25 years of the IPD-IMGT/HLA Database.

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 Next generation sequencing (NGS) has superseded previous methodologies of HLA typing and can generate large amounts of high-resolution sequencing data.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.

The IPD-IMGT/HLA Database.

It is 24 years since the IPD-IMGT/HLA Database, http://www.ebi.ac.uk/ipd/imgt/hla/, was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The database now contains over 35 000 alleles of the human Major Histocompatibility Complex (MHC) named by the WHO Nomenclature Committee for Factors of the HLA System. This complex contains the most polymorphic genes in the human genome and is now considered hyperpolymorphic. The IPD-IMGT/HLA Database provides a stable and user-friendly repository for this information. Uptake of Next Generation Sequencing technology in recent years has driven an increase in the number of alleles and the length of sequences submitted. As the size of the database has grown the traditional methods of accessing and presenting this data have been challenged, in response, we have developed a suite of tools providing an enhanced user experience to our traditional web-based users while creating new programmatic access for our bioinformatics user base. This suite of tools is powered by the IPD-API, an Application Programming Interface (API), providing scalable and flexible access to the database. The IPD-API provides a stable platform for our future development allowing us to meet the future challenges of the HLA field and needs of the community.

Widespread non-coding polymorphism in HLA class II genes of International HLA and Immunogenetics Workshop cell lines.

As the primary genetic determinant of immune recognition of self and non-self, the hyperpolymorphic HLA genes play key roles in disease association and transplantation. The large, variably sized HLA class II genes have historically been less well characterized than the shorter HLA class I genes. Here, we have used Pacific Biosciences Single Molecule Real-Time (SMRT®) DNA sequencing to perform four-field resolution HLA typing of HLA-DRB1/3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 from a panel of 181 B-lymphoblastoid cell lines from the International HLA and Immunogenetics Workshops. By interrogating all exons, introns, and the untranslated regions of these important reference cells, we have improved their HLA typing resolution on the IPD-IMGT/HLA database. We observed widespread non-coding polymorphism, with over twice as many unique genomic sequences identified compared with coding sequences (CDS). We submitted 263 unique sequences to the IPD-IMGT/HLA Database, often from multiple cell lines, including 114 confirmations of existing alleles, of which 30 were also extensions to full-length genomic sequences where only CDS was available previously. A total of 149 novel alleles were identified, largely differing from their closest reference allele sequences by a single nucleotide polymorphism (SNP). However, some highly divergent alleles were deemed to be recombinants, only detectable by full-length sequencing with long, phased reads. The fourth-field variation we observed allowed fine mapping of linkage disequilibrium patterns and haplotypes to particular ancestries. This study has highlighted the under-appreciated non-coding diversity in HLA class II genes, with potential implications for population genetic and clinical studies.

Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation.

PURPOSE: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study. METHODS: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017. RESULTS: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall P = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall P = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall P = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall P = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall P = .0003). CONCLUSION: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.

IPD-IMGT/HLA Database.

The IPD-IMGT/HLA Database, http://www.ebi.ac.uk/ipd/imgt/hla/, currently contains over 25 000 allele sequence for 45 genes, which are located within the Major Histocompatibility Complex (MHC) of the human genome. This region is the most polymorphic region of the human genome, and the levels of polymorphism seen exceed most other genes. Some of the genes have several thousand variants and are now termed hyperpolymorphic, rather than just simply polymorphic. The IPD-IMGT/HLA Database has provided a stable, highly accessible, user-friendly repository for this information, providing the scientific and medical community access to the many variant sequences of this gene system, that are critical for the successful outcome of transplantation. The number of currently known variants, and dramatic increase in the number of new variants being identified has necessitated a dedicated resource with custom tools for curation and publication. The challenge for the database is to continue to provide a highly curated database of sequence variants, while supporting the increased number of submissions and complexity of sequences. In order to do this, traditional methods of accessing and presenting data will be challenged, and new methods will need to be utilized to keep pace with new discoveries.

A novel HLA allele, HLA-B*56:67, identified in a Melanesian individual from New Caledonia.

Novel allele HLA-B*56:67 potentially formed by recombination between B*56:01:01:03 and B*40:01:01.

The IPD Databases: Cataloguing and Understanding Allele Variants.

The IMGT/HLA Database has provided a repository for information regarding polymorphism in the genes of the immune system since 1998. In 2003, it was absorbed into the Immuno Polymorphism Database (IPD). The IPD project has enabled us to create and maintain a platform for curating and publishing locus-specific databases which are either involved directly with, or relate to, the function of the Major Histocompatibility Complex across a number of species. In collaboration with specialist groups and nomenclature committees individual sections have been curated prior to their submission to the IPD for online publication. The IPD consists of five core databases, with the primary database being the IMGT/HLA Database. With the work of various nomenclature committees, the HLA Informatics Group, and alongside the European Bioinformatics Institute, we provide access to this data through the website ( http://www.ebi.ac.uk/ipd/ ) to the public domain. The IPD project continually develops new tools in conjunction with on-going scientific developments-such as Next-Generation Sequencing-to maintain efficiency and usability in response to user feedback and requests. The website is updated on a regular basis to ensure that new and confirmatory sequences are distributed to the immunogenetics community, as well as the wider research and clinical communities.