HLA-EPI: A new EPIsode in exploring donor/recipient epitopic compatibilities

Abstract

The HLA system plays a pivotal role both in transplantation and immunology. While classical HLA genotypes matching is made at the allelic level, recent progresses were developed to explore antibody-antigen recognition by studying epitopes. Donor to recipient matching at the epitopic level is becoming a trending topic in the transplantation research field because anti-HLA antibodies are epitope-specific rather than allele-specific. Indeed, different HLA alleles often share common epitopes. We present the HLA-Epi tool (hla.univ-nantes.fr) to study an HLA genotype at the epitope level. Using the international HLA epitope registry (Epregistry.com.br) as a reference, we developed HLA-Epi to easily determine epitopic and allelic compatibility levels between several HLA genotypes. The epitope database covers the most common HLA alleles (N = 2976 HLA alleles), representing more than 99% of the total observed frequency of HLA alleles. The freely accessible web tool HLA-Epi calculates an epitopic mismatch load between different sets of potential recipient-donor pairs at different resolution levels. We have characterized the epitopic mismatches distribution in a cohort of more than 10,000 kidney transplanted pairs from European ancestry, which showed low number of epitopic mismatches: 56.9 incompatibilities on average. HLA-Epi allows the exploration of epitope pairing matching to better understand epitopes contribution to immune responses regulation, particularly during transplantation. This free and ready-to-use bioinformatics tool not only addresses limitations of other related tools, but also offers a cost-efficient and reproducible strategy to analyze HLA epitopes as an alternative to HLA allele compatibility. In the future, this could improve sensitization prevention for allograft allocation decisions and reduce the risk of alloreactivity.

Keywords: HLA; HLA epitope; HLA eplet; HSCT; epitopic compatibility; solid organ transplantation.

FIGURE 1

(A) Principle of epitope matching. Example of two different potential grafts: HLA‐DRB1*11:02 recipient may receive an organ from two distinct donors with different HLA‐DRB1 alleles: 03:01 or 03:02. There is a single allelic mismatch in each case but HLA‐DRB1*03:01 (donor 1) shows higher compatibility in terms of eplet mismatch load compared with HLA‐DRB1*03:02 (donor 2). In blue: Matched eplets between the different individuals, in red: Mismatched eplets, in green: HLA Class II proteins. (B) Principles of alloantigen recognition covered by the HLA‐Epi tool: HLA‐Epi covers the concepts of direct and semi‐direct recognitions while the PIRCHE algorithm focuses on indirect recognition for solid organ transplantation. In the case of HSCT, both HLA‐Epi and PIRCHE algorithms cover the Graft versus host disease. (Created with BioRender.com)

FIGURE 2

(A) Shared eplets between the HLA class I genes, HLA‐A (blue), HLA‐B (red) and HLA‐C (green). A large number of eplets are shared between HLA class I genes, with 54 eplets shared between the 3 Class I genes. (B) Shared eplets between the HLA class II genes, HLA‐DRB1 (blue), HLA‐DQB1 (red), HLA‐DQA1 (green) and HLA‐DPB1 (yellow). Only a few eplets are shared between class II HLA genes

FIGURE 3

Input interface in manual entry mode. Recipient's and donor's genotypes need to be written manually in the different fields. Users can select to query all, exposed, cryptic, checked or unchecked eplets. HLA‐Epi can provide recipient to one or several donors comparison but this can be easily switched to donor to several potential recipients by clicking the arrow button. Up to 30 genotypes can be added for comparison by clicking the “add new donor” button. Extended version comprising HLA DQA1 and DPB1 is finally available with the “Extended” button

FIGURE 4

Example run and results page. For each potential donor, the different eplet mismatches calculated for each HLA gene (HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1, HLA‐DQB1) and for each HLA class (class I and class II) are displayed on the first line (white line). Details of the mismatched eplets names appears on the second line (gray line). The last column corresponds to the global compatibility score displayed in a gauge. (A) Results page for the recipient to donors direction; (B) Results page for the donor to recipients way. Same genotypes as A were kept but the reference recipient becomes a reference donor and potential donors become potential recipients

FIGURE 5

Eplet mismatch load distribution. In gray, 1KG simulations mismatch load distribution from three tested populations (European, Asian, and African), 5000 donor‐recipient pairs were simulated and mismatch load calculation was performed based on their high‐definition HLA genotypes. In red, real eplet mismatch load distribution (from 10,667 DIVAT cohort kidney transplanted individuals, red curve)

FIGURE 6

Disparity between allelic level and epitopic level. Regression curves were obtained for (A): Class I (HLA‐A, HLA‐B, HLA‐C) allelic mismatches versus Class I HLA epitpic mismatches, (B): Class II (HLA‐DRB1, HLA‐DQB1) allelic mismatches versus Class II HLA epitopic mismatches and (C): allelic HLA mismatch load (Class I + Class II) versus HLA epitopic mismatch load

FIGURE 7

Comparison HLA‐Epi to other epitope‐matching related tools. Correlation between HLA‐Epi scores and (A): HLAMatchmaker class I mismatch score, (B): HLAMatchmaker class II. Three scenarios were considered to further investigate the differences between tools: 1: HLA‐Epi = 0, HLAMatchmaker = 1, 2: HLA‐Epi < Matchmaker, 3: HLA‐Epi < Matchmaker. (C): PIRCHEII epitopic mismatch score. Dots were colored according to the number of HLA allelic mismatches