A new strategy for systematically classifying HLA alleles into serological specificities

Abstract

HLA serological specificities were defined by the reactivity of HLA molecules with sets of sera and monoclonal antibodies. Many recently identified alleles defined by molecular typing lack their serotype assignment. We surveyed the literature describing the correlation of the reactivity of serologic reagents with AA residues. 20 ‐ 25 AA residues determining epitopes (DEP) that correlated with 82 WHO serologic specificities were identified for HLA class I loci. Thirteen DEP each located in the beta‐1 domains that correlated with 24 WHO serologic specificities were identified for HLA‐DRB1 and ‐DQB1 loci. The designation of possible HLA‐DPB1, ‐DQA1, ‐DPA1, and additional serological specificities that result from epitopes defined by residues located at both ‐DQA1 and ‐DQB1 subunits were also examined. HATS software was developed for automated serotype assignments to HLA alleles in one of the three hierarchical matching criteria: (1) all DEP (FULL); (2) selected DEP specific to each serological specificity (SEROTYPE); (3) one AA mismatch with one or more SEROTYPES (INCOMPLETE). Results were validated by evaluating the alleles whose serotypes do not correspond to the first field of the allele name listed in the HLA dictionary. Additional 85 and 21 DEP patterns that do not correspond to any WHO serologic specificities for common HLA class I and DRB1 alleles were identified, respectively. A comprehensive antibody identification panel would allow for accurate unacceptable antigen listing and compatibility predictions in solid organ transplantation. We propose that antibody‐screening panels should include all serologic specificities identified in this study.

Resolving unknown nucleotides in the IPD-IMGT/HLA database by extended and full-length sequencing of HLA class I and II alleles

“…Therefore, the B*53:06 allele may have arisen by a gene conversion event with a double cross over, resulting in a recombination of B*51:01:01:04 with a B*53 allele, exchanging the first part of exon 3, with breakpoints between 695–726 and 810–900 (Table 3 ). With the first identification of this allele, it was already serological typed as B53/B51-like variant (Anholts et al 2001 ), the expert assigned type was also B53/B51 (Holdsworth et al 2009 ), the neural network assignment was B53 (Maiers et al 2003 ), and also the recently published systematic classification of serological specificities assigned a B53 serotype, with the comment being short cross reactive (Osoegawa et al 2022 ).…”

“…Since the serological specificity is merely depending on the serological reaction with specific antibodies against the beta-1 domain of the HLA molecule, we have also checked the exon 2 sequence of this allele. Osoegawa et al ( 2022 ) have determined that the critical residues for DQ7/8/9 are amino acids 45, 57, 74, 84, and 85, the latter 3 are identical for all 3 types, but important for distinguishing them from the other serological DQ types. In fact, the difference between DQ7, DQ8, and DQ9 only depends on the amino acids 45 and 57, where ED or EA encodes DQ7, GA encodes DQ8 and GD DQ9.…”

“…This phylogenetic tree shows three distinct groups, one reflecting the DQ7 like sequence group, one DQ8 like, and one DQ9 like group, with less distance between DQ8 and DQ9, because of less differences. Comparing the alleles in these groups with their final serological assignment based on the two amino acids in exon 2, as compiled by Osoegawa et al ( 2022 ) (Supplemental Table 5 of their paper), revealed 2 alleles, where the serological type does not fit with the full-length sequence type, namely DQB1*03:10 and 03:12 , both serologically typed as DQ9 according to Osoegawa et al ( 2022 ), whereas their full-length sequence is DQ7 like. DQB1*03:10 was previously identified by the experts as DQ3, by the neural network as DQ7 (Maiers et al 2003 ), and assigned by the WHO as DQ8 (Barker et al 2023 ), whereas DQB1*03:12 was also by the experts and by the neural network identified as DQ9.…”

“…A multiple sequence alignment was performed on the full-length sequences from position −150 up to 6502 without exon 2 from all DQB1*03 alleles for which this sequence was available in the IPD-IMGT/HLA database (vs. 3.51), excluding null and Q alleles. Since Osoegawa et al ( 2022 ) already identified DQB1*03:06 and 03:25 as DQ4 serotypes, we have excluded these alleles from this phylogenetic tree. Details of the alleles are listed in Supplemental Table 1 A.…”

Using cloud infrastructure to facilitate data collection and conversion of HLA diagnostic data for the 18th International HLA and Immunogenetics Workshop

“…Early workshops defined the names of the major histocompatibility antigens based on serological compatibility groups, providing essential foundations for matching in transplantation. These antigen groups have been further defined and categorized 2,3 by examining variations in an individual's HLA type, such as single nucleotide polymorphisms (SNPs), insertions, deletions, and recombinations in HLA genetic sequence. HLA genotypes can be further extended to define B‐cell 4,5 and T‐cell 6 epitopes to allow for studies on immunogenicity, and establish haplotype patterns 7 across the MHC, which in turn facilitates family inheritance studies 8,9 .…”