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

Abstract

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.

Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation

“…Previous reports on the extended KTC have shown correlations of epitope mismatch and DSA ( 20 ). Similarly, in the PC, correlation of epitope mismatch and CSA has been reported ( 11 , 18 , 19 , 32 ). Correlation analyses revealed a moderate to strong correlation between all evaluated epitope matching approaches, which is in line with the literature ( 20 , 33 , 34 ).…”

“…The applied epitope matching approaches - including Snowflake - do not weigh individual immunogenicity patterns. Similar to antigen mismatches varying in their immunogenicity, also epitope mismatches’ immunogenicity varies ( 11 , 12 , 19 , 32 ). Although the current epitope matching strategies add prognostic value to classic antigen matching as implemented by many allocation organizations, further refinements of these approaches may specifically integrate epitope immunogenicity, antigenicity and hierarchy ( 44 – 46 ).…”

“…The previously described pregnancy cohort (PC) of the University Hospital Basel consists of 231 pregnant women who gave live birth between September 2009 and April 2011 ( 11 , 17 – 19 ). The study was approved by the local ethics committee.…”

“…Furthermore, the number of PIRCHE-II (www.pirche.com, version 3.47) was calculated (reviewed in (27)), considering the prediction of indirect T cell epitopes. In the PC, high resolution genotyping data on 11 loci allowed for PIRCHE analysis of HLA-DRB1 (i.e PIRCHE-II), -DRB3/4/5, -DQ and, -DP as independent donor-derived peptide presenters, as suggested before (19), yielding four separate PIRCHE matching scores.…”

Dissecting the impact of molecular T-cell HLA mismatches in kidney transplant failure: A retrospective cohort study

“…The PIRCHE-II approach uses the protein sequence of HLA alleles to predict the allogeneic foreign peptides that can be presented within the recipients’ HLA Class II groove. Several reports suggest that the mismatch load of donor-derived peptides, which are absent in the recipient self-peptidome, but expressed by recipient HLA, are predictive of immune response and graft failure ( 17 – 19 ). As the peptides used for PIRCHE-II represent theoretical T-cell epitopes, it is important to verify their association with outcomes like graft failure.…”