DataSheet_1_Peptides Derived From Mismatched Paternal Human Leukocyte Antigen Predicted to Be Presented by HLA-DRB1, -DRB3/4/5, -DQ, and -DP Induce Child-Specific Antibodies in Pregnant Women.pdf

Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers’ presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters’ binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.

预测的间接可识别的人类白细胞抗原（HLA）表位（PIRCHE）已被证实是器官移植后受者产生HLA特异性抗体的显著风险因素。既往对PIRCHE的研究大多局限于对HLA-DRB1位点的呈现分析，尽管HLA-DRB3/4/5、-DQ和-DP位点也被认为能够向CD4+ T细胞呈现异源肽。在本研究中，我们分析了这些额外位点所呈现的预测异源肽对疫苗接种事件后HLA特异性抗体发生率的 影响。我们将妊娠视为HLA免疫的模型系统，并通过分娩时采集的样本观察到231位母亲在妊娠期间的儿童特异性HLA抗体（CSA）的发展。我们的数据证实，由HLA-DRB1、HLA-DRB3/4/5、-DQ和-DP位点共同呈现的PIRCHE是CSA发展的显著预测因子。尽管在母亲呈现的HLA蛋白中观察到有限的肽段重叠，但将多个呈现位点结合在一个预测因子中仅略微提高了模型性能。通过将评分归一化至各自呈现者的结合多态性，PIRCHE的预测性能进一步得到提升。在针对特定异源肽的免疫原性分析中，未能识别出在该小队列中引起免疫反应的显著驱动因素，这表明需要进一步的验证研究。