Characterisation of the novel HLA-A allele, HLA-A*29:177.
Characterisation of the novel HLA-A allele, HLA-A*29:177.
Patients treated with etrolizumab, a monoclonal antibody drug for ulcerative colitis, often develop anti-drug antibodies (ADA) and neutralising antibodies (NAb). To investigate genetic risk factors, we evaluated associations between HLA alleles and ADA/NAb development. HLA-DQB1*06:03 demonstrated the most significant association with both ADA (OR = 7.3, p ≤ 7.6 × 10−13) and NAb (OR = 13.1, p ≤ 7.7 × 10−13). After controlling for HLA-DQB1*06:03, HLA-DQA1*03:03 emerged as the next most significant allele associated with ADA (OR = 2.8, p ≤ 1.0 × 10−3) and NAb (OR = 5.0, p ≤ 1.3 × 10−3). Notably, all patients carrying both alleles (n = 5) developed ADA, suggesting these two alleles are sufficient to induce ADA to etrolizumab.
Allogeneic haematopoietic stem cell transplantation is a critical treatment for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), yet the risk of treatment failure still persists. Chimerism analysis serves as a potential tool for predicting disease recurrence and survival rates, but its specific role has not yet been clearly defined. This study aimed to explore the role of decreased T-cell and bone marrow (BM) chimerism in predicting post-transplant relapse and survival in patients with acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). The study subjects were 305 AML and ALL patients who underwent allogeneic haematopoietic stem cell transplantation at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 1, 2018, to September 1, 2023. We monitored the chimerism rate at monthly intervals after transplantation until either patient relapse or the end of follow-up. T-cell and BM chimerism were tested at the same time points. Relapse probabilities were estimated by the Kaplan–Meier method and compared with the log-rank test. Gehan-Breslow-Wilcoxon test was used to assess the impact of T-cell and BM chimerism levels on survival probabilities. In AML patients, our analysis revealed no significant correlation between the presence of initial mixed chimerism (at Day +30 post-transplantation) and the relapse rate. Among patients with ALL, the number with initial mixed chimerism was insufficient for statistical analysis. In AML patients whose bone marrow chimerism rate decreased first (n = 13) had a higher relapse rate and a lower survival rate than those whose T-cell chimerism rate decreased first (n = 11) (p < 0.01). In patients with ALL, there was no significant difference in the relapse or survival rates between patients whose bone marrow chimerism rate decreased first (n = 12) and those whose T-cell chimerism rate decreased first (n = 15) (p > 0.05). While a decrease in bone marrow chimerism effectively predicts AML relapse, T-cell chimerism demonstrates lower predictive efficacy. Further research is necessary to identify reliable predictors for relapse in ALL patients. The integration of chimerism analysis with other prognostic indicators, along with early monitoring and preemptive intervention, may enhance patient survival and quality of life.
The HLA-DRB1*13:366 allele differs from HLA-DRB1*13:214 by three nucleotide substitutions in codons 26, 28 and 30 in exon 2.
HLA-B*38:126 differs from HLA-B*38:02:02:01 by one non-synonymous nucleotide change in codon 325 in exon 7.
The HLA 8.1 extended haplotype is a well-defined haplotype within the HLA region, characterised by strong linkage disequilibrium (LD) and recognised as most prevalent among populations of European ancestry. Despite its significance, comprehensive data on the extended 8.1 haplotype, encompassing all nine HLA loci with high-resolution typing, remains limited. In this study we examined the structure of the 8.1 haplotype in a cohort of 146 unrelated Croatian individuals (HLA-A*01; C*07; B*08; DRB1*03 homozygous at low resolution level), who were additionally NGS typed for HLA-A, -C, -B, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci. All individuals remained homozygous at the HLA-DRB1 locus (100%) with only a single allele observed, while the HLA-DPB1 locus showed the lowest homozygosity (31.5%), with 18 distinct alleles identified. Four novel alleles were detected in this cohort, of which the HLA-DRB3*01:132N allele is reported here for the first time. The analysis of 4th field allelic differences revealed 30 distinct haplotypes, with HLA-A*01:01:01:01~C*07:01:01:01~B*08:01:01:01~DRB1*03:01:01:01~DRB3*01:01:02:01~ DQA1*05:01:01:02~DQB1*02:01:01:01~DPA1*02:01:02:02~DPB1*01:01:01:01 being the most frequent one (47.9%). Out of 146 individuals, 43 (29.5%) were homozygous for all nine HLA loci, encompassing three distinct haplotypes. In addition, the two (out of 21 different combinations) most frequent HLA-DPA1~DPB1 haplotypes were HLA-DPA1*02:01:02:02~DPB1*01:01:01:01 and HLA-DPA1*01:03:01:02~DPB1*04:01:01:01 which were significantly more prevalent (Pcorr < 0.0001 each). Our study provides valuable insights on the polymorphism of nine HLA loci within 8.1 extended haplotype, highlighting 4th-field allelic variations and potential haplotype formation preferences. Additionally, it underscores the genetic diversity of HLA-DPA1~DPB1 within 8.1 extended haplotype, which may influence its role in disease associations.
The HLA-C*07:1178 allele is characterised by a single nucleotide substitution in exon 6.
The HLA-B*48:09 allele differs from HLA-B*48:01:01:01 by a single non-synonymous nucleotide change in exon 1.
The anti-tumour immune response plays a pivotal role in eliminating tumour cells, with the presence of tumour-infiltrating lymphocytes (TILs) often correlated with improved patient outcomes. Among these, CD4+ T lymphocytes act as key orchestrators of the immune response, functioning as effector and regulatory cells, and are essential for establishing immunological memory. To better understand the role of CD4+ T cells in anti-tumour immunity, we analysed the HLA-II immunopeptidome of dendritic cells (DCs) from HLA-heterozygous donors pulsed with a protein extract from the MCF-7 tumour cell line. Our objective was to identify differences in the arrays of peptides binding distinct HLA-DRB1 allele combinations and the effect of DC pulsing on peptide presentation. We found that presented peptide repertoires are strongly influenced by HLA-DR heterozygosity in an allele-specific manner. Alleles with high binding strength (e.g., DRB1*01:01, DRB1*03:01 and DRB1*04:04) tended to dominate peptide presentation; however, this dominance is significantly modulated by the allelic combination, suggesting that antigen presentation is shaped not only by individual allele properties but also by their combinations. Pulsing DCs with MCF-7 extracts increased peptide overlap between donors and enabled the identification of 58 proteins putatively derived from the tumour cell line lysates. Interestingly, peptide presentation from these proteins reinforced allele-specific features of dominance and weakness previously observed across the entire immunopeptidome. Gaining insights into the peptide repertoire presented by distinct HLA-DR combinations could inform the design of personalised immunotherapies based on peptide-pulsed DCs, ultimately enhancing CD4+ TIL responses across diverse patient populations.
Two novel HLA-DQB1 alleles were detected using next-generation sequencing.
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