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To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6–<11 years, ≥11–<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self‐reported colour–race and identified a familiar history of T1D in first‐degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub‐Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA‐DQB1*03:02g, ‐DQA1*03:01g, ‐02:01g, DRB1*04:05g and ‐04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, ‐13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self‐reported colour–race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high‐risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well‐known genomic risk or protection factors for T1D. [ABSTRACT FROM AUTHOR]

The Genotype List (GL) String grammar for reporting HLA and Killer-cell Immunoglobulin-like Receptor (KIR) genotypes in a text string was described in 2013. Since this initial description, GL Strings have been used to describe HLA and KIR genotypes for more than 40 million subjects, allowing these data to be recorded, stored and transmitted in an easily parsed, text-based format. After a decade of working with HLA and KIR data in GL String format, with advances in HLA and KIR genotyping technologies that have fostered the generation of full-gene sequence data, the need for an extension of the GL String system has become clear. Here, we introduce the new GL String delimiter ?, which addresses the need to describe ambiguity in assigning a gene sequence to gene paralogs. GL Strings that do not include a ? delimiter continue to be interpreted as originally described. This extension represents version 1.1 of the GL String grammar.

Allogeneic haematopoietic stem cell transplantation (allo‐HSCT) is the only curative therapy for adult T‐cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo‐HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo‐HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA‐identical sibling donors or HLA‐A, ‐B, ‐C or ‐DRB1 allele‐matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA‐A, ‐B and ‐DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA‐B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51–0.90; p = 0.008), whereas HLA‐B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19–2.27; p = 0.003). In addition, HLA‐B62 was associated with a lower risk of transplant‐related mortality (TRM) (HR, 0.52; 95% CI: 0.32–0.85, p = 0.009), whereas HLA‐B60 was associated with a higher risk of grades III–IV acute graft‐versus‐host disease (HR, 2.63; 95% CI: 1.62–4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA‐B60‐positive patients and the lower risk of TRM in HLA‐B62‐positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo‐HSCT. [ABSTRACT FROM AUTHOR]

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen‐presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen‐presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen‐presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA‐B alleles had a higher HPV antigen‐presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2–3) than in cervicitis or early‐stage CIN (CIN1): around half of CIN2–3 had LOH of any HLA class I. Moreover, the antigen‐presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA‐B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long‐term infection and progression to advanced lesions. [ABSTRACT FROM AUTHOR]

Twenty‐five years ago, in 1998, the HLA Informatics Group of the Anthony Nolan Research Institute released the IMGT/HLA Database. Since this time, this online resource has acted as the repository for the numerous variant sequences of HLA alleles named by the WHO Nomenclature Committee for Factors of the HLA System. The IPD‐IMGT/HLA Database has provided a stable, highly accessible, user‐friendly repository for this work. During this time, the technology underlying HLA typing has undergone significant changes. Next generation sequencing (NGS) has superseded previous methodologies of HLA typing and can generate large amounts of high‐resolution sequencing data. This has resulted in a drastic increase in the number and complexity of sequences submitted to the database. The challenge for the IPD‐IMGT/HLA Database has been to maintain the highest standards of curation, while supporting the core set of tools and functionality to our users with increased numbers of submissions and sequences. Traditional methods of accessing and presenting data have been challenged and new methods utilising new computing technologies have had to be developed to keep pace and support a shifting user demographic. [ABSTRACT FROM AUTHOR]

The MHC class I region contains crucial genes for the innate and adaptive immune response, playing a key role in susceptibility to many autoimmune and infectious diseases. Genome‐wide association studies have identified numerous disease‐associated SNPs within this region. However, these associations do not fully capture the immune‐biological relevance of specific HLA alleles. HLA imputation techniques may leverage available SNP arrays by predicting allele genotypes based on the linkage disequilibrium between SNPs and specific HLA alleles. Successful imputation requires diverse and large reference panels, especially for admixed populations. This study employed a bioinformatics approach to call SNPs and HLA alleles in multi‐ethnic samples from the 1000 genomes (1KG) dataset and admixed individuals from Brazil (SABE), utilising 30X whole‐genome sequencing data. Using HIBAG, we created three reference panels: 1KG (n = 2504), SABE (n = 1171), and the full model (n = 3675) encompassing all samples. In extensive cross‐validation of these reference panels, the multi‐ethnic 1KG reference exhibited overall superior performance than the reference with only Brazilian samples. However, the best results were achieved with the full model. Additionally, we expanded the scope of imputation by developing reference panels for non‐classical, MICA, MICB and HLA‐H genes, previously unavailable for multi‐ethnic populations. Validation in an independent Brazilian dataset showcased the superiority of our reference panels over the Michigan Imputation Server, particularly in predicting HLA‐B alleles among Brazilians. Our investigations underscored the need to enhance or adapt reference panels to encompass the target population's genetic diversity, emphasising the significance of multiethnic references for accurate imputation across different populations. [ABSTRACT FROM AUTHOR]

To analyse the effect of HLA‐DPA1 and HLA‐DPB1 allelic mismatches on the outcomes of unrelated donor haematopoietic stem cell transplantation (URD‐HSCT), we collected 258 recipients with haematological disease who underwent HLA‐10/10 matched URD‐HSCT. HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, ‐DRB3/4/5, ‐DQA1, ‐DPA1 and ‐DPB1 typing was performed for the donors and recipients using next‐generation sequencing (NGS) technology. After excluding 8 cases with DQA1 or DRB3/4/5 mismatches, we included 250 cases with HLA‐14/14 matching for further analysis. Our results showed that the proportion of matched DPA1 and DPB1 alleles was only 10.4% (26/250). The remaining 89.6% of donors and recipients demonstrated DPA1 or DPB1 mismatch. In the DPA1 matched and DPB1 mismatched group, accounting for 18.8% (47/250) of the cohort, DPB1*02:01/DPB1*03:01 allelic mismatches were associated with decreased 2‐year OS and increased NRM. DPB1*02:02/DPB1*05:01 and DPB1*02:01/DPB1*05:01 mismatches showed no impact on outcomes. Moreover, the specific allelic mismatches observed were consistent with the DPB1 T‐cell epitope (TCE) classification as permissive and non‐permissive. We innovatively established an analysis method for DPA1 ~ DPB1 linkage mismatch for cases with both DPA1 and DPB1 mismatched, accounting for 70% (175/250) of the total. DPA1*02:02 ~ DPB1*05:01/DPA1*02:01 ~ DPB1*17:01 linkage mismatches were associated with lower 2‐year OS, especially among AML/MDS recipients. DPA1*02:02 ~ DPB1*05:01/DPA1*01:03 ~ DPB1*02:01 linkage mismatches showed no impact on outcomes. In conclusion, applying the DPA1 ~ DPB1 linkage mismatch analysis approach can identify different types of mismatches affecting transplant outcomes and provide valuable insight for selecting optimal donors for AML/MDS and ALL recipients. [ABSTRACT FROM AUTHOR]

Complications due to HCMV infection or reactivation remain a challenging clinical problem in immunocompromised patients, mainly due to insufficient or absent T‐cell functionality. Knowledge of viral targets is crucial to improve monitoring of high‐risk patients and optimise antiviral T‐cell therapy. To expand the epitope spectrum, genetically‐engineered dendritic cells (DCs) and fibroblasts were designed to secrete soluble (s)HLA‐A*11:01 and infected with an HCMV mutant lacking immune evasion molecules (US2‐6 + 11). More than 700 HLA‐A*11:01‐restricted epitopes, including more than 50 epitopes derived from a broad range of HCMV open‐reading‐frames (ORFs) were identified by mass spectrometry and screened for HLA‐A*11:01‐binding using established prediction tools. The immunogenicity of the 24 highest scoring new candidates was evaluated in vitro in healthy HLA‐A*11:01+/HCMV+ donors. Thus, four subdominant epitopes and one immunodominant epitope, derived from the anti‐apoptotic protein UL36 and ORFL101C (A11SAL), were identified. Their HLA‐A*11:01 complex stability was verified in vitro. In depth analyses revealed highly proliferative and cytotoxic memory T‐cell responses against A11SAL, with T‐cell responses comparable to the immunodominant HLA‐A*02:01‐restricted HCMVpp65NLV epitope. A11SAL‐specific T cells were also detectable in vivo in immunosuppressed transplant patients and shown to be effective in an in vitro HCMV‐infection model, suggesting their crucial role in inhibiting viral replication and improvement of patient's outcome. The developed in vitro pipeline is the first to utilise genetically‐engineered DCs to identify naturally presented immunodominant HCMV‐derived epitopes. It therefore offers advantages over in silico predictions, is transferable to other HLA alleles, and will significantly expand the repertoire of viral targets to improve therapeutic options. [ABSTRACT FROM AUTHOR]

The introduction of Next‐Generation Sequencing (NGS) methodology in the histocompatibility testing for both allo‐HSCT and solid organ transplantation enables the sequencing of all HLA genes, which in turn leads to the discovery of many new HLA alleles. Over the last 3 years, we have identified 28 novel alleles (HLA‐A*02:1079, A*03:01:01:112, A*11:01:01:83, A*11:01:01:87, A*24:595, A*68:01:01:15, B*07:02:01:107, B*08:01:01:67, B*08:01:01:69, B*13:02:01:25, B*15:01:82, B*15:18:08, B*18:01:01:76, B*27:02:06, B*27:05:02:34, B*40:06:01:17, B*40:517, C*04:01:01:173, C*04:477, C*05:276, C*07:01:01:130, C*12:03:80, C*12:03:01:62, DQA1*05:01:01:10, DPB1*13:01:07, DPB1*1146:01, DPB1*1456:01 and DPB1*1514:01) using the NGS method. The presented data emphasises the benefits gained by the utilisation of the NGS‐based techniques in HLA genotyping but also provides new insight on the HLA polymorphism in the Croatian population. [ABSTRACT FROM AUTHOR]

Polymorphism of killer‐cell immunoglobulin‐like receptors (KIRs) and their HLA class I ligands impacts the effector activity of cytotoxic NK cell and T cell subsets. Therefore, understanding the extent and implications of KIR and HLA class I genetic polymorphism across various populations is important for immunological and medical research. In this study, we conducted a high‐resolution investigation of KIR and HLA class I diversity in three distinct Chinese ethnic minority populations. We studied the She, Yugur, and Tajik, and compared them with the Zhejiang Han population (Zhe), which represents the majority Southern Han ethnicity. Our findings revealed that the Tajik population exhibited the most diverse KIR copy number, allele, and haplotype diversity among the four populations. This diversity aligns with their proposed ancestral origin, closely resembling that of Iranian populations, with a relatively higher presence of KIR‐B genes, alleles, and haplotypes compared with the other Chinese populations. The Yugur population displayed KIR distributions similar to those of the Tibetans and Southeast Asians, whereas the She population resembled the Zhe and other East Asians, as confirmed by genetic distance analysis of KIR. Additionally, we identified 12.9% of individuals across the three minority populations as having KIR haplotypes characterized by specific gene block insertions or deletions. Genetic analysis based on HLA alleles yielded consistent results, even though there were extensive variations in HLA alleles. The observed variations in KIR interactions, such as higher numbers of 2DL1‐C2 interactions in Tajik and Yugur populations and of 2DL3‐C1 interactions in the She population, are likely shaped by demographic and evolutionary mechanisms specific to their local environments. Overall, our findings offer valuable insights into the distribution of KIR and HLA diversity among three distinct Chinese ethnic minority populations, which can inform future clinical and population studies. [ABSTRACT FROM AUTHOR]

This family‐based study was conducted in a group of Iranians with Type 1 diabetes (T1D) to investigate the transmission from parents of risk and non‐risk HLA alleles and haplotypes, and to estimate the genetic risk score for this disease within this population. A total of 240 T1D subjects including 111 parent–child trios (111 children with T1D, 133 siblings, and 222 parents) and 330 ethnically matched healthy individuals were recruited. High‐resolution HLA typing for DRB1/DQB1 loci was performed for all study subjects (n = 925) using polymerase chain reaction–sequence‐specific oligonucleotide probe method. The highest predisposing effect on developing T1D was conferred by the following haplotypes both in all subjects and in probands compared to controls: DRB1*04:05–DQB1*03:02 (Pc = 2.97e‐06 and Pc = 6.04e‐10, respectively), DRB1*04:02–DQB1*03:02 (Pc = 5.94e‐17 and Pc = 3.86e‐09, respectively), and DRB1*03:01–DQB1*02:01 (Pc = 8.26e‐29 and Pc = 6.56e‐16, respectively). Conversely, the major protective haplotypes included DRB1*13:01–DQB1*06:03 (Pc = 6.99e‐08), DRB1*15:01–DQB1*06:02 (Pc = 2.97e‐06) in the cases versus controls. Also, DRB1*03:01–DQB1*02:01/DRB1*04:02|05–DQB1*03:02 and DRB1*03:01–DQB1*02:01/DRB1*03:01–DQB1*02:01 diplotypes conferred the highest predisposing effect in the cases (Pc = 8.65e‐17 and Pc = 6.26e‐08, respectively) and in probands (Pc = 5.4e‐15 and Pc = 0.001, respectively) compared to controls. Transmission disequilibrium test showed that the highest risk was conferred by DRB1*04:02–DQB1*03:02 (Pc = 3.26e‐05) and DRB1*03:01–DQB1*02:01 (Pc = 1.78e‐12) haplotypes and the highest protection by DRB1*14:01–DQB1*05:03 (Pc = 8.66e‐05), DRB1*15:01–DQB1*06:02 (Pc = 0.002), and DRB1*11:01–DQB1*03:01 (Pc = 0.0003) haplotypes. Based on logistic regression analysis, carriage of risk haplotypes increased the risk of T1D development 24.5 times in the Iranian population (p = 5.61e‐13). Also, receiver operating characteristic curve analysis revealed a high predictive power of those risk haplotypes in discrimination of susceptible from healthy individuals (area under curve: 0.88, p = 5.5e‐32). Our study highlights the potential utility of genetic risk assessment based on HLA diplotypes for predicting T1D risk in individuals, particularly among family members of affected children in our population. [ABSTRACT FROM AUTHOR]

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life‐saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor‐specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression‐minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor‐specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor‐specific‐antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR‐Cas9‐edited cells, to rebut the claim that the HLAMatchmaker eplets represent "functional epitopes." We further used unique sub‐cohorts of patients, those receiving an allograft with two HLA‐DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05‐heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor‐specific HLA‐DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA‐DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections. [ABSTRACT FROM AUTHOR]

Extended sequences for 13 HLA alleles were found which had limited coverage previously. [ABSTRACT FROM AUTHOR]

Full genomic sequence shows HLA‐G*01:19 differs from HLA‐G*01:04:01:01 only at position 99 in exon 2. [ABSTRACT FROM AUTHOR]

Four novel KIR alleles KIR3DL1*0010120, KIR3DS1*01315, KIR3DL3*0020703 and KIR2DL4*0010310 identified using next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Genomic sequence of HLA‐DQB1*03:01:01:60, ‐DQB1*03:01:01:61, ‐DQB1*03:01:01:62, ‐DQB1*03:01:01:63, ‐DQB1*03:02:01:23, ‐DQB1*03:02:01:24, ‐DQB1*03:02:01:25 and ‐DQB1*03:03:02:14 alleles in Spanish individuals. [ABSTRACT FROM AUTHOR]

The HLA‐Α*24:632 allele differs from HLA‐A*24:02:01:01 by a single nucleotide substitution in exon 2. [ABSTRACT FROM AUTHOR]

HLA‐C*02 246 has one nucleotide change from HLA‐C*02:02:02:01 at nucleotide 523 changing Arginine to Cysteine at residue 151. [ABSTRACT FROM AUTHOR]

HLA‐A*11:01:117 differs from HLA‐A*11:01:01:01 by a single nucleotide substitution at position 780 A>G. [ABSTRACT FROM AUTHOR]

The HLA‐B*51:197 allele is generated from the interlocus recombination of both HLA‐B*51:01:01:01 and HLA‐C*01:02:01:01 alleles. [ABSTRACT FROM AUTHOR]

Eight novel HLA class I alleles detected by next‐generation sequencing. [ABSTRACT FROM AUTHOR]

HLA‐C*04:01:01:182 differs from the HLA‐C*04:01:01:06 allele by one nucleotide substitution in the 5′UTR. [ABSTRACT FROM AUTHOR]

The newly discovered HLA‐C*04:01:01:186 allele differs from HLA‐C*04:01:01:01 by a single nucleotide substitution in intron 3. [ABSTRACT FROM AUTHOR]

In patients awaiting an allogeneic haematopoietic stem cell transplantation, platelet transfusion is a risk factor for anti‐HLA class I immunization because the resulting donor‐specific antibodies complicate the allograft process. The objective of the present study was to determine the feasibility of a novel eplet‐based strategy for identifying HLA class I mismatches between potential donors and the recipient when pre‐allograft platelet transfusions were required. We included 114 recipient/haploidentical relative pairs. For each pair, we entered HLA‐class I typing data into the HLA Eplet Mismatch calculator, defined the list of mismatched eplets (for the recipient versus donor direction) and thus identified the shared HLAs to be avoided. Using this list of HLAs, we defined the theoretical availability of platelet components (PCs) by calculating the virtual panel‐reactive antibody (vPRA). We also determined the number of PCs actually available in France by querying the regional transfusion centre's database. The mean ± standard deviation number of highly/moderately exposed eplets to be avoided in platelet transfusions was 5.8 ± 3.3, which led to the prohibition of 38.5 ± 2 HLAs‐A and ‐B. Taking into account the mismatched antigens and the eplet load, the mean ± standard deviation theoretical availability of PCs (according to the vPRA) was respectively 34.49% ± 1.95% for HLA‐A and 80% ± 2.3% for HLA‐B. A vPRA value below 94.9% for highly or moderately exposed eplets would predict that 10 PCs were actually available nationally. Although epitope protection of HLA molecules is feasible, it significantly restricts the choice of PCs. [ABSTRACT FROM AUTHOR]

HLA studies in patients with autoimmune neutropenia (AIN) have shown very consistent results for the association with HLA class II alleles at low resolution. This study aimed to examine the association of both HLA class I and class II at high resolution to clarify the contribution of risk alleles to the disease. A total of 107 AIN patients were genotyped for six loci of HLA class I (HLA‐A, ‐B and ‐C) and class II (HLA‐DRB1, ‐DQB1, and ‐DPB1) genes by a high‐resolution (3‐field, 6‐digit) analysis and compared with HLA typing of 1000 healthy controls. Compared with the controls, the allele frequencies were significantly higher in AIN patients for A*02:17:01G, C*01:02:01G, DRB1*10:01:01G, DRB1*14:01:01G, DRB1*16:01:01G, DQB1*05:02:01G, and DQB1*05:03:01G but lower significant for C*03:04:01G, DRB1*04:01:01G, DRB1*13:02:01G, DQB1*03:02:01G, and DQB1*06:04:01G. Frequently associated two‐locus haplotypes were found to be DRB1*10:01:01G‐DQB1*05:01:01G and DRB1*16:01:01G‐DQB1*05:02:01G, while the S2 (Q‐ or D‐KRAA) shared epitope (SE) was associated with lower risk. A unique association with HLA alleles was observed between patients with specific anti‐HNA‐1a antibodies and broad‐reacting anti‐FcγRIIIb. Anti‐HNA‐1a antibody‐positive patients were associated with C*01:02:01G, DRB1*01:01:01G, DRB1*16:01:01G, DQB1*05:01:01G, DQB1*05:02:01G, DQB1*06:04:01G, and DPB1*10:01:01G; the two‐locus haplotypes DRB1*01:01:01G‐DQB1*05:01:01G and DRB1*16:01:01G‐DQB1*05:02:01G; and the S3P (Q‐ or R‐RRAA) SE. Anti‐FcγRIIIb antibody‐positive patients were associated with the alleles A*02:17:01G, DRB1*10:01:01G, and DQB1*05:02:01G; the haplotypes DRB1*10:01:01G‐DQB1*05:01:01G and DRB1*11:01:02G‐DQB1*05:02:01G; and the S3D (DRRAA) SE. The different associations regarding FcγRIIIb antibody specificities could indicate disease heterogeneity. [ABSTRACT FROM AUTHOR]

Few data exist on the role of genetic factors involving the HLA system on response to Covid‐19 vaccines. Moving from suggestions of a previous study investigating the association of some HLA alleles with humoral response to BNT162b2, we here compared the HLA allele frequencies among weak (n = 111) and strong (n = 123) responders, defined as those healthcare workers with the lowest and the highest anti‐Spike antibody levels after vaccination. Individuals with clinical history of Covid‐19 or positive anti‐nucleocapside antibodies were excluded. We found the common HLA‐A*03:01 allele as an independent predictor of strong humoral response (OR = 12.46, 95% CI: 4.41–35.21, p < 0.0001), together with younger age of vaccines (p = 0.004). Correlation between antibody levels and protection from breakthrough infection has been observed, with a 2‐year cumulative incidence of 42% and 63% among strong and weak responders, respectively (p = 0.03). Due to the high frequency of HLA‐A*03:01 and the need for seasonal vaccinations against SARS‐CoV‐2 mutants, our findings provide useful information about the inter‐individual differences observed in humoral response after Covid‐19 vaccine and might support further studies on the next seasonal vaccines. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy using virus‐specific T cells (VST) is a strategy for treating common opportunistic viral infections after transplantation, particularly when these infections do not resolve through antiviral drug therapy. The availability of third‐party healthy donors allows for the immediate use of cells for allogeneic therapy in cases where patients lack an appropriate donor. Here, we present the creation of a cell donor registry of human leukocyte antigen (HLA)‐typed blood donors, REDOCEL, a strategic initiative to ensure the availability of compatible cells for donation when needed. Currently, the registry consists of 597 healthy donors with a median age of 29 years, 54% of whom are women. The most represented blood groups were A positive and O positive, with 36.52% and 34.51%, respectively. Also, donors were screened for cytomegalovirus (CMV) and Epstein–Barr virus (EBV). Almost 65% of donors were CMV‐seropositive, while less than 5% were EBV‐seronegative. Of the CMV‐seropositive donors, 98% were also EBV‐seropositive. High‐resolution HLA‐A, ‐B, ‐C, ‐DRB1 and ‐DQB1 allele and haplotype frequencies were determined in the registry. Prevalent HLA alleles and haplotypes were well represented to ensure donor‐recipient HLA‐matching, including alleles reported to present viral immunodominant epitopes. Since the functional establishment of REDOCEL, in May 2019, 87 effective donations have been collected, and the effective availability of donors with the first call has been greater than 75%. Thus, almost 89% of patients receiving an effective donation had available at least 5/10 HLA‐matched cell donors (HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1). To summarize, based on our experience, a cell donor registry from previously HLA‐typed blood donors is a useful tool for facilitating access to VST therapy. [ABSTRACT FROM AUTHOR]

This article discusses the association between the HLA-C*04:01 allele and severe COVID-19. HLA genes play a crucial role in the immune response to pathogens by presenting antigens to T cells. The study analyzes patient data and identifies HLA-C*04:01 as a marker for disease severity. While the association has been observed in multiple studies, the frequency of the allele in different populations may affect the significance of the association. Further research is needed to understand the interplay between SARS-CoV-2 and HLA genes. The findings can inform clinical management and identify at-risk individuals and populations. The research was funded by the Government of Canada and supported by the Canadian Institutes of Health Research. [Extracted from the article]

Cervical cancer (CC) is one of the leading causes of cancer‐related death in females worldwide. Genome‐wide association studies (GWASs) have identified CC‐related susceptibility loci in HLA regions. To investigate the associations between HLA genes and cervical intraepithelial neoplasia (CIN) or cervical cancer (CC), six loci of HLA class I (HLA‐A, ‐B, and ‐C) and II (HLA‐DRB1, ‐DPB1, and ‐DQB1) were selected for genotyping, and the associations between these alleles or their haplotypes with CIN or CC risk or protection from disease were evaluated. In total, 2193 participants, including 909 healthy individuals in the control group, 769 patients with CC, and 515 patients with CIN2+ (CIN II and III), were enrolled in the current study. HLA genes were genotyped using the NGSgo Illumina MiSeq workflow, and the associations between these loci and CIN2+ or CC at the allele and haplotype levels were analyzed. The allele frequencies of HLA‐A*33:03, B*58:01, C*03:02, DPB1*05:01, and DRB1*12:01 were lower in both the CC and CIN2+ groups than in the control group, whereas those of B*55:02, C*04:03, and DPB1*03:01 were higher in the CC group than in the control group. In the histologic CC type analysis, the differences in the frequencies of these alleles in squamous cell carcinoma (SCC) of the cervix and stage I CC showed a consistent trend. In the haplotype analysis, the frequency of A*33:03‐C*03:02‐B*58:01 was lower in the CC and CIN2+ groups than in the control group, and that of A*24:02‐C*04:03‐B*15:25 was higher in the CC group than in both the control and CIN2+ groups. These three different haplotype frequencies were also identified in the FIGO CC stage analysis. In addition, in human papilloma virus (HPV) genotype analyses, the frequencies of HLA‐C*03:02 and DPB1*05:01 were significantly lower in the CC and CIN2+ groups than in the control group, and in SCC subgroup, the frequencies of HLA‐DQB1*04:01 and DRB1*04:05 were higher in the HPV other genotype infection group than in the HPV16 infection group. In both HPV16 single infection and coinfection with other HPVs, the frequency of haplotype A*33:03‐C*03:02‐B*58:01 was lower in both CC and CIN2+ than in the control group, while the frequencies of A*11:01‐C*14:02‐B*51:01 and A*24:02‐C*03:04‐B*13:01 were higher in the CIN2+ than in CC and the control group. In the HPV16 and other HPV infection comparisons, the frequencies of DRB1*04:05‐DQB1*04:01‐DPB1*02:01 and DRB1*11:01‐DQB1*03:01‐DPB1*05:01 were lower in the HPV16 infection group than in the other HPV infection group. Our results suggest that the HLA class I and II genes may affect the risk of CIN and CC as well as the histologic CC types and FIGO stages of CC in the Han Chinese population. In addition, HLA genes were associated with HPV16 infection at both the allelic and haplotype levels. [ABSTRACT FROM AUTHOR]

Although killer‐cell immunoglobulin‐like receptor (KIR) gene content has been widely studied in health and disease, with the advancement of next‐generation sequencing (NGS) technology the high‐resolution characterization of this complex gene region has become achievable. KIR allele‐level diversity has lately been described across human populations. The present study aimed to analyze for the first time the allele‐level polymorphism of nine KIR genes in 155 healthy, unrelated individuals from the Bulgarian population by applying NGS. The highest degree of polymorphism was detected for the KIR3DL3 gene with 40 observed alleles at five‐digit resolution in total, 22 of which were common. On the other hand, the KIR3DS1 gene was found to have the lowest degree of polymorphism among the studied KIR genes with one common allele: KIR3DS1*01301 (31.6%). To better understand KIR allelic associations and patterns in Bulgarians, we have estimated the pairwise linkage disequilibrium (LD) for the 10 KIR loci, where KIR2DL3*00501 allele was found in strong LD with KIR2DL1*00101 (D′ = 1.00, R2 = 0.742). This is the first study investigating KIR polymorphism at the allele level in a population from the South‐East European region. Considering the effect of the populationally shaped KIR allelic polymorphism on NK cell function, this data could lead to a better understanding of the genetic heterogeneity of this region and can be carried into clinical practice by improvement of the strategies taken for NK‐mediated diseases. [ABSTRACT FROM AUTHOR]

The data enabling the estimation of the possibility of finding a matched unrelated donor (MUD) within a relatively short time is important for the success of hematopoietic stem cell transplantation (HSCT). In the present study, 738 unrelated Croatian patients in the program of unrelated HSCT were retrospectively analyzed for gender matching, donor origin (national or international), the distribution of HLA alleles and haplotypes, as well as for the probability of finding a 9‐10/10 MUD. Almost 70% of the patients in our study group had a 10/10 MUD, while among the patients with a 9/10 MUD, a 1st field resolution level mismatched donor was selected for 55.0% of patients. The majority of pairs were HLA‐A mismatched (33.8%). A comparison of HLA allele frequencies between two subgroups of patients revealed significant differences for 13 alleles. However, after p value correction, the difference in frequency remained significant only for four alleles; three HLA alleles (B*08:01, C*07:01, and DRB1*03:01) demonstrated a significantly higher frequency among patients with a 10/10 MUD (Pcorr < 0.0001, Pcorr = 0.0096, and Pcorr < 0.0001, respectively), while the B*35:08 allele was significantly more present among patients with a 9/10 MUD (Pcorr = 0.0328). The comparison of the distribution of HLA haplotypes between patients with a 10/10 MUD and patients with a 9/10 MUD showed significant differences for a number of two‐locus and three‐locus haplotypes, as well as for one five‐locus haplotype (HLA‐A*01:01~B*08:01~C*07:01~DRB1*03:01~DQB1*02:01), which was significantly more present in the group of patients with a 10/10 MUD. At least one HLA haplotype from the group of non‐frequent HLA haplotypes (positions >1000) was carried by patients with a 9/10 MUD. The data obtained by the present study will contribute to a better estimation of the probability of finding a suitable 9‐10/10 MUD for Croatian patients in need of HSCT. [ABSTRACT FROM AUTHOR]

In solid organ transplantation, formation of de novo donor‐specific HLA antibodies is induced by mismatched eplets on donor HLA molecules. While several studies have shown a strong correlation between the number of eplet mismatches and inferior outcomes, not every eplet mismatch is immunogenic. Eplets are theoretically defined entities, necessitating formal proof that they can be recognised and bound by antibodies. This antibody verification is pivotal to ensure that clinically relevant eplets are considered in studies on molecular matching. Recombinant human HLA‐specific monoclonal antibodies (mAbs) were generated from HLA‐reactive B cell clones isolated from HLA immunised individuals using recombinant HLA molecules. Subsequently, the reactivity patterns of the mAbs obtained from single antigen bead assay were analysed using HLA‐EMMA software to identify single or configurations of solvent accessible amino acids uniquely present on the reactive HLA alleles and were mapped to eplets. Two HLA class I and seven HLA class II‐specific human mAbs were generated from four individuals. Extensive mAb reactivity analysis, led to antibody verification of three HLA‐DR‐specific eplets, and conversion of five eplets (one HLA‐A, one HLA‐B, two HLA‐DR, and one HLA‐DP), from provisionally verified to truly antibody‐verified. Finally, one HLA‐DQ‐specific eplet was upgraded from level A2 to level A1 verification evidence. The generation of recombinant human HLA‐specific mAbs with different specificities contributes significantly to the antibody verification of eplets and therefore is instrumental for implementation of eplet matching in the clinical setting. [ABSTRACT FROM AUTHOR]

Eighteen HLA allele sequences were confirmed and extended: 3 HLA‐A, 6 HLA‐B, 3 HLA‐C, 2 HLA‐DRB1, and 4 HLA‐DQB1 alleles. [ABSTRACT FROM AUTHOR]

A novel null HLA‐A*24 allele, HLA‐A*24:608N, was identified in five Korean subjects including three from a family and two separate individuals. This study was performed to discern its immunological function in transplantation settings. Because this null variant had deletions of approximately 12 k base pairs from intron 3 to 3′ end of the HLA‐A gene, low resolution HLA typing and amplicon‐based next generation sequencing (NGS) typing methods had failed to assign it. Hybrid capture‐based NGS method confirmed that this novel variant had a large deletion. T‐lymphocyte crossmatching by complement‐dependent lymphocytotoxicity and flow cytometry with a serum consisting anti‐HLA‐A24 antibody revealed negative results, implying that an individual with this allele would not carry a functioning A24 antigen. These findings highlight the importance of identifying a null HLA allele by employing appropriate molecular method and providing expected crossmatching outcomes in a real‐world transplantation setting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Forty‐three novel HLA‐H alleles, including 32 identified in cohorts of French donors for Hematopoietic Stem Cell Transplantation, have been characterized by Next‐Generation Sequencing (NGS) using a long range PCR approach. A phylogenetic study confirms three main HLA‐H clades. [ABSTRACT FROM AUTHOR]

Immune dysregulation has been widely observed in patients with psychiatric disorders. This study aims to examine the association between HLA alleles and depression and anxiety. Using data from the UK Biobank, we performed regression analyses to assess the association of 359 HLA alleles with depression and anxiety, as determined by Patient Health Questionnaire (PHQ) score (n = 120,033), self‐reported depression (n = 121,685), general anxiety disorder (GAD‐7) score (n = 120,590), and self‐reported anxiety (n = 108,310). Subsequently, we conducted gene environmental interaction study (GEIS) to evaluate the potential effects of interactions between HLA alleles and environmental factors on the risk of depression and anxiety. Sex stratification was implemented in all analysis. Our study identified two significant HLA alleles associated with self‐reported depression, including HLA‐C*07:01 (β = −0.015, p = 5.54 × 10−5) and HLA‐B*08:01 (β = −0.015, p = 7.78 × 10−5). Additionally, we identified four significant HLA alleles associated with anxiety score, such as HLA‐DRB1*07:01 (β = 0.084, p = 9.28 × 10−5) and HLA‐B*57:01 (β = 0.139, p = 1.22 × 10−4). GEIS revealed that certain HLA alleles interacted with environmental factors to influence mental health outcomes. For instance, HLA‐A*02:07 × cigarette smoking was associated with depression score (β = 0.976, p = 1.88 × 10−6). Moreover, sex stratification analysis revealed significant sex‐based differences in the interaction effects of certain HLA alleles with environmental factors. Our findings indicate the considerable impact of HLA alleles on the risks of depression and anxiety, providing valuable insights into the functional relevance of immune dysfunction in these conditions. [ABSTRACT FROM AUTHOR]

The novel MICA*112:02 allele was detected by next generation sequencing. [ABSTRACT FROM AUTHOR]

Two novel MICB alleles with coding polymorphisms in exon 3 were detected by next generation sequencing. [ABSTRACT FROM AUTHOR]

Genomic sequence of HLA‐DPA1*01:03:01:73, ‐DPA1*01:03:01:80, DPA1*01:03:01:82, ‐DPA1*01:155:01:02, ‐DPA1*02:02:02:16 alleles in Spanish individuals. [ABSTRACT FROM AUTHOR]

HLA‐B*07:02:01:110 differs from the HLA‐B*07:02:01:01 allele by two nucleotide substitutions in the 3′UTR. [ABSTRACT FROM AUTHOR]

HLA‐B*40:86 differs from B*40:06:01:03 by a single nucleotide exchange in exon 3. [ABSTRACT FROM AUTHOR]

HLA‐DRB1*11:298 shows one single nucleotide substitution at position 397 T>G compared with HLA‐DRB1*11:01:01:01. [ABSTRACT FROM AUTHOR]

Five novel HLA‐C alleles detected by next‐generation sequencing: HLA‐C*02:02:73, ‐C*03:04:106, ‐C*06:382, ‐C*07:1114Q and ‐C*12:408. [ABSTRACT FROM AUTHOR]

The novel HLA‐A*02:829 allele is likely generated from the recombination of both HLA‐A*02:05:01:01 and HLA‐A*32:01:01:01 alleles. [ABSTRACT FROM AUTHOR]

Compared with HLA‐DRB1*09:01:02:05, the alleles HLA‐DRB1*09:57 and HLA‐DRB1*09:58 each show one nucleotide change, respectively. [ABSTRACT FROM AUTHOR]

Compared with HLA‐DRB1*12:02, the alleles HLA‐DRB1*12:92 and HLA‐DRB1*12:101 each show one nucleotide substitution respectively. [ABSTRACT FROM AUTHOR]

Two different single nucleotide substitutions in intron 2 give rise to novel HLA‐DQB1*03:02:01 alleles. [ABSTRACT FROM AUTHOR]

The novel HLA‐DPB1*1437:01 and HLA‐DPB1*1438:01 alleles first identified in the Chinese individuals. [ABSTRACT FROM AUTHOR]

HLA‐DQA1*05:05:17:03 differs from HLA‐DQA1*05:05:01:02 by a single base substitution in exon 1 and HLA‐DQA1*05:05:17:01 within introns 1 and 2. [ABSTRACT FROM AUTHOR]