Detection of Five Novel and Confirmation of Two HLA Class II Alleles.
Seven HLA class II alleles were detected and confirmed.
Humans↗
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Results for “HLA class II”
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A Novel HLA Class II Allele, HLA-DQB1*06:483.
The HLA-DQB1*06:483 allele differs from HLA-DQB1*06:10 by a single nucleotide substitution in exon 3.
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Characterisation of Eight Novel HLA Class II Alleles Identified in Volunteer Bone Marrow Donors.
Identification of eight novel HLA-DRB1 and HLA-DQB1 alleles by next-generation sequencing.
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Polygenic Risk Scores and HLA Class II Variants are Biomarkers of Corticosteroid Response in Childhood Nephrotic Syndrome.
INTRODUCTION: Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are currently no reliable predictors of therapy response at initial clinical presentation. METHODS: We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls. RESULTS: A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA- DRB1*07:01~DQA1*02:01~DQB1*02:02 was associated with ~4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%. CONCLUSIONS: Our findings confirm that SSNS (unlike SRNS) is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers and provide a foundation for more accurate diagnoses and tailored and individualized treatment.
HLA haplotype↗
Novel HLA class I and II insights into the pathogenesis of systemic sclerosis-associated interstitial lung disease.
OBJECTIVES: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. METHODS: We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. RESULTS: After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. CONCLUSIONS: In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.
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Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-II with CIITA.
COVID-19, severe acute respiratory syndrome coronavirus 2, rapidly spread worldwide. Severe and critical patients are expected to rapidly deteriorate. Although several studies have attempted to uncover the mechanisms underlying COVID-19 severity, most have focused on the perturbations of single genes. However, the complex mechanism of COVID-19 involves numerous perturbed genes in a molecular network rather than a single abnormal gene. Thus, we aimed to identify COVID-19 severity-specific markers in the Japanese population using gene network analysis. In order to reveal the severity-specific molecular interplays, we developed a novel computational network biology strategy that measures dissimilarity between networks based on the comprehensive information of gene network (i.e., expression levels of genes and network structure) by using Kullback-Leibler divergence. Monte Carlo simulations demonstrated the effectiveness of our strategy for differential gene network analysis. We applied this method to publicly available whole blood RNA-seq data from the Japan coronavirus disease 2019 Task Force and identified differentially regulated molecular interplays between 368 severe and 105 non-severe samples. Our analysis suggests the gene network between HLA class II, CIITA, and CD74 as a COVID-19 severity specific molecular marker. Although the association between HLA class II and COVID-19 has been demonstrated, our data analysis revealed that the molecular interplay of HLA class II with its target and/or regulator is a crucial marker for COVID-19 severity. Our findings from computational network biology analysis suggest that suppression and activation of the molecular interplay between HLA class II, CIITA, and CD74 provide crucial clues to uncover the mechanisms of COVID-19 severity.
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CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles.
UNLABELLED: Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target lineage-specific surface antigens. However, CAR T cells show limited efficacy against myeloid neoplasms and solid tumors due to challenges in identifying suitable surface targets. In this study, we present a CAR targeting the intracellular WT1 oncoprotein, cross-presented by surface HLA class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1- and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This approach broadens CAR-targetable antigens beyond traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population. SIGNIFICANCE: Leveraging the promiscuous binding of HLA-II-peptide complexes, we developed a CAR T-cell approach targeting an intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study establishes a framework for CAR therapies against intracellular antigens, extending potential CAR T-cell applications to new cancer types and patient populations.
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Extensive Analysis of Genetic Diversity in HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB: Characterisation of 236 Novel Alleles.
HLA-DMA, -DMB, -DOA and -DOB are non-classical HLA Class II genes that play a crucial role in the selection of highly stable HLA Class II/peptide complexes on antigen-presenting cells. Although the genes were initially thought to have a limited diversity with less than 13 alleles per gene documented in the IPD-IMGT/HLA Database in 2022, recent studies suggest a potential impact of certain alleles on the outcome of hematopoietic cell transplantation. To gain a deeper understanding of allelic diversity, we sequenced HLA-DMA, -DMB, -DOA and -DOB of 1880 potential stem cell donors from Germany, Poland, Great Britain and Chile, achieving full-gene resolution. Remarkably, we identified 3968 previously undescribed sequences, including 28 distinct novel proteins. The observed allele frequencies were consistent across all studied populations with one dominating protein for each gene: HLA-DMA*01:01 (> 77%), HLA-DMB*01:01 (> 63%), HLA-DOA*01:01 (> 97%) and HLA-DOB*01:01 (> 77%). Notably, a much higher diversity was observed in full-genomic resolution. Finally, we submitted 51 distinct novel sequences for HLA-DMA, 58 for HLA-DMB, 80 for HLA-DOA and 47 for HLA-DOB to the IPD-IMGT/HLA Database. This comprehensive reference database update will not only simplify future genotyping of HLA-DMA, -DMB, -DOA and -DOB but will hopefully also enhance our understanding of the complex process of peptide selection and loading to the HLA Class II proteins.
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The identification of novel potential injury mechanisms and candidate biomarkers in renal allograft rejection by quantitative proteomics.
Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a "hub" protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.
Acute Kidney Injury↗
Maternal-Foetal HLA-DQB1 Incompatibility Is Associated With Pregnancy-Induced Hypertensive Disorders in a Genetically Isolated Population.
In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disorders. Nonetheless, maternal-foetal HLA-DQB1 mismatch seems to play a role in the aetiology of hypertensive complications during pregnancy in this population.
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Identification of the Novel HLA-DPB1*1465:01 Allele in a Spanish Bone Marrow Donor.
Characterisation of HLA-DPB1*1465:01, a novel HLA class II allele.
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HLA-DQB1*06:02 and a critical amino acid variant in protection against occult hepatitis B virus infection.
The human leukocyte antigen (HLA) system plays a critical role in determining the outcomes of hepatitis B virus (HBV) infection, yet the genetic mechanisms underlying occult HBV infection (OBI), a form marked by detectable HBV DNA in the absence of hepatitis B surface antigen, remain poorly defined. Here, we performed high-resolution HLA genotyping and amino acid-based association analysis in a Chinese population comprising 239 OBI cases and 545 healthy controls. We identified the HLA class II allele DQB1*06:02 as a protective signal against OBI, with conditional analysis confirming its independent effect. This allele is carried on the conserved haplotype DRB1*15:01~DQA1*02:01~DQB1*06:02, which was significantly underrepresented in OBI cases. Conversely, the DRB1*09:01~DQA1*03:02~DQB1*03:03 haplotype was associated with increased OBI risk. Analysis of the HLA-DQB1 amino acid residues revealed that position 119, located in an α-helix of the peptide-binding groove, drives a substantial portion of the observed association. The phenylalanine variant at this site remained strongly protective after multiple-testing correction and is encoded by DQB1*06:02. Our study thus delineates both allele and amino acid level HLA determinants of OBI susceptibility, highlighting a key structural residue that may influence antigen presentation and immune clearance of HBV. These findings provide a refined genetic framework for understanding host and virus interactions in occult HBV persistence.
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Mendelian Randomization Using a Japanese GWAS Identifies an HLA-Linked Causal Effect of Chronic Hepatitis B on Cholangiocarcinoma Risk.
BACKGROUND: Cholangiocarcinoma (CCA) is a highly malignant cancer that develops in the bile ducts. Its incidence is particularly high in East Asian populations, but the underlying genetic factors remain unclear. To investigate potential risk factors for CCA, we conducted a Mendelian randomization study to infer causality. METHODS: Using large-scale genome-wide association study data from the BioBank Japan resource, we systematically investigated the causal effects of genetic predisposition to seven conditions, chronic hepatitis B (CHB), chronic hepatitis C, autoimmune hepatitis, type 1 diabetes, type 2 diabetes, chronic gastritis, and chronic pancreatitis, on CCA risk. RESULTS: Our analysis reveals a significant association between genetic susceptibility to CHB with a 24% higher likelihood of developing CCA than non-susceptible individuals (Inverse-Variance Weighted Odds Ratio = 1.24, 95% Confidence Interval: 1.08-1.42; p = 0.002). This genetic association is significantly driven by instrumental variables enriched in the immune-regulatory HLA class II region (6p21), suggesting a plausible biological mechanism. For the primary outcome (CCA), statistical significance was assessed across seven exposures at a Bonferroni-corrected threshold (two-sided p<0.0071). Notably, the CHB-CCA association remains significant after correction. This primary finding is strongly supported by comprehensive sensitivity analyses that showed no evidence of confounding by horizontal pleiotropy or heterogeneity. Conversely, no significant causal effects on CCA were identified for the other six conditions. CONCLUSIONS: Our MR analysis supports a causal role of HBV infection in CCA development, highlighting the importance of targeted HBV screening and surveillance.
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Circulating tumor-associated autoantibody signatures for diagnosis and prognosis in small-cell lung cancer and lung adenocarcinoma.
BACKGROUND: Tumour-associated autoantibodies (TAAbs) are promising biomarkers for cancer detection, but their induction and clinical relevance in lung cancer remain unclear. METHODS: Serum samples from 695 individuals were analysed for TAAb profiling by protein-array screening and two-stage ELISA validation. Diagnostic models were constructed with identified TAAbs and compared with conventional tumour markers. Potential mechanisms, clinical and prognostic features of TAAb seropositivity were analysed and its presence in prediagnostic sera was evaluated to assess the potential for early detection. RESULTS: Six TAAbs for small cell lung cancer (SCLC) and four for lung adenocarcinoma (LUAD) were identified, demonstrating excellent diagnostic performance (AUC > 0.8) and outperforming ProGRP and CEA. TAAb induction correlated with antigen overexpression, somatic mutations and HLA class II amino acid polymorphisms. TAAb panel seropositivity was associated with older age and advanced stage in both subtypes, and predicted poor survival in SCLC but a favourable outcome in advanced LUAD. In prediagnostic sera, the TAAb concentration increased progressively, with detectability up to 2 years before clinical diagnosis. CONCLUSIONS: Distinct TAAb panels were identified for SCLC and LUAD, serving as accurate diagnostic markers that enable early detection and as indicators of prognosis in different clinical contexts.
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A Missense Substitution in Exon 2 Generates the First HLA-DQB1*04 Allele With Glutamine at Residue 52, DQB1*04:108.
HLA-DQB1*04:108, the first HLA-DQB1*04 allele with Glutamine at residue 52 in the peptide-binding domain.
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HLA-DRB5*01:133, the First HLA-DRB5 Allele With Arginine at Position 16 in the Peptide-Binding Domain.
A transition in codon 16 in the peptide-binding domain results in the novel HLA-DRB5*01:133 allele.
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Donor HLA Class I Evolutionary Divergence and Late Allograft Rejection After Liver Transplantation in Children: An Emulated Target Trial.
HLA evolutionary divergence (HED), a continuous metric quantifying the differences between each amino acid of two homologous HLA alleles, reflects the importance of the immunopeptidome presented to T lymphocytes. It has been associated with rejection after liver transplantation. This retrospective cohort study aimed to analyse the potential effect of donor or recipient HED on liver transplant rejection in a new series of patients transplanted during childhood and followed in adulthood. The study included 120 children who had been transplanted between 1991 and 2010 and were followed by routine biopsies and histological evaluations with a median of 14.1 years post-LT. Liver biopsies were performed routinely 1, 5, 10 and 20 years after transplantation and in the event of liver dysfunction. HED was calculated using the physicochemical Grantham distance for donor and recipient Class I (HLA-A, -B, -C) and Class II (HLA-DRB1, -DQB1) alleles. The influence of HED on rejection was analysed using inverse probability weighting (IPW) and target trial emulation using the g method. Based on the IPW score, donor HED class I was correlated with the occurrence of late (> 90 days) rejection (HR, 1.19, 95% CI: 1.01-1.40) independently of HLA mismatches, donor age and initial induction. The emulated target trial confirmed that donor HED Class I has a causal effect on liver graft rejection and this relationship was observed long-term.
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Immune Aging in Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a life-long autoimmune disease caused by the confluence of genetic and environmental variables that lead to loss of self-tolerance and persistent joint inflammation. RA occurs at the highest incidence in individuals >65 years old, implicating the aging process in disease susceptibility. Transformative approaches in molecular immunology and in functional genomics have paved the way for pathway paradigms underlying the replacement of immune homeostasis with autodestructive immunity in affected patients, including the process of immune aging. Patients with RA have a signature of premature immune aging, best understood for CD4+ T cells, which function as pathogenic effectors in this HLA class II-associated disease. Premature immune aging is present in healthy HLA-DRB1*04+ individuals, placing accelerated immune aging before joint inflammation. Aging-related molecular abnormalities directly implicated in turning RA CD4+ T cells into proinflammatory effector cells are linked to malfunction of subcellular organelles, such as mitochondria, lysosomes, lipid droplets, and the endoplasmic reticulum. Resulting changes in T cell behavior include cellular hypermobility, tissue invasiveness, unopposed mammalian target of rapamycin complex (mTORC)1 activation, excessive release of tumor necrosis factor, lysosomal failure, clonal expansion, and immunogenic cell death. Aged and metabolically reprogrammed T cells in patients with RA are accompanied by age-associated B cells, which specialize in autoantibody production. Clonal hematopoiesis drives myeloid cell aging by producing aged monocytes and hypermetabolic macrophages, which sustain the process of inflammaging. Here, we synthesize insights into the relationship of RA risk and immune aging and discuss mechanisms through which immune aging can cause autoimmunity.
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