Human Leukocyte Antigen Haplotypes Research Articles

Phenomic landscape and pharmacogenomic implications for HLA region in a Taiwan Han Chinese population

BackgroundThe human leukocyte antigen (HLA) genes, exhibiting significant genetic diversity, are associated with susceptibility to various clinical diseases and diverse in drug responses. High costs of HLA sequencing and the population-specific architecture of this genetic region necessitate the establishment of a population-specific HLA imputation reference panel. Moreover, there is a lack of understanding about the genetic and phenotypic landscape of HLA variations within the Taiwanese population.MethodsWe created models for a Taiwanese-specific HLA imputation reference panel. These models were trained with the array genotype data and HLA sequencing data from 845 Taiwanese subjects. HLA imputation was applied for 59,448 Taiwanese subjects to characterize the HLA allele and haplotype frequencies. Additionally, a phenome-wide association study (PheWAS) was conducted to identify the phenotypes associated with HLA variations. The association of the biallelic HLA variants with the binary and quantitative traits were evaluated with additive logistic and linear regression models, respectively. Furthermore, an omnibus test with likelihood-ratio test was applied for each HLA amino acid position in the multiallelic HLA amino acid polymorphisms to compare the difference between a fitted model and a null model following a χ2 distribution of n-1 degree of freedom at a position with n residues. Finally, we estimated the prevalence of adverse drug reactions (ADR)-related HLA alleles in the Taiwanese population.ResultsIn this study, the reference panel models displayed remarkable accuracy, with averages of 99.3%, 98.9%, and 99.1% for 2-, 4-, 6-digit alleles of the eight classical HLA genes, respectively. For PheWAS, a total of 18,136 significant associations with HLA variants across 26 phenotypes are identified (p < 5×10-8), highlighting the pleiotropy feature of the HLA region. Among the independent signals, 15 are novel, including the association of HLA-B pos 138 variation with ankylosing spondylitis (AS), and rs9266290 and rs9266292 with allergy. Through an analysis spanning the entire HLA region, we identified clusters of phenotype correlations. Finally, the carriers of pharmacogenomic related HLA alleles, including HLA-C*01:02 (35.86%), HLA-B*58:01 (20.9%), and HLA-B*15:02 (8.38%), were characterized in the Taiwanese general population.ConclusionsWe successfully delivered the HLA imputation for 59,448 Taiwanese subjects and characterized the genetic and phenotypic landscapes of the HLA variations. In addition, we quantified the estimated prevalence of the ADR-related HLA alleles in the Taiwanese population. The developed HLA imputation reference panel could be used for estimation of population HLA allele frequencies, which can facilitate further studies in the role of HLA variants in a wider range of phenotypes in the population.

Multiple polygenic risk scores can improve the prediction of systemic lupus erythematosus in Taiwan

ObjectiveTo identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE.MethodsThe study enrolled 2429 patients with...

The influence of HLA allele and haplotype on RhE alloimmunization among pregnant females in the Chinese Han population.

Anti-E alloantibody is the most common and important red blood cell(RBC) alloantibody during pregnancy. The study aimed to determine the correlation between RhE alloimmunization and human leukocyte antigen (HLA)allele polymorphism, as well as haplotype diversity, among pregnant individuals in the Chinese Han population. All individuals included in our study were RhE-negative pregnant women of Chinese Han ethnicity, confirmed through serological testing. Pregnancy could be the only potential stimulating factor in RBC alloimmunization. Given the serological testing, the participants were divided into anti-E (responders) and non-anti-E-producing group (non-responders). The class I and II classical HLA genotyping were determined using next-generation sequencing, and the HLA genotype and haplotype frequencies were compared between the responders and non-responders. In total, 76 responders and 94 non-responders were enrolled in this study. Comparison results showed that all HLA class I alleles had no difference between the two groups. For HLA class II phenotypes, responders had higher frequencies of HLA-DRB1*09:01, HLA-DQA1*03:02 and HLA-DQB1*03:03 phenotypes than non-responders, and the differences were statistically significant (pc < 0.05). In addition, the haplotype frequency of HLA-DRB1*09:01-DQA1*03:02-DQB1*03:03 in the RhE responders was significantly higher than in the non-responders (31.58% vs. 12.77%; odds ratio, 3.154; 95% confidence interval, 1.823-5.456; pc value, 1.25 × 10-3). Our findings indicated that HLA-DRB1*09:01, HLA-DQA1*03:02 and HLA-DQB1*03:03 might be susceptible alleles for RhE alloimmunization among Chinese Han pregnant females. These three susceptible alleles constituted the unique three-locus haplotype in the RhE responders and collaborated to RhE alloimmunization.

Establishment and validation of prediction models for human leukocyte antigen haplotypes and human leukocyte antigen genotypes

Objective: To establish prediction models for human leukocyte antigen (HLA) haplotypes and HLA genotypes, and verify the prediction accuracy. Methods: The prediction models were established based on the characteristic of HLA haplotype inheritance and linkage disequilibrium (LD), as well as the invention patents and software copyrights obtained. The models include algorithm and reference databases such as HLA A-C-B-DRB1-DQB1 high-resolution haplotypes database, B-C and DRB1-DQB1 LD database, G group alleles table, and NMDP Code alleles table. The prediction algorithm involves data processing, comparison with reference data, filtering results, probability calculation and ranking, confidence degree estimation, and output of prediction results. The accuracy of the predictions was verified by comparing them with the correct results, and the relationship between prediction accuracy and the probability distribution and confidence degree of the predicted results was analyzed. Results: The HLA haplotypes and genotypes prediction models were established. The prediction algorithm included the prediction of A-C-B-DRB1-DQB1 haplotypes according to HLA-A, B, DRB1, C, DQB1 genotypes, the prediction of C and DQB1 high-resolution results according to A, B and DRB1 high-resolution results, and the prediction of A, B, DRB1, C and DQB1 high resolution results according to the A, B and DRB1 intermediate or low resolution results. Validation results of "Predicting A-C-B-DRB1-DQB1 haplotypes basing on HLA-A, B, DRB1, C, DQB1 genotypes" model: for 787 data, the accuracy was 94.0% (740/787) with 740 correct predictions, 34 incorrect predictions, and 13 instances with no predicted results. For 847 data, the accuracy was 100% (847/847). The 2 411 and 2 594 haplotype combinations predicted from 787 and 847 data were grouped according to confidence degree, the accuracy was 100% (48/48, 114/114) for a confidence degree of 1, 96.2% (303/315) and 97.8% (409/418) for a confidence degree of 2 respectively. Validation results of "Predicting A, B, DRB1 and C, DQB1 high-resolution genotypes basing on HLA-A, B, DRB1 high, intermediate, or low resolution genotypes" model: when predicting C and DQB1 high resolution genotypes basing on A, B, and DRB1 high resolution genotypes, 89.3% (1 459/1 634) of the predictions were correct. The accuracy for the top 2 predicted probability (GPP) ranking was 79.2% (1 156/1 459), and for the top 10, it was 95.0% (1 386/1 459). Furthermore, when GPP≥90% and GPP 50%-90%, the prediction accuracy was 81.3% (209/257) and 72.8% (447/614) respectively. The accuracy of predicting C and DQB1 high resolution genotypes basing on the results of A, B, and DRB1 high resolution genotypes from the China Marrow Donor Program was 87.0% (20/23). The accuracy of predicting A, B, DRB1, C, and DQB1 high resolution genotypes basing on the results of A, B, and DRB1 intermediate or low-resolution genotypes was 70.0% (7/10) and 52.5% (21/40) respectively. When predicting whether the patient is likely to have a HLA 10/10 matched donor, the accuracy of the top 2 GPP combinations with a proportion of ≥50% was 85.7% (6/7). Conclusions: When using A, B, DRB1, C, DQB1 genotypes to predict A-C-B-DRB1-DQB1 haplotype combinations, the results with a confidence degree of 1 and 2 are reliable. When predicting C and DQB1 genotypes according to A, B and DRB1 genotypes, the top 10 results ranked by GPP are reliable, and the top 2 results with GPP≥50% are more reliable.

Genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes.

We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications. The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01 , and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size. Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.

Frequency distribution of HLA class I and II alleles in Greek population and their significance in orchestrating the National Donor Registry Program.

Human leukocyte antigens (HLA) represent one of the most polymorphic systems in humans, responsible for the identification of foreign antigens and the presentation of immune responses. Therefore, HLA is considered to play a major role in human disorders, donor-recipient matching and transplantation outcomes. This study aimed to determine the HLA class I and II alleles and haplotypes in the Greek population. Moreover, a comparative analysis of HLA alleles and haplotype frequencies found in Greek and pooled European populations was also performed to acquire a better knowledge about the HLA alleles distribution. A total number of 1896 healthy individuals were typed for their HLA alleles in the National Tissue Typing Center of Greece. High-resolution HLA typing for the HLA-A, -B, -C and -DR, -DQ, -DP with the use of the next-generation sequencing analysis was performed, followed by data analysis for establishing the HLA allele and haplotype differences. The results of this study showed that the most frequent alleles for the HLA-A were the A*02:01:01 (27.1%), *24:02:01 (14.4%), *01:01:01 (9.3%), for the HLA-B were the B*51:01:01 (15.3%), *18:01:01 (9.7%), *35:01:01 (6.8%) and for the HLA-C were the C*04:01:01 (15.4%), *07:01:01 (13.1%), *12:03:01 (9.6%). For the HLA class II, the most frequent alleles for the HLA-DRB1 were the DRB1*11:04:01 (16.4%), *16:01:01 (11.3%), *11:01:01 (9.5%), for the HLA-DQB1 were the DQB1*03:01:01 (30.5%), *05:02:01 (15.1%), *05:01:01 (10.6%) and for the HLA-DPB1 were the DPB1*04:01:01 (34.8%), *02:01:01 (11.6%), *04:02:01 (7.3%). Additionally, the most frequent haplotypes were the A*02:01:01∼C*07:01:01-B*18:01:01∼DRB1*11:04:01 (2.3%), followed by the A*01:01:01∼C*07:01:01∼B*08:01:01∼DRB1*03:01:01 (2.2%), A*24:02:01∼C*04:01:01∼B*35:02:01∼DRB1*11:04:01 (1.4%) and A*02:01:01∼C*04:01:01∼B*35:01:01-DRB1*14:01:01 (1.2%). The results herein were comparable to those obtained from the pooled European populations. Moreover, these results can be used for the improvement of the donor-recipient matching procedure and to understand better the disease association in Greece.

Inclusion Body Myositis in Children: Does it Exist?

Context: Sporadic inclusion body myositis (sIBM) is a rare type of juvenile idiopathic inflammatory myopathies (JIIMs). It mainly affects skeletal muscles but can also affect the skin and other organs in the body. Sporadic inclusion body myositis prevalence in children under 18 years old is very rare. Objectives: This review provides an overview of the evidence of sIBM in children, discusses the possible clinical and pathological features, and explores the proposed pathogenesis. Methods: A literature review of over 44 articles in PubMed and other medical libraries, such as Google Scholar and Web of Science, was carried out using terms such as JIIM, IBM, Inflammatory Myopathies in Children, and Inherited IBM. Two documented reports for sIBM were found, and the rest included the disease pathogenesis, prevalence of inherited IBM, and other myopathies in children. Results: This review discussed the prevalence and incidence of JIIM, in particular sIBM in children. While IBM is typically sporadic, there have been rare cases where it is familial and inherited. Genetic susceptibility factors are believed to play a role in sIBM. Most patients with sIBM are over 50 years old and experience significant weakness in the quadriceps; however, patients with inherited IBM (h-IBM) typically present earlier in adulthood with a distinct pattern of weakness. Sporadic inclusion body myositis can be misdiagnosed as other forms of myopathies, such as juvenile dermatomyositis (JDM) or limb-girdle muscular dystrophy (LGMD), during the early stages of the disease. The exact causes of sIBM are still unknown; however, environmental factors, genetic predispositions, and immune dysregulation might contribute to the pathogenesis of the disease. Conclusions: Sporadic inclusion body myositis is a rare form of JIIMs. Its early diagnosis in children can be challenging due to the presence of other coexisting diseases. Discussions have revolved around potential environmental factors, such as viral infections, specific myositis-specific antibodies (MSAs), such as anti-Ro52, and possibly certain human leukocyte antigen (HLA) haplotypes. Given the rarity of reported cases of sIBM in children, it is important to encourage further studies to better understand the underdiagnosed instances of this condition.

Development and characterization of a cell donor registry for virus-specific T cell manufacture in a blood bank.

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.

Contribution of HLA class I (A, B, C) and HLA class II (DRB1, DQA1, DQB1) alleles and haplotypes in exploring ethnic origin of central Tunisians

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.

T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery.

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility.

Utilizing Massively Parallel Sequencing (MPS) of Human Leukocyte Antigen (HLA) Gene Polymorphism to Assess Relatedness in Deficiency Parentage Testing.

In the realm of DNA testing with legal implications, the reliability and precision of genetic markers play a pivotal role in confirming or negating paternity claims. This study aimed to assess the potential utility of human leukocyte antigen (HLA) gene polymorphism through massively parallel sequencing (MPS) technology as robust forensic markers for parentage testing involving genetic deficiencies. It sought to redefine the significance of HLA genes in this context. Data on autosomal short tandem repeat (aSTR) mutational events across 18 paternity cases involving 16 commonly employed microsatellite loci were presented. In instances where traditional aSTR analysis failed to establish statistical certainty, kinship determination was pursued via HLA genotyping, encompassing the amplification of 17 linked HLA loci. Within the framework of this investigation, phase-resolved genotypes for HLA genes were meticulously generated, resulting in the definition of 34 inherited HLA haplotypes. An impressive total of 274 unique HLA alleles, which were classified at either the field 3 or 4 level, were identified, including the discovery of four novel HLA alleles. Likelihood ratio (LR) values, which indicated the likelihood of the observed data under a true biological relationship versus no relationship, were subsequently calculated. The analysis of the LR values demonstrated that the HLA genes significantly enhanced kinship determination compared with the aSTR analysis. Combining LR values from aSTR markers and HLA loci yielded conclusive outcomes in duo paternity cases, showcasing the potential of HLA genes and MPS technology for deeper insights and diversity in genetic testing. Comprehensive reference databases and high-resolution HLA typing across diverse populations are essential. Reintegrating HLA alleles into forensic identification complements existing markers, creating a potent method for future forensic analysis.

Clinical‐grade hPSC‐derived RPE grafts for the treatment of age‐related macular degeneration

Aims/Purpose: Age‐related Macular Degeneration (AMD), a prevalent global cause of vision loss in the elderly, necessitates the development of efficacious treatments. Existing therapies do not cure AMD due to its complexity and the irreversible loss of photoreceptors and Retinal Pigment Epithelium (RPE). Cell replacement therapies targeting faulty RPE cells offer potential for slowing AMD progression, but the immunocompatibility of such therapies is challenging. We aim to develop a cell therapy strategy to minimize immune rejection.Methods: Our strategy entailed establishing a Good Manufacturing Practice (GMP)‐compatible induced Pluripotent Stem Cell (iPSC) cell bank representing the most frequent homozygous human leukocyte antigen (HLA) haplotypes in the Andalusian population, facilitating derivation of immunocompatible RPE cells. We utilized and refined existing RPE differentiation protocols for generating clinically compliant RPE cells. Furthermore, we tested three bioscaffolds for RPE growth and maturation and compared the physical properties of the resulting RPE cell‐bioscaffold biopatch for transplantability.Results: We successfully established three GMP‐compatible iPSC lines featuring common homozygous HLA profiles. Through our refined differentiation protocols, these iPSCs were converted into functional, high‐purity and safe RPE cells. Comparative analysis of different bioscaffolds revealed variable capabilities for RPE growth, maturation and transplantability, thereby informing the final bioscaffold selection for RPE biopatch generation.Conclusions: Our study underscores the feasibility of generating clinical‐grade, immunocompatible iPSC‐derived RPE grafts using GMP‐compliant procedures for AMD treatment. This innovative approach addresses a critical unmet medical need and suggests potential for similar strategies in other cell replacement therapies. The selection of an optimal bioscaffold for RPE growth and maturation is critical for effective RPE biopatch development. Further pre‐clinical and clinical studies are required to evaluate the safety and efficacy of these RPE grafts in AMD treatment.

Association of human leukocyte antigen (HLA) footprints with the comorbidity of latent autoimmune diabetes in adults (LADA) and hepatitis C virus (HCV) infection: A multicenter cross-sectional study

AimsThis study aims to investigate the interplay between hepatitis C virus (HCV) infection and major forms of diabetes: type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA). MethodsThis multicenter study analyzed a cohort of 2699 diabetic and 7344 non-diabetic subjects who visited medical centers in China from 2014 to 2021. T1D, T2D, LADA, and HCV were diagnosed using standard procedures. High-throughput sequencing was conducted to identify genetic footprints of human leukocyte antigen (HLA) alleles and haplotypes at the DRB1, DQA1, and DQB1 loci. ResultsHCV infection was detected in 3 % (23/766) of LADA patients, followed by 1.5 % (15/977) of T2D patients, 1.4 % (13/926) of T1D patients, and 0.5 % (38/7344) of non-diabetic individuals. HCV prevalence was significantly higher in people with diabetes than in non-diabetic individuals (p < 0.01). HLA alleles (DQB1*060101, DQB1*040101) and haplotypes (DRB1*080302-DQA1*010301-DQB1*060101) in LADA patients with HCV revealed higher frequencies than in LADA patients without HCV (adjusted p < 0.03). Furthermore, a higher risk of diabetes complications was found among LADA patients with HCV infection (p < 0.001). ConclusionsLADA patients are susceptible to HCV infection, potentially associated with certain HLA alleles/haplotypes. Early diagnosis and treatment of HCV infection among people with diabetes are important for the management of severe complications.

Increased risk of persistent neuropathic pain after traumatic nerve injury and surgery for carriers of a human leukocyte antigen haplotype.

It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

Outcome differences in HPV-driven head and neck squamous cell carcinoma attributable to altered human leukocyte antigen frequencies.

Effective immune surveillance requires a functioning immune system and natural killer (NK) and T cells for adequate innate and antigen-specific immune responses critically depending on human leukocyte antigens (HLAs) and haplotypes representing advantageous combinations of HLA antigens. Recently, we reported a link between altered frequencies of HLA alleles and haplotypes and developing head and neck squamous cell carcinoma (HNSCC). Whereas the majority of HNSCCs seem to be related to classical risk factors alcohol and tobacco, a subset of HNSCC and especially oropharyngeal squamous cell carcinoma (OPSCC) were etiologically linked to human papillomavirus (HPV) recently. Here, we demonstrate in HPV-driven (p16-positive high risk-HPV DNA-positive) HNSCC a deviating distribution of HLA antigens and haplotypes and their relevance to outcome. Leukocyte DNA of n = 94 HPV-driven HNSCC patients (n = 57 OPSCC, n = 37 outside oropharynx) underwent HLA SSO typing, allowing allele, antigen (allele group), and haplo-typing. Besides comparing these frequencies with those of German blood donors, we analyzed their impact on outcome using Kaplan-Meier plots and Cox proportional hazard regression. Antigen and haplotype frequencies demonstrate enrichment of rare antigens and haplotypes. The HLA score for unselected HNSCC patients was not predictive for outcome here. However, together with alcohol consumption, tobacco smoking, T category, and extranodal extension of locoregional metastases and treatment applied, eight HLA traits allow for predicting progression-free and tumor-specific survival. Patients can be categorized into low, intermediate-low, intermediate-high, and high risk groups. Using a new PFS risk score for HPV-driven HNSCC may allow to improve prognostication.

Honduras HIV cohort: HLA class I and CCR5-Δ32 profiles and their associations with HIV disease outcome.

We identify both canonical and novel human leukocyte antigen (HLA)-HIV associations, providing a first step toward improved understanding of HIV immune control among the understudied Honduras Mestizo population. Our results are relevant to understanding the protective or detrimental effects of HLA subtypes in Latin America because their unique HLA diversity poses challenges for designing vaccines against HIV and interpreting results from such vaccine trials. Likewise, the description of the HLA profile in an understudied population that shows a unique HLA immunogenetic background is not only relevant for HIV immunology but also relevant in population genetics, molecular anthropology, susceptibility to other infections, autoimmune diseases, and allograft transplantation.

Human leukocyte antigen-DQ risk heterodimeric haplotypes of left ventricular dysfunction in cardiac sarcoidosis: an autoimmune view of its role

Cardiac sarcoidosis (CS) is the scarring of heart muscles by autoimmunity, leading to heart abnormalities and patients with sarcoidosis with cardiac involvements have poor prognoses. Due to the small number of patients, it is difficult to stratify all patients of CS by human leukocyte antigen (HLA) analysis. We focused on the structure of antigen-recognizing pockets in heterodimeric HLA-class II, in addition to DNA sequences, and extracted high-affinity combinations of antigenic epitopes from candidate autoantigen proteins and HLA. Four HLA heterodimer-haplotypes (DQA1*05:03/05:05/05:06/05:08-DQB1*03:01) were identified in 10 of 68 cases. Nine of the 10 patients had low left ventricular ejection fraction (< 50%). Fourteen amino-acid sequences constituting four HLA anchor pockets encoded by the HLA haplotypes were all common, suggesting DQA1*05:0X-DQB1*03:01 exhibit one group of heterodimeric haplotypes. The heterodimeric haplotypes recognized eight epitopes from different proteins. Assuming that autoimmune mechanisms might be activated by molecular mimicry, we searched for bacterial species having peptide sequences homologous to the eight epitopes. Within the peptide epitopes form the SLC25A4 and DSG2, high-homology sequences were found in Cutibacterium acnes and Mycobacterium tuberculosis, respectively. In this study, we detected the risk heterodimeric haplotypes of ventricular dysfunction in CS by searching for high-affinity HLA-class II and antigenic epitopes from candidate cardiac proteins.

Immune-mediated cholangiopathies in children: the need to better understand the pathophysiology for finding the future possible treatment targets.

Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.

Creating an HLA-homozygous iPS cell bank for the Brazilian population: Challenges and opportunities.

Identifying human leukocyte antigen (HLA) haplotype-homozygous donors for the generation of induced pluripotent stem (iPS) cell lines permits the construction of biobanks immunologically compatible with significant numbers of individuals for use in therapy. However, two questions must be addressed to create such a bank: how many cell lines are necessary to match most of the recipient population and how many people should be tested to find these donors? In Japan and the UK, 50 and 100 distinct HLA-A, -B, and -DRB1 triple-homozygous haplotypes would cover 90% of those populations, respectively. Using data from the Brazilian National Registry of Bone Marrow Donors (REDOME), encompassing 4,017,239 individuals, we identified 1,906 distinct triple-homozygous HLA haplotypes. In Brazil, 559 triple-homozygous cell lines cover 95% of the population, and 3.8 million people would have to be screened. Finally, we show the contribution of the 30 most frequent triple-homozygous HLA haplotypes in Brazil to populations of different countries.

Important denominator between autoimmune comorbidities: a review of class II HLA, autoimmune disease, and the gut.

Human leukocyte antigen (HLA) genes are associated with more diseases than any other region of the genome. Highly polymorphic HLA genes produce variable haplotypes that are specifically correlated with pathogenically different autoimmunities. Despite differing etiologies, however, many autoimmune disorders share the same risk-associated HLA haplotypes often resulting in comorbidity. This shared risk remains an unanswered question in the field. Yet, several groups have revealed links between gut microbial community composition and autoimmune diseases. Autoimmunity is frequently associated with dysbiosis, resulting in loss of barrier function and permeability of tight junctions, which increases HLA class II expression levels and thus further influences the composition of the gut microbiome. However, autoimmune-risk-associated HLA haplotypes are connected to gut dysbiosis long before autoimmunity even begins. This review evaluates current research on the HLA-microbiome-autoimmunity triplex and proposes that pre-autoimmune bacterial dysbiosis in the gut is an important determinant between autoimmune comorbidities with systemic inflammation as a common denominator.