（P50 A）和两个新的CFH（R1149 X）和THBD（T44 I）基因突变。我们的研究结果表明，严重的补体失调和消耗伴随着侵袭性肺炎球菌病（IPD）相关的SP-HUS的进展和补体基因的遗传变异可能有助于这种并发症的发展，在一定比例的受影响的患者。
Background. Atypical forms of haemolytic uraemic syndrome (aHUS) include HUS caused by defects in the regulation of alternative complement pathway and HUS linked to neuraminidase-producing pathogens, such as Streptococcus pneumoniae. Increasing data support a pathogenic role of neuraminidase in the development of S. pneumoniae-associated haemolytic uraemic syndrome (SP-HUS), but the role of complement has never been clarified in detail. Therefore, we aimed to investigate whether the pathologic complement profile and genetic risk factors of aHUS are present in patients with SP-HUS.Methods. Enrolling five patients with SP-HUS classical and alternative pathway activity, besides C3, C4, factors H, B, I and anti-factor H autoantibody levels were determined. The coding regions of CFH, CFI, CD46 (MCP), THBD, C3 and CFB genes were sequenced and the copy number of CFI, CD46, CFH and related genes were also analyzed.Results. We found that in the acute phase samples of SP-HUS patients, complement components C4, C3 and activity of the classical and alternative pathways were decreased, indicating severe activation and complement consumption, but most of these alterations normalized later in remission. Three of the patients carried mutations and risk haplotypes in complement-mediated aHUS associated genes. The identified mutations include a previously published CFI variant (P50A) and two novel ones in CFH (R1149X) and THBD (T44I) genes.Conclusions. Our results suggest that severe complement dysregulation and consumption accompany the progress of invasive pneumococcal disease (IPD)-associated SP-HUS and genetic variations of complement genes may contribute to the development of this complication in a proportion of the affected patients.