Leukocyte Antigen System Research Articles

Anti-Human Leukocyte Antigen Antibody Detection from Terasaki’s Humoral Theory to Delisting Strategies in 2024

The human leukocyte antigen (HLA) system plays a critical role in transplant immunology, influencing outcomes through various immune-mediated rejection mechanisms. Hyperacute rejection is driven by preformed donor-specific antibodies (DSAs) targeting HLAs, leading to complement activation and graft loss within hours to days. Acute rejection typically occurs within six months post-transplantation, involving cellular and humoral responses, including the formation of de novo DSAs. Chronic rejection, a key factor in long-term graft failure, often involves class II DSAs and complex interactions between the innate and adaptive immune systems. Advancements in HLA antibody detection, particularly single antigen bead (SAB) assays, have improved the sensitivity and characterization of DSAs. However, these assays face challenges like false positives from denatured antigens and false negatives due to low antibody titers or complement competition. Furthermore, molecular mismatch (MM) analysis has emerged as a potential tool for refining donor–recipient compatibility but faces some issues such as a lack of standardization. Highly sensitized patients with calculated panel-reactive antibodies (cPRA) of 100% face barriers to transplantation. Strategies like serum dilution, novel therapies (e.g., Imlifidase), and delisting approaches could refine immunological risk assessment and delisting strategies are essential to expand transplant opportunities for these patients.

CAR natural killer cell therapy: Natural killer cell activation and expansion

Currently, chimeric antigen receptor (CAR) T-cell therapy is an effective treatment method of hematological malignancies. However, T-lymphocyte-based immunotherapy has certain limitations for the scope of application of this approach. A promising alternative is CAR therapy based on natural killer (NK) cells, since it does not require detailed donor selection according to the human leukocyte antigen system; NK cells have a unique mechanism for recognizing and destroying tumor cells. In addition, NK cells do not cause severe toxic reactions when infused. The creation of a CAR NK product is a complex task includes cell culturing, using genetic engineering methods, and quality control testing of the resulting biomedical cell product (BMCP). For proliferation and effector function enhancement, NK cells require the presence of interleukins, feeder cells or their components, and immune system activators in the nutrient medium. This review focuses on various approaches to the activation and expansion of natural killer cells during cultivation, and also addresses the issues of the advantages and disadvantages of the chosen therapy and the regulatory aspects of creating a full-fledged BMCP.

New Associations with the HIV Predisposing and Protective Alleles of the Human Leukocyte Antigen System in a Peruvian Population.

The accurate determination of an individual's unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to either increased protection or susceptibility in the context of infectious and autoimmune diseases. This study aimed to determine the frequency and association of HLA alleles between people living with HIV (PLHIV) as the case group and Peruvian individuals without HIV with high-risk behaviors of sexually transmitted diseases as the control group. Whole exome sequencing (WES) was used to determine high-resolution HLA allelotypes using the OptiType and arcas HLA tools. The HLA alleles present in HLA classes I (A, B, and C loci) and II (DPB1, DQA1, DQB1, and DRB1 loci) were determined in a cohort of 59 PLHIV (cases) and 44 individuals without HIV (controls). The most frequent HLA alleles were A*02:01, DPB1*04:02, and DQB1*03:419 at 36%, 30%, and 28% prevalence in general population. We found that C*07:01 (p = 0.0101; OR = 10.222, 95% IC: 1.40-74.55), DQA1*03:02 (p = 0.0051; OR = 5.297, 95% IC: 1.48-19.02), and DRB1*09:01 (p = 0.0119; OR = 4.788, 95% IC: 1.39-16.44) showed an association with susceptibility to HIV infection, while DQB1*03:419 (p = 0.0478; OR = 0.327, 95% IC: 0.11-0.96) was associated with protection from HIV infection. Our findings contribute to the knowledge of HLA allele diversity in the Peruvian population (around 70% South American indigenous ancestry) lays the groundwork for further valuable large-scale use of HLA typing and offers a novel association with HIV infection that is relevant to vaccine studies.

Targeting CD3-CD16+CD56+ NK Cells and NK Cell Activity by Intralipid in the Management of Reproductive Failure

Immunological risk factors in recurrent pregnancy loss include autoantibodies, alterations in NK cell number and function, regulatory T cells, the human leukocyte antigen system (HLA), etc., where the treatment options aim to regulate immune dysfunction. Intralipid is a synthetic product traditionally used as a dietary supplement consisting of soybean oil combined with refined egg phospholipids. It has been shown that intralipid exerts physiologic activities, including altering immunological functions, that may benefit patients with certain types of infertility. In this review, we summarize the current state of the art of targeting NK cells and NK cell activity in women with implantation failure or/and recurrent pregnancy loss. We focus on intralipid mechanisms of action and outcomes of clinical trials regarding the efficacy and safety of intralipid infusions in women with reproductive failure. More studies are needed to reveal all the aspects of the safety and effectiveness of intralipid administration in reproductive failure treatment.

The Immune Modulation HLA-G*01:01:01 Full Allele Is Associated with Gastric Adenocarcinoma Development.

The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles' extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease.

HLA-C Peptide Repertoires as Predictors of Clinical Response during Early SARS-CoV-2 Infection.

The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation.

Variation within the non-coding genome influences genetic and epigenetic regulation of the human leukocyte antigen genes.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

Generation of integration-free human induced pluripotent stem cell line MURAi003-A derived from the peripheral blood mononuclear cells of a donor with homozygous Class I and Class II HLAs (A*11:01, B*46:01; C*01:02; DRB1*09:01; DQB1*03:03)

The human leukocyte antigen (HLA) system comprises cell-surface proteins responsible for the presentation of peptide antigens. HLAs play an essential role in the regulation of the human immune system, and their studies have been crucial to its understanding. To create a sustainable model for the investigation of HLAs, we successfully generated the human iPSC line MURAi003-A derived from the peripheral blood mononuclear cells of a donor with homozygous Class I and Class II HLAs (A*11:01, B*46:01; C*01:02; DRB1*09:01; DQB1*03:03) using non-integrative reprogramming episomes. MURAi003-A exhibited pluripotent stem cell characteristics with consistent demonstrations of pluripotency and expression of stem cell-associated markers.

Environmental and Genetic Determinants of Ankylosing Spondylitis.

Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors.

Global insights into keloid formation: An international systematic review of regional genetic risk factors and commonalities.

Keloid disorder is a morbid and disfiguring benign fibroproliferative disease with a higher incidence in groups with darker skin pigmentation. Predicting keloidogenesis in patients is difficult with treatment primarily aimed at preventing further scar expansion and improving aesthetics without addressing their unknown underlying pathophysiology. We aimed to identify potential genetic predispositions to keloid scarring in the literature. A search was conducted on 21 August 2023, by the first and second authors independently from 1985 to August 2023 using PubMed, MEDLINE, Embase, Web of Science, Scopus and CINAHL. The following MeSH terms were used: 'Keloid', 'Risk' and 'Genetic'. Two researchers independently searched for studies based on titles and abstracts and screened filtered articles by reviewing full text. If no agreement could be reached, a third senior author designated whether the article should be included. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement as the basis of our organisation. Human studies with genetic analysis to determine an association of a protein or gene to keloidogenesis were selected for inclusion. Studies in languages other than English, reviews, conference articles, and book chapters were excluded. Fifty studies met inclusion criteria. The human leukocyte antigen (HLA) system was broadly implicated, and the DRB1*15 allele was associated with an increased risk of keloid in three separate ethnic groups. Some HLA Class I alleles were associated with keloid in one population but not in others. Additionally, polymorphisms in the E3 ubiquitin-protein ligase (NEDD4) signal cascade and vitamin D receptor (VDR) have been implicated in diverse groups. No current genetic test can predict keloid risk. Our review identified candidate predisposing genes, including NEDD4, VDR and components of the HLA system. Further studies in heterogeneous populations are needed to identify reliable screening targets.

The Future of TCR-like Antibodies in Diagnosis and Potential Application Targets.

The human leukocyte antigen (HLA, also known as the major histocompatibility complex or MHC) system, is responsible for immune monitoring of the intracellular proteome of all nucleated cells. The presentation of antigen peptides separates malignant or infected cells from their healthy counterparts and forms aberrant cells tagged as the foundation for identification. Therefore, peptide-MHC molecules can give potential diagnostic targets for cancer or infection. TCR-like antibodies recognize specific peptides that bind to MHC molecules, allowing them to target Such inaccessible cytoplasmic or nuclear tumors or virus-associated antigens. It binds to MHC, presenting peptides found on the surface of target cells. These antibodies have shown promising clinical applications in diagnosing and imaging cancer and infected cells. This review presents the current situation of TCR-like antibodies and its prospects for application in the field of intracellular antigen diagnostics. It also lists the potential application targets of TCR, like antibodies in various disease diagnoses, providing valuable information for developing diagnostic reagents and selecting targets in the future.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant (β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document}-defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

Investigation of HLA susceptibility alleles and genotypes with hematological disease among Chinese Han population.

Several genes involved in the pathogenesis have been identified, with the human leukocyte antigen (HLA) system playing an essential role. However, the relationship between HLA and a cluster of hematological diseases has received little attention in China. Blood samples (n = 123913) from 43568 patients and 80345 individuals without known pathology were genotyped for HLA class I and II using sequencing-based typing. We discovered that HLA-A*11:01, B*40:01, C*01:02, DQB1*03:01, and DRB1*09:01 were prevalent in China. Furthermore, three high-frequency alleles (DQB1*03:01, DQB1*06:02, and DRB1*15:01) were found to be hazardous in malignant hematologic diseases when compared to controls. In addition, for benign hematologic disorders, 7 high-frequency risk alleles (A*01:01, B*46:01, C*01:02, DQB1*03:03, DQB1*05:02, DRB1*09:01, and DRB1*14:54) and 8 high-frequency susceptible genotypes (A*11:01-A*11:01, B*46:01-B*58:01, B*46:01-B*46:01, C*01:02-C*03:04, DQB1*03:01-DQB1*05:02, DQB1*03:03-DQB1*06:01, DRB1*09:01-DRB1*15:01, and DRB1*14:54-DRB1*15:01) were observed. To summarize, our findings indicate the association between HLA alleles/genotypes and a variety of hematological disorders, which is critical for disease surveillance.

Torben Fog – A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Association of Human Leukocyte Antigens (HLA) with Keloids and Hypertrophic Scar in Thais

Background: Keloids and hypertrophic scars are abnormal fibro-proliferative lesions. Associations between genes, the human leukocyte antigen (HLA) system in particular, and keloids have been studied in various ethnic groups but not in Thais. Objective: To investigate the association of HLA alleles with keloids and hypertrophic scars in Thais. Materials and Methods: The present study employed a retrospective case-control design. Scar assessment was performed on 139 kidney donors who underwent nephrectomy at Ramathibodi Hospital between January 2008 and December 2015. The wound scars after nephrectomy were evaluated and graded by a plastic surgeon using the modified Vancouver Scar Scale. Kidney donors who were unable to communicate well or who had autoimmune diseases or complications from surgery were excluded from the study. The diagnosis of a keloid scar, hypertrophic scar, and flat scar was made by clinical criteria. The donors were categorized into groups with three scar types, flat as the control group, hypertrophic, and keloid. The associations between the frequencies of HLA antigen with hypertrophic scar and keloids were measured with an odds ratio using logistic regression analysis. Results: Of the 139 living kidney donors, 15 (10.8%) had keloids, 46 (33.1%) had hypertrophic scars, and 78 (56.1%) had flat scars. Sixty-one HLA-A, -B, -DRB1, and -DQB1 alleles were evaluated in the present study. Compared with controls, the allele frequency of HLA-DRB1*15 was significantly higher in the keloid group at 43.33% versus 24.36% (odds ratio 2.37, 95% confidence interval 1.06 to 5.33, p=0.036). No significant association between HLA alleles and hypertrophic scars was found. Conclusion: The present study demonstrated the positive association of HLA-DRB1*15 with keloids in Thai individuals. The HLA-DRB1*15 could be a susceptibility factor for the development of keloids. Keywords: Human leukocyte antigen; Keloids; Thais, HLA-DRB1; Positive association

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers.

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.

HLA-EpiCheck: novel approach for HLA B-cell epitope prediction using 3D-surface patch descriptors derived from molecular dynamic simulations.

The human leukocyte antigen (HLA) system is the main cause of organ transplant loss through the recognition of HLAs present on the graft by donor-specific antibodies raised by the recipient. It is therefore of key importance to identify all potentially immunogenic B-cell epitopes on HLAs in order to refine organ allocation. Such HLAs epitopes are currently characterized by the presence of polymorphic residues called "eplets". However, many polymorphic positions in HLAs sequences are not yet experimentally confirmed as eplets associated with a HLA epitope. Moreover, structural studies of these epitopes only consider 3D static structures. We present here a machine-learning approach for predicting HLA epitopes, based on 3D-surface patches and molecular dynamics simulations. A collection of 3D-surface patches labeled as Epitope (2117) or Nonepitope (4769) according to Human Leukocyte Antigen Eplet Registry information was derived from 207 HLAs (61 solved and 146 predicted structures). Descriptors derived from static and dynamic patch properties were computed and three tree-based models were trained on a reduced non-redundant dataset. HLA-Epicheck is the prediction system formed by the three models. It leverages dynamic descriptors of 3D-surface patches for more than half of its prediction performance. Epitope predictions on unconfirmed eplets (absent from the initial dataset) are compared with experimental results and notable consistency is found. Structural data and MD trajectories are deposited as open data under doi: 10.57745/GXZHH8. In-house scripts and machine-learning models for HLA-EpiCheck are available from https://gitlab.inria.fr/capsid.public_codes/hla-epicheck.

The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer's disease in APOE [Formula: see text]4-negative Japanese adults.

Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia among those older than 65 years. The onset of LOAD is influenced by neuroinflammation. The human leukocyte antigen (HLA) system is involved in regulating inflammatory responses. Numerous HLA alleles and their haplotypes have shown varying associations with LOAD in diverse populations, yet their impact on the Japanese population remains to be elucidated. Here, we conducted a comprehensive investigation into the associations between LOAD and HLA alleles within the Japanese population. Using whole-genome sequencing (WGS) data from 303 LOAD patients and 1717 cognitively normal (CN) controls, we identified four-digit HLA class I alleles (A, B, and C) and class II alleles (DRB1, DQB1, and DPB1). We found a significant association between the HLA-DRB1*09:01-DQB1*03:03 haplotype and LOAD risk in APOE [Formula: see text]4-negative samples (odds ratio = 1.81, 95% confidence interval = 1.38-2.38, P = 2.03[Formula: see text]). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in APOE [Formula: see text]4-negative samples (r2 = 0.88). Because HLA class II molecules interact with T-cell receptors (TCRs), we explored potential disparities in the diversities of TCR α chain (TRA) and β chain (TRB) repertoires between APOE [Formula: see text]4-negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in APOE [Formula: see text]4-negative samples, irrespective of the HLA DRB1*09:01-DQB1*03:03 haplotype. Our study enhances the understanding of the etiology of LOAD in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

Allele Frequency Net Database.

The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the website contains data from 1784 population samples in more than 14 million individuals from 129 countries on the frequency of genes from different polymorphic regions including data for the human leukocyte antigen (HLA) system. In addition, over the last four years, AFND has also incorporated genotype raw data from 85,000 individuals comprising 215 population samples from 39 countries. Moreover, more population data sets containing next generation sequencing data spanning >3 million individuals have been added. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, epitope prediction algorithms for population coverage in vaccine development, population genetics, among many others. In this chapter, we present an update of the most used searching mechanisms as described in a previous volume and some of the latest developments included in AFND.

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.