Development of an immunogenicity score for HLA‐DQ eplets: A conceptual study

Abstract

Eplets are defined as distinct amino acid configurations on the surface of HLA molecules. The aim of this study was to estimate the immunogenicity of HLA-DQ eplets in a cohort of 221 pregnancies with HLA-DQ mismatches. We defined the immunogenicity of an eplet by the frequency of antibody responses against it. Around 90% of all listed DQB1 or DQA1 eplets were at least five times mismatched and thus included for the calculation of their immunogenicity. The DQB1 eplets with the five highest immunogenicity scores were 55PP, 52PR, 52PQ, 85VG and 45EV; 25% of all DQB1 eplets were not reacting. The DQA1 eplets with the five highest immunogenicity scores were 25YS, 47QL, 55RR, 187T and 18S; 17% of all DQA1 eplets were not reacting. The immunogenicity score had a slightly higher area under the curve to predict development of childspecific antibodies than various molecular mismatch scores (eg, eplet mismatch load, amino acid mismatch load). Overlapping eplets were identified as a barrier to unambiguously assign the immunogenicity score based on HLA antibody reaction patterns. In this conceptual study, we explored the immunogenicity of HLA-DQ eplets and created a map of potentially immunogenic regions on HLA-DQ molecules, which requires validation in clinical transplant cohorts.

On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss

“…These EMMs (e.g., 55PP, 52PR, and 52PQ2 [52PQ+85VG]) are highlighted in Table 2 and Supplementary Material S2 . 43 In addition, like our observation, some previously AbVer EMMs were found to be nonreactive (e.g., 28T, 46VY, and 52P), whereas other previously non-AbVer were found to be reactive (e.g., 85VA, 56PV). Validation of our observations in additional datasets from diverse populations with measured allele-level genotypes is required to support prioritizing donor-recipient matching on the higher-risk eplets identified by this study.…”

“… HLA-DQB1 EMMs found to be reactive by Schawalder et al. 43 are bolded . An asterisk (∗) in the Selected EMM predictive of DCGF column highlights eplet mismatches predictive of DCGF by the least absolute shrinkage and selection operator (Lasso) penalized Cox regression model.…”

“…Eplet mismatches associated with death-censored graft failure in Accelerated Failure Time models accounting for false discovery rate are emphasized using italics. HLA-DQB1 EMMs found to be reactive by Schawalder et al43 are bolded. An asterisk (*) in the Selected EMM predictive of DCGF column highlights eplet mismatches predictive of DCGF by the least absolute shrinkage and selection operator (Lasso) penalized Cox regression model.…”

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

“…As all mismatches do not seem to have equivalent impact on risk of immune‐mediated injury, it is critical to elucidate the respective importance of particular eplets to prioritize matching accordingly. Efforts to establish relative immunogenicity of eplets have been put forth by establishing the relative frequency of DSA against HLA‐DQ in the context of pregnancy, where mothers have up to 1 HLA‐DQ allele difference in reference to babies (Schawalder et al, 2020). With a similar objective, Tambur et al conceived the 2MM1DSA paradigm.…”

“…Efforts to establish relative immunogenicity of eplets have been put forth by establishing the relative frequency of DSA against HLA-DQ in the context of pregnancy, where mothers have up to 1 HLA-DQ allele difference in reference to babies (Schawalder et al, 2020).…”