Identification of eight novel HLA-DRB1 and HLA-DQB1 alleles by next-generation sequencing.
Identification of eight novel HLA-DRB1 and HLA-DQB1 alleles by next-generation sequencing.
Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is commonly used in patients without a fully matched donor. HLA evolutionary divergence (HED), a surrogate for the diversity of the immunopeptidome, can predict HLA-matched HSCT outcomes. Because of the peculiarities of HED measurement in haplo-HSCT, we designed a new HEDD->R metric to proxy the fraction of the recipient-specific immunopeptidome not recognised as self by the haplo-identical donor, and evaluated its predictive value on haplo-HSCT outcomes with the aim of providing help in choosing the best donor. We retrospectively studied 104 patients who underwent PTCy haplo-HSCT for haematological malignancy and calculated per-locus and per-class HED in the recipient (HEDR), the donor (HEDD), across mismatched haplotypes (HEDMM) as well as HEDD->R. Patients with low class 1 HEDR had worse OS (hazard ratio (HR) 2.16, 95% confidence intervals (CI) 1.06–4.40, p = 0.033), whereas no significant impact of HEDD or HEDMM at any HLA locus was observed. Moreover, in multivariate analysis of patients surviving at least 100 days, low class 1 HEDD->R was associated with inferior OS (HR 2.67, 95% CI 1.13–6.28; p = 0.025). In addition to strengthening the impact of recipient class 1 HED on HSCT outcomes regardless of donor type, our results suggest that our novel, publicly available, HEDD->R metric could help select the most appropriate donor among haploidentical candidates.
HLA-C*05:311, a novel HLA class I allele detected by next-generation sequencing.
HLA-DQB1*05:367 differs from HLA-DQB1*05:01:01:01 by one nucleotide substitution in codon 7 in exon 2.
Alloreactivity entails the recognition of cells and tissues from one individual as foreign by T cells and other immune effectors from another individual. Alloreactive immune responses play an important role in various clinical contexts, in particular in transplantation. Major drivers of these responses are the highly immunogenic, non-self HLA molecules. However, the immunogenicity of these allogeneic HLA molecules has been observed to vary according to certain immunobiological and immunogenetic parameters, leading to the concept of differential alloreactivity. Recent progress in unveiling the underpinnings of this phenomenon has been made for the frequently mismatched HLA-DP allotypes, whose singular genomic, structural and population genetics characteristics offer an ideal scenario for these investigations. Studies in the HLA-DP context have highlighted the immunopeptidome overlap between self and non-self HLA allotypes, as well as its editing by non-classical class II chaperones HLA-DM and HLA-DO, as a main determinant of their immunogenicity likely via indirect effects of thymic education. Recent evidence suggests that these observations could also be extended to alloresponses directed against HLA molecules encoded by other loci. How these functional characteristics of HLA molecules shape allorecognition by T-cell subsets, and how they translate into different clinical consequences in the context of transplantation will be the subject of the present review.
HLA-F*01:31 differs from HLA-F*01:04:01 by one nonsynonymous nucleotide substitution in codon 183 in exon 3.
HLA-DQA1*03:02:05 differs from HLA-DQA1*03:02:01:01 by one nucleotide substitution at position 639 located in exon 4.
HLA-A*02:540:02N differs from A*02:01:01:01 by one nucleotide substitution in codon 99 in exon 3.
One nucleotide substitution in codon 133 of HLA-DQB1*03:03:02:01 results in a novel allele HLA-DQB1*03:319.
Single molecule real-time sequencing identifies the novel recombinant allele HLA-DPB1*01:01:01:31.
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