Microbiome signatures and their role in uveitis: Pathogenesis, diagnostics, and therapeutic perspectives.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Simple SummaryClassic Hodgkin lymphoma (cHL) is a B-cell malignancy with involvement of Epstein–Barr virus (EBV) in about 30% of the European population. The risk to develop cHL is strongly linked to genetic variants in the human leukocyte antigen (HLA) genomic region and to certain HLA alleles. This may be caused by the function of HLA alleles, or by genetic linkage to non-HLA genes. HLA can present EBV-derived and tumour-cell specific antigens and this may lead to anti-tumour immune responses. However, the tumour cells downregulate HLA expression in a proportion of the cases, which may result in immune escape. In this study, we tested whether the loss of HLA expression is related to the presence of certain protective HLA alleles. We found that loss and retention of HLA expression is indeed associated with presence of known susceptibility HLA alleles. These findings suggest that HLA itself is involved in development of cHL.Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to classic Hodgkin lymphoma (cHL), also in subgroups stratified for presence of the Epstein–Barr virus (EBV). We tested the hypothesis that the pressure on cHL tumour cells to lose HLA expression is associated with HLA susceptibility alleles. A meta-analysis was carried out to identify consistent protective and risk HLA alleles in a combined cohort of 839 cHL patients from the Netherlands and the United Kingdom. Tumour cell HLA expression was studied in 338 cHL cases from these two cohorts and correlated to the presence of specific susceptibility HLA alleles. Carriers of the HLA-DRB1*07 protective allele frequently lost HLA class II expression in cHL overall. Patients carrying the HLA-DRB1*15/16 (DR2) risk allele retained HLA class II expression in EBV− cHL and patients with the HLA-B*37 risk allele retained HLA class I expression more frequently than non-carriers in EBV+ cHL. The other susceptibility alleles showed no significant differences in expression. Thus, HLA expression by tumour cells is associated with a subset of the protective and risk alleles. This strongly suggests that HLA associations in cHL are related to peptide binding capacities of specific HLA alleles.

Hepatotoxicity is associated with small molecule tyrosine kinase inhibitors (TKI) in use for the treatment of a variety of cancers. Retrospective studies have identified and confirmed that specific Class II Human Leukocyte Antigen (HLA) alleles are strongly associated with ALT elevation in women treated with the TKI lapatinib for breast cancer. This study aimed to further evaluate and validate the role of the specified HLA alleles as predictors of elevated ALT in a pre-defined analysis of a large, randomized, double-blind, placebo-controlled study of lapatinib monotherapy in early stage HER2 positive breast cancer, the TEACH study (Tykerb Evaluation After Chemotherapy, EGF105485). This prospectively defined pharmacogenetic study compared the frequency of hepatobiliary adverse events between pre-specified Major Histocompatibility Complex (MHC) genetic variants, including the HLA alleles DQA1*02:01 and DRB1*07:01. The primary focus was on elevated ALT, as well as rare cases of concurrent ALT (>3x ULN) and bilirubin (>2x ULN) elevation, which represent possible Hy's Law cases and a high risk of acute liver failure, among 1194 patients randomized to lapatinib treatment from whom pharmacogenetic data was available. This study prospectively validated prior reports of the association of the specified MHC variants with elevated ALT among women treated with lapatinib. The strongest effects were observed for carriers of the HLA alleles DQA1*02:01 and DRB1*07:01, with odds ratios of 20 (95% CI: 8–40) between cases (n = 34) and controls (n = 807–808). These two HLA alleles are highly correlated, inherited together in most individuals and are consistent with a single genetic association. The overall risk of patients having an ALT (>3xULN) elevation was 3.0% and 0.7% during treatment with lapatinib and placebo respectively. Carriers of either HLA allele had a 12% chance (positive predictive value) of having an elevated ALT (>3xULN), in contrast to a 0.9% risk (negative predictive value, 99.1%) for non-carriers of the specified HLA alleles. These associations were maintained for higher ALT elevation thresholds and for cases of concurrent ALT and TBL elevation, consistent with possible Hy's Law cases. These results strongly support the role of Class II HLA-modulated immune mechanisms in lapatinib-induced hepatotoxicity. Our results validate the large strength of association of the HLA alleles DRB1*07:01 and DQA1*02:01 with hepatotoxicity and provide the possibility of managing the risk of hepatotoxicity in women receiving lapatinib for early or late stage HER2 positive breast cancer. This association with immune mechanisms may have implications for toxicities with other TKIs in current use in cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-05.

Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

Advances in HLA: Practical Implications for Selecting Adult Donors and Cord Blood Units

To determine the association between human leukocyte antigen (HLA) alleles and migraine, migraine subtypes, and sex-specific factors. It has long been hypothesized that inflammation contributes to migraine pathophysiology. This study examined the association between migraine and alleles in the HLA system, a key player in immune response and genetic diversity. We performed a case-control study and included 13,210 individuals with migraine and 86,738 controls. All participants were part of the Danish Blood Donor Study Genomic Cohort. Participants were genotyped and 111 HLA alleles on 15 HLA genes were imputed. We examined the association between HLA alleles and migraine subtypes, considering sex-specific differences. We found no association between HLA alleles and migraine, neither overall, nor in the sex-specific analysis. In the migraine subtype analysis, three HLA alleles were associated with migraine without aura; however, these associations could not be replicated in an independent Icelandic cohort (2191 individuals with migraine without aura and 278,858 controls). Furthermore, we found no association between HLA alleles and migraine with aura or chronic migraine. We found no evidence of an association between the HLA system and migraine, suggesting that genetic factors related to the HLA system do not play a significant role in migraine susceptibility.

BackgroundFew studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.MethodsA total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.ResultsCompared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048–0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified.ConclusionsHLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

Disruption of the human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. However, although genomic loss of HLA is frequent in non-small cell lung cancer (NSCLC) and in some types of breast cancer, the extent and importance of transcriptomic disruption to HLA presentation, including transcript repression and alternative splicing (AS), remains unclear. To address this, we developed MHC Hammer, a tool to call HLA allele-specific mutations, loss of heterozygosity (LOH), transcriptional repression, and alternative splicing. We first assessed HLA allelic expression and the prevalence of AS in normal tissue. Applying MHC Hammer to 510 normal lung samples and 407 normal breast samples from the Genotype-Tissue Expression cohort, we identified extensive heterogeneity in HLA allelic expression depending on both the allele and tissue type. In addition, HLA allelic AS, occurring in at least 20% of the allele transcripts, was observed in 19% of normal lung and 13% of normal breast samples. Next, we applied MHC Hammer to 413 TRACERx NSCLCs and 743 TCGA breast tumours. While mutations were uncommon, HLA LOH was a frequent event, occurring in 32% of lung adenocarcinomas (LUAD) and 57% of lung squamous cell carcinomas (LUSC). We observed a similar rate of HLA LOH in estrogen receptor positive (ER+) and negative (ER-) tumors (ER+: 14%, ER-: 15%), while in triple negative breast tumours we observed a higher rate of LOH (31%). Due to the heterogeneity in HLA expression observed in the normal samples, to measure tumor specific HLA repression and alternative splicing, we restricted our analysis to tumours with WES, tumor and tumor-adjacent normal RNAseq data. This resulted in a cohort of 88 NSCLCs from the TRACERx study as well as 44 ER+ breast tumours from the TCGA cohort. 61% of LUAD, 75% of LUSC and 35% of ER+ tumours harbored class I HLA transcriptional repression that could not be explained by underlying genomic loss. 27% of LUAD, 7% of LUSC and 55% of ER+ breast tumor patients exhibited no HLA disruption. Tumor specific AS affecting HLA exons 2, 3 or 4, potentially disrupting HLA antigen presentation, was identified in 8% of LUADs, 11% of LUSC and 7% of ER+ breast tumours. Tumor specific AS of exon 5, yielding soluble HLA molecules without a transmembrane domain was identified in 20% of LUAD, 14% of LUSCs and 18% of ER+ breast tumours. LUAD and LUSC tumor regions without HLA LOH or repression were enriched for somatic HLA AS events and alleles with somatic HLA AS had a higher neoantigen burden than those without. We found no relationship between survival and HLA expression or AS in the normal tissue. However, consistent with the importance of HLA dysfunction in tumor evolution, LUADs with low HLA expression in at least one tumor region were associated with shorter disease-free survival, HLA LOH was more common in LUAD’s that metastasized and HLA repression was enriched in LUSC primary regions seeding metastases. Citation Format: Clare Puttick, Thomas P. Jones, Michelle Leung, Oriol Pich, Felipe Galvez Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Carlos Martinez-Ruiz, Robert Bentham, Krijn K. Dijkstra, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A. Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A. Quezada, Nicholas McGranahan, Charles Swanton. Pervasive HLA disruption fuels cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1201.

Human Leukocyte Antigen Contributes to Childhood Endemic Burkitt Lymphoma in Eastern Africa: A Case-Control Association Study

). Highly sensitized patientshave only a small chance to receive a crossmatch negativedonor kidney, because they have developed antibodiesagainstmanydifferentHLAantigensresultingfrompreviouscontacts with allogeneic cells by pregnancy, blood transfu-sions,orprevioustransplants.Ifnospecialmeasurementsaretaken, these patients will accumulate on the transplant wait-ing lists. More and more transplant centers are developingstrategiestoremovecirculatingHLAalloantibodiesinthesepa-tients to be able to transplant the patient with a donor kidneydespite a positive crossmatch (

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BackgroundUp to 17% of cancer survivors have been reported to develop second primary cancers (SPC), which cause significant physical and economic distress and often complicate clinical decision-making. However, understanding of SPC remains limited and superficial. Human leukocyte antigen (HLA) is characterized by its polymorphism and has been associated with various diseases. This study aims to explore the role of HLA diversity in SPC incidence.MethodsWe analyzed a cohort of 47,550 cancer patients from the UK Biobank. SNP-derived HLA alleles were used and SPC-related HLA alleles were identified using logistic regression, followed by stepwise filtering based on the Akaike information criterion (AIC) and permutation tests. Additionally, we examined the association between extragenetic factors and the risk of SPC in patients carrying hazardous HLA alleles.ResultsDuring a median follow-up of 3.11 years, a total of 2894 (6.09%) participants developed SPC. We identified three protective HLA alleles (DRB1*04:03 and DPA1*02:02 for males and DRB5*01:01 for females) and two hazardous alleles (A*26:01 for males and DPB1*11:01 for females) about SPC. The presence of the protective alleles was associated with a reduced SPC risk (males: hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.59–0.89; females: HR 0.81, 95% CI 0.70–0.93), while the hazardous alleles were linked to an increased risk (males: HR 1.27, 95% CI 1.03–1.56; females: HR 1.35, 95% CI 1.07–1.70). The hazardous allele A*26:01 indicated skin-lung organ-specific SPC occurrence in males. Animal fat and vitamin C were associated with SPC risk in males carrying the hazardous alleles, while free sugar and vegetable fat were linked to SPC risk in females.ConclusionsThese results suggest that HLA alleles may serve as biomarkers for the susceptibility and organ-specific occurrence of SPC, while dietary modulation may mitigate hazardous alleles-related SPC risk, potentially aiding in the early prediction and prevention of SPC.

Human leucocyte antigen (HLA) molecules are the principal determinants of graft antigenicity and constitute a formidable barrier to allogeneic organ transplantation.1 Clinical outcomes after kidney transplantation are particularly strongly associated with the degree of HLA matching between donor and recipient [A] [B]. Here, we collate web‐based resources related to the immunobiology and practice of HLA typing of interest to basic scientists and transplant clinicians alike. Links [A] https://www.eurotransplant.org/cms/index.php?page=et_manual [B] http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp [C] http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ [D] http://www.ebi.ac.uk/ipd/imgt/hla/ [E] http://www.allelefrequencies.net/hla6003a.asp [F] http://hla-net.eu/ [G] http://hla.alleles.org/ [H] http://epregistry.com.br/index/index [I] http://www.hlamatchmaker.net/ The HLA molecules are membrane‐bound glycoproteins that bind antigenic peptides for presentation to T cells.2 According to their structure and function, classical HLA molecules fall into 2 classes: Class I molecules comprise a single peptide‐binding, α-polypeptide chain that associates with β2‐microglobulin and an antigenic peptide to form a mature complex; class II molecules are composed of an α- and β-polypeptide, both of which contribute to binding of antigenic peptides. The HLA class I molecules are expressed by most somatic cells, whereas class II molecules are usually only expressed by specialized cell subsets with immunological function. Classic class I and II molecules are genetically encoded within the major histocompatibility complex (MHC) locus on chromosome 6p21.3, which is a region of very high gene density, extreme polymorphism and clustering of genes with related immunological functions.3 The 3 genes encoding HLA class I molecules, namely, HLA-A, HLA-B, and HLA-C, reside within the class I region alongside 2 clusters of nonclassic class I genes. Genes for the class II molecules, namely, HLA-DP, HLA-DO, HLA-DM, HLA-DQ, and HLA-DR, are located in the class II region.FigurePolymorphism is a defining feature of HLA genes.4 The IMGT/HLA database [C] at the European Bioinformatics Institute serves as an official repository for HLA allele sequences, as well as offering a selection of online tools for categorizing and comparing HLA alleles.5 The dbMHC website [D] hosted at NCBI is a publicly accessible database for HLA allele sequence and related clinical data. The catalogue of HLA allele frequencies in diverse human populations is a particularly valuable resource. For reasons that are not fully explained, the overall rate of genetic recombination in the MHC region is lower than that in the rest of the genome; as a result, many HLA alleles exist in marked linkage disequilibrium. Presumably, a felicitous consequence of inheriting HLA genes as “haplotypic blocks” is that identifying a well‐matched donor is more probable than it would otherwise be. Usefully, the dbMHC website also lists HLA haplotype frequencies in different racial groups, as does allelefrequencies.net [E]6 and hla-net.eu [F].7 Naming of HLA alleles is standardized by the World Health Organization Nomenclature Committee for Factors of the HLA System. In April 2010, the system of HLA nomenclature was changed to accommodate the large number of allelic variants in some families. An accessible source of information about the current naming of HLA alleles is available at hla.alleles.org [G]. This neatly curated website also provides up‐to‐date lists of recognized HLA alleles and proteins, as well as a convenient nomenclature conversion tool. At a molecular level, interactions between non‐self HLA molecules and T-cell receptors or antibodies are well explained. Much effort has been invested in describing epitopes of HLA‐specific antibodies, which are now being systematically named and collated in an online archive at epregistry.com.br [H], which also lists epitope frequencies, epitope‐carrying alleles in Luminex panels, and alleles with antibody‐verified epitopes.8 A practical consequence of this work is an algorithm, known as HLAMatchmaker [I], which is now used by Eurotransplant as part of its “acceptable mismatch” program.9 Assessing “epitope load” might also provide valuable information for selecting organs for nonsensitized recipients or guiding their posttransplant management.10 In summary, knowledge of the HLA system and its relevant nomenclature is important for all transplant professionals. Accurate recording of HLA typing information at the highest available resolution is very valuable, especially in the context of clinical trials. In addition to the vast specialist literature, there exist many excellent online sources of information about HLA typing and variety of helpful web‐based tools.11

Scrhla-Typing: A Method for Quantifying HLA Transcripts in Single Cells

BackgroundEstimation of HLA (Human leukocyte Antigen) alleles’ frequencies in populations is essential to explore their ethnic origin. Anthropologic studies of central Tunisian population were rarely reported. Then, in this work, we aimed to explore the origin of central Tunisian population using HLA alleles and haplotypes frequencies.MethodsHLA class I (A, B, C) and HLA class II (DRB1, DQA1, DQB1) loci genotyping of 272 healthy unrelated organ donors was performed by Polymerase Chain Reaction-Sequence Specific Oligonucleotide (PCR-SSO). We compared central Tunisians with other populations (Arabs, Berbers, Mediterraneans, Europeans, Africans, etc.) using alleles and haplotypes frequencies, genetic distances, Neighbour-Joining dendrogram and correspondence analysis.ResultsAmong the 19 HLA A alleles, the 26 HLA B alleles, the 13 HLA C alleles, the 15 HLA DRB1 alleles, the 6 HLA DQA1 alleles and the 5 HLA DQB1 alleles identified in the studied population, HLA A*02 (22.8%), HLA B*50 (13.1%), HLA C*06 (21.8%), HLA DRB1*07 (17.8%), HLA DQA1*01 (32.1%) and HLA DQB1*03 (31.6%) were the most frequent alleles. The extended haplotypes HLA A*02-B*50-C*06-DRB1*07-DQA1*02-DQB1*02 (1.97%) was the most frequent HLA six-loci haplotype.ConclusionCentral Tunisians were very close to other Tunisian populations, to Iberians and North Africans. They were rather distant from sub-Saharan populations and eastern Mediterraneans especially Arabs although the strong cultural and religious impact of Arabs in this population.