Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, DK-2800 Lyngby, Denmark.
Immunology. 2011 Mar;132(3):394-400. doi: 10.1111/j.1365-2567.2010.03373.x. Epub 2010 Nov 11.
Up to one in four lung-transplanted patients develop pulmonary infiltrates and impaired oxygenation within the first days after lung transplantation. Known as primary graft dysfunction (PGD), this condition increases mortality significantly. Complex interactions between donor lung and recipient immune system are the suspected cause. We took an integrative, systems-level approach by first exploring whether the recipient's immune response to PGD includes the development of long-lasting autoreactivity. We next explored whether proteins displaying such differential autoreactivity also display differential gene expression in donor lungs that later develop PGD compared with those that did not. We evaluated 39 patients from whom autoantibody profiles were already available for PGD based on chest radiographs and oxygenation data. An additional nine patients were evaluated for PGD based on their medical records and set aside for validation. From two recent donor lung gene expression studies, we reanalysed and paired gene profiles with autoantibody profiles. Primary graft dysfunction can be distinguished by a profile of differentially reactive autoantibodies binding to 17 proteins. Functional analysis showed that 12 of these proteins are part of a protein-protein interaction network (P=3 x 10⁻⁶) involved in proliferative processes. A nearest centroid classifier assigned correct PGD grades to eight out of the nine patients in the validation cohort (P=0·048). We observed significant positive correlation (r=0·63, P=0·011) between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long-lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.
多达四分之一的肺移植患者在肺移植后的头几天内会出现肺部浸润和氧合受损。这种情况被称为原发性移植物功能障碍（PGD），会显著增加死亡率。供肺和受者免疫系统之间的复杂相互作用是其怀疑的原因。我们采用了一种综合的系统水平方法，首先探索受者对 PGD 的免疫反应是否包括持久自身反应性的发展。接下来，我们探索了在发生 PGD 的供体肺中，是否存在显示这种差异自身反应性的蛋白质也显示出与未发生 PGD 的供体肺相比差异表达的基因。我们评估了 39 名患者，这些患者已经根据胸部 X 光片和氧合数据的 PGD 自身抗体谱进行了评估。另外 9 名患者根据其病历进行了 PGD 评估，并被排除在外进行验证。从最近的两项供体肺基因表达研究中，我们重新分析并将基因谱与自身抗体谱配对。通过与 17 种蛋白质结合的差异反应性自身抗体谱可以区分原发性移植物功能障碍。功能分析表明，这 12 种蛋白质中的 12 种是参与增殖过程的蛋白质-蛋白质相互作用网络（P=3×10⁻⁶）的一部分。最近 centroid 分类器将验证队列中 9 名患者中的 8 名正确分配到 PGD 等级（P=0·048）。我们观察到 IgM 反应性差异与基因表达水平差异之间存在显著的正相关（r=0·63，P=0·011）。这种供体肺基因表达与针对一组特定蛋白质的持久受者 IgM 自身抗体之间的联系表明了 PGD 中自身免疫发展的一种机制。
