PMID- 36389845 OWN - NLM STAT- MEDLINE DCOM- 20221121 LR - 20221122 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Snowflake epitope matching correlates with child-specific antibodies during pregnancy and donor-specific antibodies after kidney transplantation. PG - 1005601 LID - 10.3389/fimmu.2022.1005601 [doi] LID - 1005601 AB - Development of donor-specific human leukocyte antigen (HLA) antibodies (DSA) remains a major risk factor for graft loss following organ transplantation, where DSA are directed towards patches on the three-dimensional structure of the respective organ donor's HLA proteins. Matching donors and recipients based on HLA epitopes appears beneficial for the avoidance of DSA. Defining surface epitopes however remains challenging and the concepts underlying their characterization are not fully understood. Based on our recently implemented computational deep learning pipeline to define HLA Class I protein-specific surface residues, we hypothesized a correlation between the number of HLA protein-specific solvent-accessible interlocus amino acid mismatches (arbitrarily called Snowflake) and the incidence of DSA. To validate our hypothesis, we considered two cohorts simultaneously. The kidney transplant cohort (KTC) considers 305 kidney-transplanted patients without DSA prior to transplantation. During the follow-up, HLA antibody screening was performed regularly to identify DSA. The pregnancy cohort (PC) considers 231 women without major sensitization events prior to pregnancy who gave live birth. Post-delivery serum was screened for HLA antibodies directed against the child's inherited paternal haplotype (CSA). Based on the involved individuals' HLA typings, the numbers of interlocus-mismatched antibody-verified eplets (AbvEPS), the T cell epitope PIRCHE-II model and Snowflake were calculated locus-specific (HLA-A, -B and -C), normalized and pooled. In both cohorts, Snowflake numbers were significantly elevated in recipients/mothers that developed DSA/CSA. Univariable regression revealed significant positive correlation between DSA/CSA and AbvEPS, PIRCHE-II and Snowflake. Snowflake numbers showed stronger correlation with numbers of AbvEPS compared to Snowflake numbers with PIRCHE-II. Our data shows correlation between Snowflake scores and the incidence of DSA after allo-immunization. Given both AbvEPS and Snowflake are B cell epitope models, their stronger correlation compared to PIRCHE-II and Snowflake appears plausible. Our data confirms that exploring solvent accessibility is a valuable approach for refining B cell epitope definitions. CI - Copyright (c) 2022 Niemann, Strehler, Lachmann, Halleck, Budde, Honger, Schaub, Matern and Spierings. FAU - Niemann, Matthias AU - Niemann M AD - Research and Development, PIRCHE AG, Berlin, Germany. FAU - Strehler, Yara AU - Strehler Y AD - Center for Tumor Medicine, H&I Laboratory, Charite University Medicine Berlin, Berlin, Germany. FAU - Lachmann, Nils AU - Lachmann N AD - Center for Tumor Medicine, H&I Laboratory, Charite University Medicine Berlin, Berlin, Germany. FAU - Halleck, Fabian AU - Halleck F AD - Department of Nephrology and Medical Intensive Care, Charite-Universitatsmedizin Berlin, Berlin, Germany. FAU - Budde, Klemens AU - Budde K AD - Department of Nephrology and Medical Intensive Care, Charite-Universitatsmedizin Berlin, Berlin, Germany. FAU - Honger, Gideon AU - Honger G AD - Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland. AD - Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. AD - HLA-Diagnostics and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland. FAU - Schaub, Stefan AU - Schaub S AD - Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland. AD - Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland. AD - HLA-Diagnostics and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland. FAU - Matern, Benedict M AU - Matern BM AD - Center for Translational Immunology, University Medical Center, Utrecht, Netherlands. FAU - Spierings, Eric AU - Spierings E AD - Center for Translational Immunology, University Medical Center, Utrecht, Netherlands. AD - Central Diagnostic Laboratory, University Medical Center, Utrecht, Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221028 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Isoantibodies) RN - 0 (Epitopes, B-Lymphocyte) RN - 0 (Solvents) SB - IM MH - Pregnancy MH - Humans MH - Female MH - *Kidney Transplantation MH - Isoantibodies MH - Epitopes, B-Lymphocyte MH - Tissue Donors MH - Solvents PMC - PMC9649433 OTO - NOTNLM OT - HLA OT - deep learning OT - epitope matching OT - kidney transplantation OT - pregnancy OT - solvent accessibility COIS- MN works for PIRCHE AG, which develops and operates the PIRCHE web service. PIRCHE AG and UMC Utrecht have filed a patent application on the prediction of an alloimmune response against allele-specific solvent-accessible amino acid mismatches. MN and ES are listed as inventors on this patent. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/11/18 06:00 MHDA- 2022/11/22 06:00 PMCR- 2022/01/01 CRDT- 2022/11/17 12:45 PHST- 2022/07/28 00:00 [received] PHST- 2022/09/26 00:00 [accepted] PHST- 2022/11/17 12:45 [entrez] PHST- 2022/11/18 06:00 [pubmed] PHST- 2022/11/22 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.1005601 [doi] PST - epublish SO - Front Immunol. 2022 Oct 28;13:1005601. doi: 10.3389/fimmu.2022.1005601. eCollection 2022.