A combined DPA1∼DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer

Abstract

Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-012-0615-3) contains supplementary material, which is available to authorized users.

Functional distance between recipient and donor HLA-DPB1 determines nonpermissive mismatches in unrelated HCT

“…32 (B) FD Allele scores of 19 HLA-DPB1 alleles occurring with a frequency of .0.5% in Europeans. 56 TCE group assignment of the HLA-DPB1 alleles 16,32,54 is shown on top.…”

“…16 FD is present at 3 interdependent levels: the AA level, the HLA-DPB1 allele level, and the HCT patient-donor pair level ( Figure 1). [54][55][56] FD at the AA level (FD AA ) is a numerical score reporting the difference in the median relative response (RR) of 17 different alloreactive T-cell effectors to WT HLA-DPB1*09:01 (arbitrarily set as 1) and to mutant HLA-DPB1*09:01 carrying 1 out of 12 naturally occurring AA substitutions at 10 different polymorphic positions, each as single-point mutation. 32 Figure 1B).…”

Genetic risk factors for sclerotic graft-versus-host disease

“…Haplotype frequencies for these Q and GPM encoding alleles occur much less frequently than expected from their respective individual frequencies. 9 Nonetheless, staining with two different HLA-DP-specific antibodies demonstrated surface expression of HLA-DP on B cells from individuals with alleles encoding only Q-bearing DPa chains and GPM-bearing DPb chains, indicating no intrinsic physical constraint on their ability to form stable heterodimers (supplemental Figure 1). Therefore, we defined P1 pocket motifs by considering DPa;DPb heterodimers encoded in trans, together with those encoded in cis.…”

“…HLA-DP molecules have peptide-presentation P1 peptide-binding pockets characterized by M (methionine) or Q (glutamine) at position 31 of the DPa chain and by glutamic acid-alanine-valine (EAV) or glycine-proline-methionine (GPM) motifs at positions 85 to 87 of the DPb chain (Figure 3). 9 As a second approach in unraveling the paradox, we evaluated associations of each P1 pocket motif with the risk of sclerotic GVHD (Table 5). Previous studies have shown significant negative LD between HLA-DPA1 alleles encoding Q and HLA-DPB1 alleles encoding GPM.…”

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…43 Of note, only 12 DPB1 and 2 DPA1 alleles account for over 90% of the variants observed in worldwide populations. 44 Therefore, homozygosity (ie, the same DP allele present on both chromosomes of an individual) is frequent, often resulting in unidirectional (ie, only in graft-versus-host [GVH] or host-versus-graft [HVG] direction) HLA-DP mismatches in UD-recipient pairs.…”