Identification of the novel HLA-DPB1*1591:01 allele by next-generation sequencing.

The novel HLA-DPB1*1591:01 allele was detected during the HLA typing for kidney transplantation.

The novel HLA-DPB1*05:01:20 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*05:01:20 differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.

The novel HLA-DPB1*1500:01N allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*1500:01N differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.

The novel HLA-DPB1*1467:01 allele characterised by two different sequencing-based typing techniques.

The novel allele HLA-DPB1*1467:01 differs from HLA-DPB1*09:01:01:01 by one non-synonymous nucleotide substitution in exon 2.

Revised HLA-DP TCE-Core Permissiveness Model Better Defines Relapse Risk and Survival following Haploidentical Transplant.

The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.

Characterisation of the novel HLA-DPB1*1437:01 and HLA-DPB1*1438:01 alleles by next-generation sequencing.

The novel HLA-DPB1*1437:01 and HLA-DPB1*1438:01 alleles first identified in the Chinese individuals.

The novel HLA-DPB1*03:01:29 allele, identified by sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*03:01:29 differs from HLA-DPB1*03:01:01:01 by one nucleotide in exon 2.

Characterization of the novel HLA-DPB1*1584:01 allele, identified by next-generation sequencing.

HLA-DPB1*1584:01 differs from HLA-DPB1*104:01:01:03 by one nucleotide substitution in exon 2.

Identification of four novel HLA alleles: HLA-B*27:265, -B*35:569, -DRB1*08:117 and -DPB1*1435:01.

Identification of four new HLA alleles (B*27:265, B*35:569, DRB1*08:117, and DPB1*1435:01) in Brazilian bone marrow donors.

The novel HLA-DPB1*1550:01 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*1550:01 differs from HLA-DPB1*02:02:01:01 by one nucleotide in exon 2.

Identification of the novel null allele HLA-DPB1*1449:01N by next-generation sequencing.

The novel HLA-DPB1*1449:01N allele differs from HLA-DPB1*16:01:01:01 by a nucleotide at codon 92 in exon 2.

The novel HLA-DPB1*05:01:21 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*05:01:21 differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.

[Risk prediction and function evaluation by T-cell epitope model and expression model of HLA-DPB1 mismatching in unrelated-donor hematopoietic stem cell transplantations].

Objective: To evaluate the risk prediction and assessment function of HLA-DPB1 T-cell epitope (TCE) model and expression model in human leukocyte antigen (HLA)-matched unrelated hematopoietic stem cell transplantation (MUD-HSCT) with HLA-DPB1 mismatching. Methods: A total of 364 (182 pairs) potential MUD-HSCT donors and recipients confirmed by HLA high-resolution typing in Shaanxi Blood Center from 2016 to 2019 were analyzed retrospectively. Of the 182 recipients, there were 121 males and 61 females with an average age of (26.3±14.2) years. Of the 182 donors, there were 148 males and 34 females with an average age of (33.7±7.5) years. Polymerase chain reaction-sequence-based typing (PCR-SBT), next-generation sequencing (NGS) and polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) based on LABScan®3D platform were used for high-resolution typing of HLA-A, B, C, DRB1, DQB1, DPB1 gene, and PCR-SBT was used for single nucleotide polymorphism (SNP) typing. TCE model and expression model were used to predict and evaluate the HLA-DPB1 mismatch pattern and acute graft-versus-host-disease (aGVHD) risk. Results: A total of 26 HLA-DPB1 alleles and their 3'-UTR rs9277534 SNP genotypes were detected in this study population, and two new alleles HLA-DPB1*1052∶01 and HLA-DPB1*1119∶01 were found and officially named. The overall mismatch rate of HLA-DPB1 in MUD-HSCT donors and recipients was 90.66% (165/182). In TCE model, the HLA-DPB1 mismatch rates of permissible mismatch (PM) and non-permissible mismatch (non-PM) were 47.80% (87/182) and 42.86% (78/182), respectively. The non-PM in GvH direction was 13.73% (25/182), and which in HvG direction was 29.12% (53/182). A total of 73 pairs of donors and recipients in TCE model met the evaluation criteria of expression model. Among of TCE PM group, recipient DP5 mismatches accounted for 34.25% (25/73) were predicted as aGVHD high risk according to expression model. For the TCE non-PM group, both the recipient DP2 mismatches of 6.85% (5/73) and recipient DP5 mismatches of 10.86% (8/73) were predicted to be at high risk for aGVHD. Risk prediction by TCE model and expression model was 27.27% concordant and 16.97% unconcordant. Conclusions: TCE model and expression model are effective tools to predict aGVHD risk of MUD-HSCT. Comprehensive application of the two models is helpful to the hierarchical assessment of HSCT risk.

Characterization of the novel HLA-DPB1*1516:01 allele by sequencing-based typing.

HLA-DPB1*1516:01 differs from HLA-DPB1*1229:01 by seven nucleotide substitutions in exon 3.

Next-generation sequencing identifies two novel HLA-DPB1 alleles: HLA-DPB1*1069:01 and DPB1*1072:01.

Characterization of two novel HLA-DPB1 alleles: HLA-DPB1*1069:01, and DPB1*1072:01 containing non-synonymous nucleotide substitutions.

The novel alleles, HLA-G*01:04:09 and HLA-DPB1*04:01:01:136, detected in a hematopoietic cell donor.

Two novel alleles, HLA-G*01:04:09 and HLA-DPB1*04:01:01:136, were identified in a single healthy individual.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Is Associated with HLA-A*3303 and HLA-DPB1*0501.

We determined the genetic association between specific human leucocyte antigen (HLA) loci and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Our results showed that autoimmune GFAP astrocytopathy was associated with HLA-A*3303 (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.32-3.06, p = 0.00072, padj. = 0.046) and HLA-DBP1*0501 (OR = 0.51, 95% CI = 0.36-0.71, p = 0.000048, padj. = 0.0062). Moreover, HLA-A*3303 carriers with the disease had a longer hospital stay (p = 0.0005) than non-carriers. This study for the first time provides evidence for a role of genetic factor in the development of autoimmune GFAP astrocytopathy. ANN NEUROL 2024;95:901-906.

Fifty novel HLA-DPB1 alleles identified in a UK cohort of unrelated hematopoietic cell donors and recipients.

HLA-DPB1 is the classical HLA class II genes with the least recorded variation on the IPD-IMGT/HLA Database, suggesting the full extent of its diversity is perhaps yet to be characterized. Here, a full-gene typing strategy was employed to genotype a UK cohort of 1470 HCT recipients (n = 744) and donors (n = 726). In total, 2940 full-length HLA-DPB1 sequences were generated, comprising 193 distinct alleles. Of these, 107 sequences contained novel variation, totaling 49 unique intronic HLA-DPB1 alleles, and one coding variant (HLA-DPB1*1188:01). Full-gene sequencing resulted in zygosity changes for 129 individuals by identifying two distinct intronic variants of the same coding allele. We verified the existence of nine unconfirmed alleles and extended the sequence of two existing alleles on the IPD-IMGT/HLA Database.

HLA-DPB1*13:01 associates with enhanced, and KIR2DS4*001 with diminished protection from developing severe COVID-19.

Extreme polymorphism of HLA and killer-cell immunoglobulin-like receptors (KIR) differentiates immune responses across individuals. Additional to T cell receptor interactions, subsets of HLA class I act as ligands for inhibitory and activating KIR, allowing natural killer (NK) cells to detect and kill infected cells. We investigated the impact of HLA and KIR polymorphism on the severity of COVID-19. High resolution HLA class I and II and KIR genotypes were determined from 403 non-hospitalized and 1575 hospitalized SARS-CoV-2 infected patients from Italy collected in 2020. We observed that possession of the activating KIR2DS4*001 allotype is associated with severe disease, requiring hospitalization (OR = 1.48, 95% CI 1.20-1.85, pc = 0.017), and this effect is greater in individuals homozygous for KIR2DS4*001 (OR = 3.74, 95% CI 1.75-9.29, pc = 0.003). We also observed the HLA class II allotype, HLA-DPB1*13:01 protects SARS-CoV-2 infected patients from severe disease (OR = 0.49, 95% CI 0.33-0.74, pc = 0.019). These association analyses were replicated using logistic regression with sex and age as covariates. Autoantibodies against IFN-α associated with COVID-19 severity were detected in 26% of 156 hospitalized patients tested. HLA-C*08:02 was more frequent in patients with IFN-α autoantibodies than those without, and KIR3DL1*01502 was only present in patients lacking IFN-α antibodies. These findings suggest that KIR and HLA polymorphism is integral in determining the clinical outcome following SARS-CoV-2 infection, by influencing the course both of innate and adaptive immunity.

HLA sequencing identifies novel associations and suggests clinical relevance of DPB1*04:01 in ANCA-associated Granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Major contributions of HLA genes have been reported; however, HLA typing-based diagnosis or risk prediction in GPA has not been established. We have performed a sequencing-based HLA genotyping in a north Indian GPA cohort and controls to identify clinically relevant novel associations. PR3-ANCA-positive 40 GPA patients and 40 healthy controls from north India were recruited for the study. Targeted sequencing of HLA-A,-B,-C,-DRB1,-DQB1, and -DPB1 was performed. Allelic and haplotypic associations were tested. Molecular docking of susceptibility HLA alleles with reported super-antigen epitopes was performed. The association of substituted amino acids located at the antigen-binding domain of HLA was evaluated. Genetic association of five HLA-alleles was identified in GPA. The novel association was identified for C*15:02 (p = 0.04; OR = 0.27(0.09-0.88)). The strongest association was observed for DPB1*04:01 (p < 0.0001; OR = 6.2(3.08-11.71)), previously reported in European studies. 35 of 40 GPA subjects had at least one DPB1*04:01 allele, and its significant risk was previously not reported from the Indian population. Significantly associated haplotypes DRB1*03:01-DQB1*02:01-DPB1*04:01 (p = 0.02; OR = 3.46(1.11-12.75)) and DRB1*07:01-DQB1*02:02-DPB1*04:01 (p = 0.04; OR = 3.35(0.95-14.84)) were the most frequent in GPA patients. Ranging from 89 % to 100 % of GPA patients with organ involvement can be explained by at least one DPB1*04:01 allele. A strong interaction between the HLA and three epitopes of the reported super antigen TSST-1 of Staphylococcus aureus was confirmed. Our study highlighted the potential applicability of HLA typing for screening and diagnosis of GPA. A large multi-centric study and genotype-phenotype correlation analysis among GPA patients will enable the establishment of HLA-typing based GPA diagnosis.