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The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome

发布于：2013年7月2日    文字：【大】【中】【小】

Nephrol Dial Transplant. 2013 Jun 19. [Epub ahead of print]

The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome.

Szilágyi A, Kiss N, Bereczki C, Tálosi G, Rácz K, Túri S, Gy?rke Z, Simon E, Horváth E, Kelen K, Reusz GS, Szabó AJ, Tulassay T, Prohászka Z.

Source

3rd Department of Medicine, Research Laboratory, Faculty of Medicine, Semmelweis University, Budapest, Hungary.

Abstract

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.

C ONCLUSIONS:

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.

KEYWORDS:

Streptococcus pneumoniae, alternative pathway, classical pathway, complement, mutation, haemolytic uraemic syndrome

背景：不典型性溶血尿毒综合征（aHUS）包括由补旁路蛋白缺陷引起的HUS以及由产神经氨酸苷酶的病原体（如肺炎链球菌）引起的HUS。目前关于神经氨酸苷酶在肺炎链球菌相关HUS（SP-HUS）中的致病机制的研究越来越多，但补体在SP-HUS中的地位还没有细致的研究。因此我们研究的目的是研究在aHUS中表现的补体水平异常以及基因突变是否在SP-HUS患者中出现。

方法：在5例SP-HUS患者中检测补体旁路活化状态，包括C3、C4、CFH、CFB、CFI以及H因子抗体水平的检测。进行CFH、CFI、CD46、THBD、C3和CFB的编码区基因测序以及CFI、CD46、CFH及其他相关基因的拷贝数变异检测。

结果：我们发现急性期SP-HUS患者C3、C4以及补体经典途径及旁路途径活性降低，提示补体成分的活化和消耗。在患者处于疾病缓解期时，这些补体水平的指标逐渐恢复正常。在3例患者中存在aHUS中发现的危险相关的基因突变及单倍型。这些基因突变包括以往报道的CFI变异（P50A）及两个新发现的突变（CFH(R1149X) 及 THBD (T44I)）。

结论：我们的研究结果提示，侵袭性肺炎链球菌相关的SP-HUS发病过程中可能伴随补体的过度激活及消耗。补体基因变异可能在这种疾病中的部分患者中其致病作用。