220 results on '"HLA-B7 Antigen genetics"'
Search Results
2. Major histocompatibility complex (MHC) gene frequency in acquired dermal macular hyperpigmentation: a case control study.
- Author
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Vinay K, Kamat D, Narayan R V, Minz RW, Singh J, Bishnoi A, Chatterjee D, Parsad D, and Kumaran MS
- Subjects
- Humans, Female, Male, Case-Control Studies, Adult, HLA-DRB1 Chains genetics, Middle Aged, HLA-A Antigens genetics, Young Adult, HLA-B Antigens genetics, HLA-C Antigens genetics, India epidemiology, HLA-DR Antigens genetics, HLA-B7 Antigen genetics, HLA-DQ alpha-Chains genetics, Adolescent, HLA Antigens genetics, HLA Antigens immunology, Hyperpigmentation genetics, Hyperpigmentation immunology, Gene Frequency, HLA-DQ beta-Chains genetics
- Abstract
Background: Human leukocyte antigen (HLA) allele frequencies have a known association with the pathogenesis of various autoimmune diseases., Methods: We recruited 31 Indian patients of acquired dermal macular hyperpigmentation (ADMH) and 60 unrelated, age-and-gender-matched healthy controls. After history and clinical examination, 5 ml of blood in EDTA vials was collected. These samples were subjected to DNA extraction and the expression of HLA A, B, C, DR, DQ-A, and DQ-B was studied., Results: There was a predominance of females with a gender ratio of 23 : 8 and the most common phototype was Fitzpatrick type IV (83.9%). There was a significant association of HLA A*03:01 (OR: 5.8, CI: 1.7-17.0, P = 0.005), HLA B*07:02 (OR: 5.3, CI: 1.9-14.6, P = 0.003), HLA C*07:02 (OR: 4.3, CI: 1.8-9.6, P = 0.001), HLA DRB1*10:01 (OR: 7.6, CI: 1.7-38.00, P = 0.022), and HLA DRB1*15:02 (OR: 31.0, CI: 4.4-341.8, P < 0.001) with patients compared to controls, whereas HLA DQB*03:01 was less associated with patients compared to controls (OR: 0.2, CI: 0.0-0.6, P = 0.009)., Conclusion: Patients with ADMH are more likely to have the HLA A*03:01, HLA B 07*02, HLA C*07:02, HLA DRB1*10:01, HLA DRB1*15:02 and less likely to have the HLA DQB*03:01 allele. Larger cohort studies may thus be conducted studying these specific alleles., (© 2024 the International Society of Dermatology.)
- Published
- 2024
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3. Characterisation of the novel HLA-B*07:02:01:110 allele by next-generation sequencing.
- Author
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Kouniaki D, Athanassiades T, and Tsirogianni A
- Subjects
- Humans, HLA-B7 Antigen genetics, Exons, Sequence Analysis, DNA methods, Sequence Alignment, Alleles, High-Throughput Nucleotide Sequencing methods, 3' Untranslated Regions, Histocompatibility Testing methods, Base Sequence
- Abstract
HLA-B*07:02:01:110 differs from the HLA-B*07:02:01:01 allele by two nucleotide substitutions in the 3'UTR., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2024
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4. Anti-HLA-B7/HLA-B44 strong cross immunoreactivity observed in flow cytometry HLA-B27 immunotyping.
- Author
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Francois F, Waeckel L, Berger AE, and Lambert C
- Subjects
- Humans, HLA-B Antigens immunology, HLA-B Antigens genetics, Genotype, Immunophenotyping methods, Flow Cytometry methods, Cross Reactions immunology, HLA-B27 Antigen immunology, HLA-B27 Antigen genetics, Haplotypes genetics, HLA-B7 Antigen immunology, HLA-B7 Antigen genetics, HLA-B44 Antigen immunology, HLA-B44 Antigen genetics, Antibodies, Monoclonal immunology
- Abstract
Cross reactivities are known for human leukocyte antigen inside HLA-B7 related Cross-Reactive Group (B7CREG). Some CE-IVD flow-cytometry kits use double monoclonal antibodies (mAb) to distinguish HLA-B27 and HLA-B7 but practice reveals more complexes results. This study explores the performances of this test. Analysis of 466 consecutive cases using HLA-B27 IOTest™ kit on a Navios™ cytometer from Beckman-Coulter, partially compared to their genotypes. Expected haplotypes HLA-B27-/HLA-B7- (undoubtedly HLA-B27 negative) and HLA-B27+/HLA-B7- (undoubtedly HLA-B27+) were clearly identified according to the manufacturer's instructions. On the opposite, patients strongly labeled with anti-HLA-B7 showed three different phenotypes regarding anti-HLA-B27 labeling: (1) most of the cases were poorly labeled in accordance with cross reactivity inside B7CREG (HLA-B27-/HLA-B7+ haplotype); (2) rare cases had strong B7 and B27 labeling corresponding to HLA-B27+/HLA-B7+ haplotype; (3) even less cases had strong labeling by anti-HLA-B7 but non for anti-HLA-B27, all expressing HLA-B44 and no B7CREG molecules. Surprisingly, more cases were not labeled with anti-HLA-B7 antibody but partially labeled with anti-HLA-B27 suggesting another cross reactivity out of B7CREG. mAb HLA typing suggests new, cross reactivities of anti-HLA-B27 antibody to more molecules out of B7CREG and of anti-HLA-B7 antibody but not anti-HLA-B27 to HLA-B44 molecule also out of B7CREG. HLA-B27 could surely be excluded in most samples labeled with HLA-B27, below a "grey zone" on intermediate intensity. More comparison is needed in future studies., (© 2024 International Society for Advancement of Cytometry.)
- Published
- 2024
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5. The ancestral haplotype markers HLA -A3 and B7 do not influence the likelihood of advanced hepatic fibrosis or cirrhosis in HFE hemochromatosis.
- Author
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Olynyk JK, Grainger R, Currie H, Ramm LE, and Ramm GA
- Subjects
- Humans, HLA-A3 Antigen genetics, Haplotypes, Histocompatibility Antigens Class I genetics, HLA-B7 Antigen genetics, Hemochromatosis Protein genetics, Liver Cirrhosis genetics, Liver Cirrhosis pathology, Iron, Homozygote, HLA Antigens genetics, Hemochromatosis genetics, Hemochromatosis pathology
- Abstract
Advanced hepatic fibrosis occurs in up to 25% of individuals with C282Y homozygous hemochromatosis. Our aim was to determine whether human leukocyte antigen (HLA)-A3 and B7 alleles act as genetic modifiers of the likelihood of advanced hepatic fibrosis. Between 1972 and 2013, 133 HFE C282Y homozygous individuals underwent clinical and biochemical evaluation, HLA typing, liver biopsy for fibrosis staging and phlebotomy treatment. Hepatic fibrosis was graded according to Scheuer as F0-2 (low grade hepatic fibrosis), F3-4 (advanced hepatic fibrosis), and F4 cirrhosis. We analysed associations between the severity of fibrosis and HLA-A3 homozygosity, heterozygosity or absence, with or without the presence of HLA-B7 using categorical analysis. The mean age of HLA-A3 homozygotes (n = 24), heterozygotes (n = 65) and HLA-A3 null individuals (n = 44) was 40 years. There were no significant differences between the groups for mean(± SEM) serum ferritin levels (1320 ± 296, 1217 ± 124, 1348 ± 188 [Formula: see text]g/L), hepatic iron concentration (178 ± 26, 213 ± 22, 199 ± 29 [Formula: see text]mol/g), mobilizable iron stores (9.9 ± 1.5, 9.5 ± 1.5, 11.5 ± 1.7 g iron removed via phlebotomy), frequency of advanced hepatic fibrosis (5/24[12%], 13/63[19%], 10/42[19%]) or cirrhosis (3/24[21%], 12/63[21%], 4/42[24%]), respectively. The presence or absence of HLA-B7 did not influence the outcome. Thus, HLA-A3 and HLA-B7 alleles are not associated with the risk of advanced hepatic fibrosis or cirrhosis in C282Y hemochromatosis., (© 2023. The Author(s).)
- Published
- 2023
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6. CD8 + T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses.
- Author
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Lineburg KE, Grant EJ, Swaminathan S, Chatzileontiadou DSM, Szeto C, Sloane H, Panikkar A, Raju J, Crooks P, Rehan S, Nguyen AT, Lekieffre L, Neller MA, Tong ZWM, Jayasinghe D, Chew KY, Lobos CA, Halim H, Burrows JM, Riboldi-Tunnicliffe A, Chen W, D'Orsogna L, Khanna R, Short KR, Smith C, and Gras S
- Subjects
- Amino Acid Sequence, Coronavirus classification, Coronavirus immunology, Coronavirus Nucleocapsid Proteins chemistry, Cross Reactions, Epitopes, T-Lymphocyte chemistry, Epitopes, T-Lymphocyte immunology, HLA-B7 Antigen chemistry, HLA-B7 Antigen genetics, HLA-B7 Antigen immunology, Humans, Immunodominant Epitopes chemistry, Immunologic Memory, Models, Molecular, Peptides chemistry, Peptides immunology, Receptors, Antigen, T-Cell chemistry, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, CD8-Positive T-Lymphocytes immunology, COVID-19 immunology, Coronavirus Nucleocapsid Proteins immunology, Immunodominant Epitopes immunology, SARS-CoV-2 immunology
- Abstract
Efforts are being made worldwide to understand the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7
+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses because of different peptide conformations. T cell receptor (TCR) sequencing indicated that cross-reactivity was driven by private TCR repertoires with a bias for TRBV27 and a long CDR3β loop. Our findings demonstrate the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
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7. Human leukocyte antigen B*0702 is protective against ocular Stevens-Johnson syndrome/toxic epidermal necrolysis in the UK population.
- Author
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Butt GF, Hassan A, Wallace GR, Kinoshita S, Ahmad S, Ueta M, and Rauz S
- Subjects
- Adolescent, Adult, Aged, Alleles, Child, Child, Preschool, Eye Diseases epidemiology, Eye Diseases immunology, Female, HLA-B7 Antigen immunology, Humans, Incidence, Male, Middle Aged, Protective Factors, Stevens-Johnson Syndrome epidemiology, Stevens-Johnson Syndrome immunology, United Kingdom epidemiology, Young Adult, Eye Diseases genetics, Genetic Predisposition to Disease, HLA-B7 Antigen genetics, Stevens-Johnson Syndrome genetics
- Abstract
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are part of a disease continuum of vesiculobullous mucocutaneous reactions affecting the skin and mucous membranes including the ocular surface. Manifestations of disease range from mild dry eye to progressive conjunctival cicatrisation, limbal epithelial stem cell failure and corneal blindness. In Far Eastern and South East Asian populations where SJS/TEN is prevalent, numerous human leukocyte antigen (HLA) gene variants at the A, B and C loci have been identified as risk factors for developing SJS/TEN with severe ocular complications (SOC). By contrast, the incidence of SJS/TEN with SOC in European countries is relatively low. To date, ocular SJS/TEN risk altering alleles have not been widely investigated in European populations. In this study, we analysed the association of HLA -A, -B and -C alleles with SJS/TEN in 33 patients residing in the UK with age matched controls. The data showed statistically significant novel negative allele association with HLA-B*0702 and a trend with HLA-C*0702 in the patient group, indicating these alleles are protective. Further characterisation of protective and risk alleles in other ethnic groups is required to fully elucidate the putative role of these alleles in the susceptibility of SJS/TEN with or without severe ocular complications in patients in the UK.
- Published
- 2021
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8. Strong Correlation between HLA and Clinical Course of Subacute Thyroiditis-A Report of the Three Siblings.
- Author
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Stasiak M and Lewiński A
- Subjects
- Adult, Alleles, Autoantibodies blood, Diseases in Twins genetics, Diseases in Twins immunology, Female, Genetic Predisposition to Disease, Graves Disease genetics, Graves Disease immunology, HLA-B7 Antigen genetics, HLA-DRB1 Chains genetics, Histocompatibility Testing, Humans, Male, Receptors, Thyrotropin immunology, HLA Antigens genetics, Thyroiditis, Subacute genetics, Thyroiditis, Subacute immunology
- Abstract
Subacute thyroiditis (SAT) is a thyroid inflammatory disease with susceptibility associated with the presence of human leukocyte antigen ( HLA)-B*35 , -B*18:01 , -DRB1*01 and -C*04:01 . Previous viral infection is considered as a triggering factor in genetically predisposed individuals. The influence of HLA on the SAT course was previously suggested. We aim to present the three siblings-female twins and their brother-with very close onset but different clinical courses of SAT, which appeared to be HLA-dependent. The HLA profile in the reported three siblings is strongly correlated with both SAT and Graves' disease (GD), however the coexistence of particular sets of high risk and protective alleles seems to be crucial for the GD development and the SAT course. The co-occurrence of HLA-DRB1*15:01 and/or -B*07:02 , possibly together with the lack of HLA-A*01:01 and -B*41:01 seems to be key factors protecting against the development of GD with high TRAb levels, as well as against the recurrent SAT course and steroid dependence.
- Published
- 2020
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9. Heterotypic immunity against vaccinia virus in an HLA-B*07:02 transgenic mousepox infection model.
- Author
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Kumar A, Suryadevara NC, Wolf KJ, Wilson JT, Di Paolo RJ, Brien JD, and Joyce S
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Disease Models, Animal, Ectromelia virus pathogenicity, Ectromelia, Infectious immunology, HLA-B7 Antigen metabolism, Immunodominant Epitopes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Viral Vaccines administration & dosage, Viral Vaccines immunology, Ectromelia, Infectious prevention & control, HLA-B7 Antigen genetics, Peptides immunology, Vaccinia virus immunology, Viral Proteins chemistry
- Abstract
Vaccination with vaccinia virus (VACV) elicits heterotypic immunity to smallpox, monkeypox, and mousepox, the mechanistic basis for which is poorly understood. It is generally assumed that heterotypic immunity arises from the presentation of a wide array of VACV-derived, CD8
+ T cell epitopes that share homology with other poxviruses. Herein this assumption was tested using a large panel of VACV-derived peptides presented by HLA-B*07:02 (B7.2) molecules in a mousepox/ectromelia virus (ECTV)-infection, B7.2 transgenic mouse model. Most dominant epitopes recognized by ECTV- and VACV-reactive CD8+ T cells overlapped significantly without altering immunodominance hierarchy. Further, several epitopes recognized by ECTV-reactive CD8+ T cells were not recognized by VACV-reactive CD8+ T cells, and vice versa. In one instance, the lack of recognition owed to a N72K variation in the ECTV C4R70-78 variant of the dominant VACV B8R70-78 epitope. C4R70-78 does not bind to B7.2 and, hence, it was neither immunogenic nor antigenic. These findings provide a mechanistic basis for VACV vaccination-induced heterotypic immunity which can protect against Variola and Monkeypox disease. The understanding of how cross-reactive responses develop is essential for the rational design of a subunit-based vaccine that would be safe, and effectively protect against heterologous infection.- Published
- 2020
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10. Human Leukocyte Antigen Genotype as a Marker of Multiple Sclerosis Prognosis.
- Author
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Lysandropoulos AP, Perrotta G, Billiet T, Ribbens A, Du Pasquier R, Pot Kreis C, Maggi P, and Théaudin M
- Subjects
- Adolescent, Adult, Aged, Disease Progression, Female, Genotype, HLA-A2 Antigen genetics, HLA-B44 Antigen genetics, HLA-B7 Antigen genetics, HLA-B8 Antigen genetics, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive diagnostic imaging, Multiple Sclerosis, Chronic Progressive drug therapy, Multiple Sclerosis, Chronic Progressive physiopathology, Multiple Sclerosis, Relapsing-Remitting diagnostic imaging, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis, Relapsing-Remitting physiopathology, Prognosis, Young Adult, HLA-DQ beta-Chains genetics, Histocompatibility Antigens Class I genetics, Multiple Sclerosis, Chronic Progressive genetics, Multiple Sclerosis, Relapsing-Remitting genetics
- Abstract
Objective: In a previous pilot monocentric study, we investigated the relation between human leukocyte antigen (HLA) genotype and multiple sclerosis (MS) disease progression over 2 years. HLA-A*02 allele was correlated with better outcomes, whereas HLA-B*07 and HLA-B*44 were correlated with worse outcomes. The objective of this extension study was to further investigate the possible association of HLA genotype with disease status and progression in MS as measured by sensitive and complex clinical and imaging parameters., Methods: Hundred and forty-six MS patients underwent HLA typing. Over a 4-year period of follow-up, we performed three clinical and magnetic resonance imaging (MRI) assessments per patient, which respectively included Expanded Disability Status Scale, Multiple Sclerosis Severity Scale, Timed-25-Foot-Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, Brief Visual Memory Test, California Verbal Learning Test-II, and whole-brain atrophy, fluid-attenuated inversion recovery (FLAIR) lesion volume change and number of new FLAIR lesions using icobrain. We then compared the clinical and MRI outcomes between predefined HLA patient groups., Results: Results of this larger study with a longer follow-up are in line with what we have previously shown. HLA-A*02 allele is associated with potentially better MS outcomes, whereas HLA-B*07, HLA-B*44, HLA-B*08, and HLA-DQB1*06 with a potential negative effect. Results for HLA-DRB1*15 are inconclusive., Conclusion: In the era of MS treatment abundance, HLA genotype might serve as an early biomarker for MS outcomes to inform individualized treatment decisions.
- Published
- 2020
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11. HLA-B*13:64, a novel allele, identified in a Chinese individual.
- Author
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Li JP, Zhang X, Lin FQ, Zhang KL, and Li XF
- Subjects
- China, Codon, Genotype, HLA-A Antigens genetics, HLA-A11 Antigen genetics, HLA-B7 Antigen genetics, HLA-DRB1 Chains genetics, Hematopoietic Stem Cell Transplantation, Humans, Isoleucine genetics, Software, Threonine genetics, Alleles, HLA-B13 Antigen genetics
- Abstract
HLA-B*13:64 has one amino acid change from HLA-B*13:02:01:01 where 94 Threonine is changed to Isoleucine., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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12. A novel case of linear IgG4-antibody mediated tubulointerstitial nephritis with concomitant HLA-B7, ANCA-MPO.
- Author
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Sinniah R, Kop T, and Chin G
- Subjects
- Biopsy, Fibrosis diagnosis, Fibrosis genetics, Fibrosis immunology, Fibrosis pathology, Humans, Immunoglobulin G4-Related Disease genetics, Immunoglobulin G4-Related Disease immunology, Immunoglobulin G4-Related Disease pathology, Immunosuppression Therapy, Kidney immunology, Kidney pathology, Male, Nephritis, Interstitial genetics, Nephritis, Interstitial immunology, Nephritis, Interstitial pathology, Plasma Exchange, Young Adult, Antibodies, Antineutrophil Cytoplasmic analysis, HLA-B7 Antigen genetics, Immunoglobulin G blood, Immunoglobulin G4-Related Disease diagnosis, Nephritis, Interstitial diagnosis, Renal Insufficiency therapy
- Published
- 2019
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13. Characterization of the novel HLA-B*07:02:73 allele by sequencing-based typing.
- Author
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Elsermans V, Visentin J, Top I, Varlet P, and Labalette M
- Subjects
- Alleles, Amino Acid Substitution, Base Sequence, Humans, Sequence Homology, HLA-B7 Antigen genetics, Histocompatibility Testing methods, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods
- Abstract
HLA-B*07:02:73 differs from HLA-B*07:02:01:01 by one nucleotide substitution in codon 136 in exon 3., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
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14. Treatment of Active Crohn's Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition.
- Author
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Svolos V, Hansen R, Nichols B, Quince C, Ijaz UZ, Papadopoulou RT, Edwards CA, Watson D, Alghamdi A, Brejnrod A, Ansalone C, Duncan H, Gervais L, Tayler R, Salmond J, Bolognini D, Klopfleisch R, Gaya DR, Milling S, Russell RK, and Gerasimidis K
- Subjects
- Adolescent, Adult, Animals, Bacteria isolation & purification, Bacteria metabolism, Bacterial Load, Child, Crohn Disease diagnosis, Crohn Disease microbiology, Crohn Disease physiopathology, Disease Models, Animal, Feces microbiology, Female, HLA-B27 Antigen genetics, HLA-B7 Antigen genetics, Humans, Male, Nutritional Status, Rats, Transgenic, Recurrence, Remission Induction, Scotland, Time Factors, Treatment Outcome, Young Adult, Bacteria growth & development, Crohn Disease diet therapy, Enteral Nutrition, Gastrointestinal Microbiome, Nutritive Value
- Abstract
Background & Aims: Exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn's disease (CD), but its acceptability is limited. There is a need for novel dietary treatments for CD., Methods: We evaluated the effects of an individualized food-based diet (CD-TREAT), with similar composition to EEN, on the gut microbiome, inflammation, and clinical response in a rat model, healthy adults, and children with relapsing CD. Twenty-five healthy adults randomly received EEN or CD-TREAT for 7 days, followed by a 14-day washout period, followed by the alternate diet. Fecal microbiome and metabolome were assessed before and after each diet. HLA-B7 and HLA-B27 transgenic rats with gut inflammation received EEN, CD-TREAT, or standard chow for 4 weeks. Fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation were assessed. Five children with active CD activity received CD-TREAT and their clinical activity and calprotectin were evaluated after 8 weeks of treatment., Results: For healthy adults, CD-TREAT was easier to comply with and more acceptable than EEN. CD-TREAT induced similar effects to EEN (EEN vs CD-TREAT) on fecal microbiome composition, metabolome, mean total sulfide (increase 133.0 ± 80.5 vs 54.3 ± 47.0 nmol/g), pH (increase 1.3 ± 0.5 vs 0.9 ± 0.6), and the short-chain fatty acids (μmol/g) acetate (decrease 27.4 ± 22.6 vs 21.6 ± 20.4), propionate (decrease 5.7 ± 7.8 vs 5.2 ± 7.9), and butyrate (decrease 7.0 ± 7.4 vs 10.2 ± 8.5). In the rat model, CD-TREAT and EEN produced similar changes in bacterial load (decrease 0.3 ± 0.3 log
10 16S rRNA gene copies per gram), short-chain fatty acids, microbiome, and ileitis severity (mean histopathology score decreases of 1.25 for EEN [P = .015] and 1.0 for CD-TREAT [P = .044] vs chow). In children receiving CD-TREAT, 4 (80%) had a clinical response and 3 (60%) entered remission, with significant concurrent decreases in fecal calprotectin (mean decrease 918 ± 555 mg/kg; P = .002)., Conclusion: CD-TREAT replicates EEN changes in the microbiome, decreases gut inflammation, is well tolerated, and is potentially effective in patients with active CD. ClinicalTrials.gov, numbers NCT02426567 and NCT03171246., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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15. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02.
- Author
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Tziotzios C, Petridis C, Dand N, Ainali C, Saklatvala JR, Pullabhatla V, Onoufriadis A, Pramanik R, Baudry D, Lee SH, Wood K, Liu L, Seegobin S, Michelotti GA, Lwin SM, Christou EAA, Curtis CJ, de Rinaldis E, Saxena A, Holmes S, Harries M, Palamaras I, Cunningham F, Parkins G, Kaur M, Farrant P, McDonagh A, Messenger A, Jones J, Jolliffe V, Ali I, Ardern-Jones M, Mitchell C, Burrows N, Atkar R, Banfield C, Alexandroff A, Champagne C, Cooper HL, Vañó-Galván S, Molina-Ruiz AM, Perez NO, Patel GK, Macbeth A, Page M, Bryden A, Mowbray M, Wahie S, Armstrong K, Cooke N, Goodfield M, Man I, de Berker D, Dunnill G, Takwale A, Rao A, Siah TW, Sinclair R, Wade MS, Dlova NC, Setterfield J, Lewis F, Bhargava K, Kirkpatrick N, Estivill X, Stefanato CM, Flohr C, Spector T, Watt FM, Smith CH, Barker JN, Fenton DA, Simpson MA, and McGrath JA
- Subjects
- Adaptive Immunity, Alopecia diagnosis, Alopecia genetics, Alopecia physiopathology, Case-Control Studies, Cohort Studies, Cytochrome P-450 CYP1B1 genetics, Cytochrome P-450 CYP1B1 immunology, Female, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-B7 Antigen immunology, Humans, Immunity, Innate, Polymorphism, Single Nucleotide, Alopecia congenital, Genetic Loci, Genetic Predisposition to Disease, HLA-B7 Antigen genetics, Transcriptome immunology
- Abstract
Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02.
- Published
- 2019
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16. Simple, rapid and inexpensive typing of common HLA class I alleles for immunological studies.
- Author
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Law SC, Haigh OL, Walpole CM, Keane C, Miles JJ, Gandhi MK, Radford KJ, and Steptoe RJ
- Subjects
- Humans, Alleles, DNA Primers genetics, HLA-A2 Antigen genetics, HLA-B7 Antigen genetics, HLA-B8 Antigen genetics, Histocompatibility Testing, Polymerase Chain Reaction
- Abstract
Current HLA-typing methods are typically designed to provide exquisitely-detailed identification of multiple HLA-alleles to satisfy the requirements for organ and bone marrow transplantation or genetic studies. Many human immunological studies, on the other hand, focus around only a small number of HLA alleles that are abundant or of relevance to specific diseases. Consequently, for such studies, many HLA typing approaches are not cost-effective and are potentially complicated, slow and not easily performed in-house. Work-flow would be streamlined by a simple, inexpensive and rapid typing method able to be performed in-house. We outline a straightforward approach that provides appropriate data for much immunological research. In a predominantly Caucasian population, flow cytometry using anti-HLA-A2, -B8 and -B7 antibodies consistently and accurately screened for samples carrying the highly-abundant HLA class I alleles HLA-A*02:01, -B*08:01 and -B*07:02 that form the focus of immunological studies. Next, we describe a straightforward and simple strategy for design and use of allele-specific PCR primers to identify, at high-resolution, alleles of interest. When combined with a simple gDNA extraction technique this provides reliable, simple and inexpensive in-house HLA typing demonstrated here for highly-abundant HLA class I alleles., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
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17. Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.
- Author
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Chi C, Shao X, Rhead B, Gonzales E, Smith JB, Xiang AH, Graves J, Waldman A, Lotze T, Schreiner T, Weinstock-Guttman B, Aaen G, Tillema JM, Ness J, Candee M, Krupp L, Gorman M, Benson L, Chitnis T, Mar S, Belman A, Casper TC, Rose J, Moodley M, Rensel M, Rodriguez M, Greenberg B, Kahn L, Rubin J, Schaefer C, Waubant E, Langer-Gould A, and Barcellos LF
- Subjects
- Black or African American, Alleles, Asian, Female, Genome-Wide Association Study, HLA-A3 Antigen genetics, HLA-B7 Antigen genetics, Haplotypes, Hispanic or Latino, Humans, Male, Multiple Sclerosis pathology, Polymorphism, Single Nucleotide, White People, Genetic Predisposition to Disease, HLA-DRB1 Chains genetics, Multiple Sclerosis genetics, Transcription Factors genetics
- Abstract
Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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18. HLA-B gene somatic insertion/deletion mutations in patients with acute myelogenous leukaemia.
- Author
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Königova N, Skoumalova I, Onderkova J, Ambruzova Z, Szotkowski T, Koristek Z, Maluskova A, Raida L, and Mrazek F
- Subjects
- Humans, Male, Middle Aged, HLA-B7 Antigen genetics, HLA-B8 Antigen genetics, INDEL Mutation, Leukemia, Myeloid, Acute genetics, Neoplasm Proteins genetics
- Abstract
Loss of heterozygosity is considered to be the most common type of tumour-specific somatic mutation of the human leucocyte antigens (HLA) genes in patients with haematological malignancies. Nevertheless, subtle DNA sequence changes, namely short insertions/deletions, may also abolish the expression of HLA molecules and interfere with routine HLA typing. Two male patients with acute myelogenous leukaemia (AML) were indicated for the search of a suitable donor for allogeneic haematopoietic stem cell transplantation (aHSCT). The patients and their relatives were initially HLA typed by serological and DNA techniques at a low-resolution level. The HLA high-resolution (HR) type was obtained by means of sequencing-based typing (SBT). In both cases, anomalous frameshifts in the sequence were observed in the HLA-B gene, namely in exon 3 (Case 1, heterozygous deletion of two bases) and exon 4 (Case 2, heterozygous insertion of two bases). In the second case, the insertion variant was associated with a loss of HLA-B8 expression. To reveal whether these sequence patterns may be caused by somatic mutations in the malignant cells, blood sample in remission (Case 1) and buccal swab sample (Case 2) were collected from the patients. In an important manner, the SBT in these germline samples revealed common HLA-B*07:02,*15:01 (Case 1) and HLA-B*08:01,*35:02 (Case 2) types with no evidence for the sequence alteration observed in the initial samples. In conclusion, the insertion/deletion sequence variants of the HLA-B gene in two patients were limited to the initial blood samples with a substantial proportion of AML cells and thus may be attributed to the somatic mutation in the malignant cells. HLA somatic mutations should be taken into account in patients with haematological malignancies to prevent HLA mistyping and inappropriate selection of an aHSCT donor., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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19. Genomic sequences of HLA-A*68:169, HLA-B*07:298 and HLA-B*39:129.
- Author
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Balas A, Planelles D, Rodríguez-Cebriá M, Puig N, and Vicario JL
- Subjects
- Amino Acid Sequence, HLA-A Antigens chemistry, HLA-B Antigens chemistry, HLA-B7 Antigen chemistry, Haplotypes, Humans, Peptides chemistry, Alleles, Base Sequence, HLA-A Antigens genetics, HLA-B Antigens genetics, HLA-B7 Antigen genetics, Sequence Analysis, DNA
- Abstract
Three new HLA class I alleles were described in the Spanish population. HLA-A*68:169 and -B*39:129 show one amino acid replacement at the α1-domain, compared to A*68:02 (P47 > L47) and -B*39:06 (S11 > A11), respectively. HLA-B*07:298 presents one nucleotide mutation within exon 1, resulting in a new amino acid position -14, L>Q, which has not been previously described in any HLA protein. Prediction of the B*07:298 signal peptide cleavage did not show significant differences in comparison with that obtained for the rest of HLA-B genes., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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20. HLA-B*07, HLA-DRB1*07, HLA-DRB1*12, and HLA-C*03:02 Strongly Associate With BMI: Data From 1.3 Million Healthy Chinese Adults.
- Author
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Shen J, Guo T, Wang T, Zhen Y, Ma X, Wang Y, Zhang ZX, Cai JP, Mao W, Zhu FM, Li JP, Wang ZL, Zhang DM, Liu ML, Shan XY, Zhang BW, Zhu CF, Deng ZH, Yu WJ, Chen Q, Li GL, Yang T, Lu S, Pan QQ, Fan S, Wang XY, Zhao X, Bi XY, Qiao YH, Su PC, Lv R, Li GY, Li HC, Pei B, Jiao LX, Shen G, Liu J, Feng ZH, Su YP, Xie YB, Di WY, Wang XY, Liu X, Zhang XP, Du D, Liu Q, Han Y, Chen JW, Gu M, and Baier LJ
- Subjects
- Adolescent, Adult, Body Mass Index, China, Female, Genotype, Humans, Male, Middle Aged, Overweight genetics, Phenotype, Sex Factors, Young Adult, Asian People genetics, HLA-B7 Antigen genetics, HLA-C Antigens genetics, HLA-DRB1 Chains genetics, Obesity genetics
- Abstract
Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI ( P = 6.89 × 10
-10 , 1.32 × 10-9 , 1.52 × 10-9 , and 4.45 × 10-8 , respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects ( Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B , DRB1 , and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity., (© 2018 by the American Diabetes Association.)- Published
- 2018
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21. Characterization of the novel HLA-B*07:305 allele by sequencing-based typing.
- Author
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Guidicelli G, Elsermans V, Top I, Ralazamahaleo M, and Visentin J
- Subjects
- Base Sequence, Exons genetics, Humans, Sequence Alignment, Alleles, HLA-B7 Antigen genetics, Histocompatibility Testing methods, Sequence Analysis, DNA
- Abstract
HLA-B*07:305 differs from HLA-B*07:02:01:01 by one nucleotide substitution at position 255., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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22. Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide.
- Author
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Chan KF, Gully BS, Gras S, Beringer DX, Kjer-Nielsen L, Cebon J, McCluskey J, Chen W, and Rossjohn J
- Subjects
- HLA-B7 Antigen chemistry, HLA-B7 Antigen genetics, Humans, Models, Molecular, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Neoplasms genetics, Peptides chemistry, Peptides genetics, Protein Binding, Receptors, Antigen, T-Cell chemistry, Receptors, Antigen, T-Cell genetics, HLA-B7 Antigen metabolism, Neoplasm Proteins metabolism, Neoplasms metabolism, Peptides metabolism, Receptors, Antigen, T-Cell metabolism
- Abstract
Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4
+ TRAJ21+ -TRBV28+ TRBJ2-3+ and TRAV4+ TRAJ8+ -TRBV9+ TRBJ2-1+ ), originating from a polyclonal T-cell repertoire, bind to HLA-B*07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72 . Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72 -HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition.- Published
- 2018
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23. HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E.
- Author
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Chikata T, Tran GV, Murakoshi H, Akahoshi T, Qi Y, Naranbhai V, Kuse N, Tamura Y, Koyanagi M, Sakai S, Nguyen DH, Nguyen DT, Nguyen HT, Nguyen TV, Oka S, Martin MP, Carrington M, Sakai K, Nguyen KV, and Takiguchi M
- Subjects
- Adult, Alleles, Asian People, CD4 Lymphocyte Count, Genotype, HIV Infections immunology, HIV Infections virology, HIV-1 pathogenicity, HLA-A Antigens genetics, HLA-A Antigens immunology, HLA-B7 Antigen genetics, HLA-B7 Antigen immunology, HLA-C Antigens genetics, HLA-C Antigens immunology, Haplotypes genetics, Haplotypes immunology, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Mutation, Vietnam, Viral Load, Virus Replication, Genes, MHC Class I genetics, Genes, MHC Class I immunology, Genetic Fitness, HIV-1 genetics, HIV-1 immunology, pol Gene Products, Human Immunodeficiency Virus genetics, pol Gene Products, Human Immunodeficiency Virus immunology
- Abstract
HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control. IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1 subtype A/E infection which are different from those identified for cohorts infected with HIV-1 subtypes B and C., (Copyright © 2018 American Society for Microbiology.)
- Published
- 2018
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24. Mapping HLA-A2, -A3 and -B7 supertype-restricted T-cell epitopes in the ebolavirus proteome.
- Author
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Lim WC and Khan AM
- Subjects
- Ebolavirus isolation & purification, Genetic Variation, HLA-A2 Antigen genetics, HLA-A2 Antigen immunology, HLA-A2 Antigen metabolism, HLA-A3 Antigen genetics, HLA-A3 Antigen immunology, HLA-A3 Antigen metabolism, HLA-B7 Antigen genetics, HLA-B7 Antigen immunology, HLA-B7 Antigen metabolism, Hemorrhagic Fever, Ebola metabolism, Hemorrhagic Fever, Ebola virology, Humans, Proteome metabolism, T-Lymphocytes, Cytotoxic immunology, Ebolavirus immunology, Epitope Mapping methods, Epitopes, T-Lymphocyte immunology, Hemorrhagic Fever, Ebola immunology, Proteome immunology, Viral Proteins immunology
- Abstract
Background: Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family., Methods: All publicly available ZEBOV sequences (14,098) for each of the nine viral proteins were retrieved, removed of irrelevant and duplicate sequences, and aligned. The overall proteome diversity of the non-redundant sequences was studied by use of Shannon's entropy. The sequences were predicted, by use of the NetCTLpan server, for HLA-A2, -A3, and -B7 supertype-restricted epitopes, which are relevant to African and other ethnicities and provide for large (~86%) population coverage. The predicted epitopes were mapped to the alignment of each protein for analyses of antigenic sequence diversity and relevance to structure and function. The putative epitopes were validated by comparison with experimentally confirmed epitopes., Results & Discussion: ZEBOV proteome was generally conserved, with an average entropy of 0.16. The 185 HLA supertype-restricted T-cell epitopes predicted (82 (A2), 37 (A3) and 66 (B7)) mapped to 125 alignment positions and covered ~24% of the proteome length. Many of the epitopes showed a propensity to co-localize at select positions of the alignment. Thirty (30) of the mapped positions were completely conserved and may be attractive for vaccine design. The remaining (95) positions had one or more epitopes, with or without non-epitope variants. A significant number (24) of the putative epitopes matched reported experimentally validated HLA ligands/T-cell epitopes of A2, A3 and/or B7 supertype representative allele restrictions. The epitopes generally corresponded to functional motifs/domains and there was no correlation to localization on the protein 3D structure. These data and the epitope map provide important insights into the interaction between EBOV and the host immune system.
- Published
- 2018
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25. Unbiased Identification of T-Cell Receptors Targeting Immunodominant Peptide-MHC Complexes for T-Cell Receptor Immunotherapy.
- Author
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Lorenz FKM, Ellinger C, Kieback E, Wilde S, Lietz M, Schendel DJ, and Uckert W
- Subjects
- Humans, K562 Cells, Peptides genetics, Adoptive Transfer methods, HLA-B15 Antigen genetics, HLA-B15 Antigen immunology, HLA-B7 Antigen genetics, HLA-B7 Antigen immunology, Neoplasms genetics, Neoplasms immunology, Neoplasms pathology, Neoplasms therapy, Peptides immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, T-Lymphocytes immunology
- Abstract
T-cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best-suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate, and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01) and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.
- Published
- 2017
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26. Discovery of a novel HLA-B*07 variant, HLA-B*07:294, in a Chinese individual.
- Author
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Liu B, Lv J, and Ma Z
- Subjects
- Amino Acid Substitution, Asian People, Base Sequence, Codon chemistry, Female, Gene Expression, Genotype, HLA-B7 Antigen immunology, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Polymerase Chain Reaction, Sequence Alignment, Sequence Analysis, DNA, Transplant Recipients, Alleles, Exons, HLA-B7 Antigen genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
The novel HLA-B*07:294 allele differs from the closest matching allele, HLA-B*07:02:01 by 1 nucleotide substitution., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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27. An HLA-B7-specific antibody in an HLA-B*07 positive patient explained by a nonexpressed allele (HLA-B*07:181N).
- Author
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Wenda S, Faé I, and Fischer GF
- Subjects
- Adult, Base Sequence, Female, Gene Expression, Genotype, HLA-B39 Antigen immunology, HLA-B7 Antigen immunology, High-Throughput Nucleotide Sequencing, Histocompatibility Testing, Humans, Polymerase Chain Reaction, Protein Isoforms genetics, Protein Isoforms immunology, Sequence Alignment, Sequence Analysis, DNA, Tissue Donors, Transplantation, Homologous, Alleles, HLA-B39 Antigen genetics, HLA-B7 Antigen genetics, Isoantibodies genetics, Kidney Transplantation methods, Transplant Recipients
- Abstract
Antibody identification by a bead array assay in a kidney patient revealed several HLA-specific antibodies including one directed against the HLA-B7 antigen. Low-resolution typing of the patient indicated the presence of an HLA-B*07 allele. To rule out an HLA-specific autoantibody the HLA-typing of the patient was further refined by nucleotide sequencing on a next-generation sequencing platform and eventually showed an HLA-B*39:01:01:03 and HLA-B*07:181N genotype. Thereby the allospecific nature of the antibody was proven. The HLA-B7-specific antibody could be explained by an immunization during the first kidney-transplantation in 1996 with an HLA-B*07 positive donor. When assessing the plausibility of antibodies, the presence of nonexpressed alleles should be taken into consideration., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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28. Full-length sequences of 3 HLA-B alleles, B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing.
- Author
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Li Z and Zou HY
- Subjects
- Asian People, Base Sequence, Cloning, Molecular, Codon chemistry, Gene Expression, HLA-B14 Antigen immunology, HLA-B18 Antigen immunology, HLA-B7 Antigen immunology, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Introns, Polymerase Chain Reaction, Sequence Alignment, Sequence Analysis, DNA, Tissue Donors, Alleles, Exons, HLA-B14 Antigen genetics, HLA-B18 Antigen genetics, HLA-B7 Antigen genetics, Polymorphism, Genetic
- Abstract
Full-length sequences of HLA-B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing in Chinese donors., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
29. RNA processing and protein expression of HLA-B*07:44N.
- Author
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Balas A, García-Sánchez F, and Vicario JL
- Subjects
- Alleles, Bone Marrow Transplantation, Cloning, Molecular, Codon, Terminator, DNA, Complementary genetics, DNA, Complementary immunology, Exons, Flow Cytometry, HLA-B7 Antigen immunology, Humans, RNA, Messenger immunology, Sequence Alignment, Sequence Analysis, DNA, Terminology as Topic, Tissue Donors, Alternative Splicing, Base Sequence, HLA-B7 Antigen genetics, RNA, Messenger genetics, Sequence Deletion
- Abstract
Background: The assignment of human leukocyte antigen (HLA) null alleles is clinically relevant in the setting of stem cell transplantation. Cell surface expression profiling and mRNA processing analysis of the HLA-B allele previously designated as B*07:44, have been performed., Materials and Methods: Cell surface expression of HLA-B*07:44 was determined using flow cytometry. Genomic full-length and HLA-B*07-specific cDNA sequencing were carried out by Sanger procedure., Results: Flow cytometric analysis confirmed previous serologic results and demonstrated a lack of cell membrane expression of the HLA-B protein. The mRNA processing, studied using direct HLA-B*07-specific cDNA sequencing, revealed the presence of a unique, aberrantly spliced mRNA, with a deletion of the last 43 bp on the 5'-end of exon 4. The substitution from T to G at genomic position 1799 compared to B*07:02:01 introduced a new and stronger splice donor site at exon 4. This alternative splicing produced an mRNA containing a premature stop codon at position 280, explaining the absence of mature HLA-B7 protein on the cell surface., Conclusion: These findings led us to consider this HLA-B variant as a HLA null allele. The World Health Organization (WHO) Nomenclature Committee has since renamed this variant B*07:44N ., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
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30. Position 97 of HLA-B, a residue implicated in pathogenesis of ankylosing spondylitis, plays a key role in cell surface free heavy chain expression.
- Author
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Chen L, Shi H, Yuan J, and Bowness P
- Subjects
- ATP-Binding Cassette Transporters deficiency, ATP-Binding Cassette Transporters genetics, Aminopeptidases deficiency, Aminopeptidases genetics, Antigens, Surface metabolism, Asparagine genetics, Flow Cytometry, HLA-B27 Antigen chemistry, HLA-B27 Antigen metabolism, HLA-B51 Antigen genetics, HLA-B51 Antigen metabolism, HLA-B7 Antigen genetics, HLA-B7 Antigen metabolism, HeLa Cells, Humans, Membrane Transport Proteins deficiency, Membrane Transport Proteins genetics, Minor Histocompatibility Antigens genetics, Mutation, Serine genetics, Spondylitis, Ankylosing immunology, Threonine genetics, Transfection, Valine genetics, beta 2-Microglobulin genetics, Antigens, Surface genetics, HLA-B27 Antigen genetics, Spondylitis, Ankylosing genetics, beta 2-Microglobulin metabolism
- Abstract
Objective: Association of position 97 (P97) residue polymorphisms in human leucocyte antigen (HLA)-B, including HLA-B*27, with ankylosing spondylitis (AS) has recently been reported. We studied the effect of P97 variations on cell surface expression of the AS-associated HLA-B*27 and HLA-B*51, and the AS-protective HLA-B*7., Methods: Flow cytometry was used to measure surface expression of HLA-B*27 in C1R/HeLa cells expressing HLA-B*27 (N97) and six mutants at P97 (N97T, N97S, N97V, N97R, N97W and N97D). Transporter associated with antigen processing-deficient T2, tapasin-deficient 220, β2m-deficient HCT15 and endoplasmic reticulum aminopeptidase 1 or β2m-clustered regularly interspaced short palindromic repeats/Cas9-knockout HeLa cells were used to provide evidence for specific protein interactions. Surface expression of HLA-B*7/HLA-B*51 P97 mutants was also studied., Results: Mutation of HLA-B*27 P97 to the AS risk residue threonine increased cell surface free heavy chain (FHC) expression. Protective residues (serine or valine) and non-AS-associated residues (arginine or tryptophan) did not alter FHC expression. The N97D mutation reduced expression of conventional and FHC forms of HLA-B*27. Differences in FHC expression levels between HLA-B*27, HLA-B*27-N97T and HLA-B*27-N97D were dependent on the presence of functional β2m. HLA-B*7, which has an AS-protective serine at P97, expressed lower levels of FHC than HLA-B*27 or HLA-B*51. Introduction of asparagine at P97 of both HLA-B*7 and HLA-B*51 increased FHC expression., Conclusions: The nature of P97 residue affects surface expression of HLA-B*27, B*7 and B*51, with AS-associated residues giving rise to higher FHC expression levels. The association of P97 amino acid polymorphisms with AS could be, at least in part, explained by its effect on HLA-B*27 FHC cell surface expression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Published
- 2017
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31. Identification of a novel HLA-B*07 variant, B*07:269, by sequence-based typing in a Taiwanese bone marrow stem cell donor.
- Author
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Yang KL and Lin PY
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Codon chemistry, HLA-B7 Antigen immunology, Haplotypes, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Polymerase Chain Reaction, Sequence Alignment, Sequence Analysis, DNA, Taiwan, Alleles, Exons, HLA-B7 Antigen genetics, Point Mutation, Tissue Donors
- Abstract
One nucleotide replacement at residue 559 of HLA-B*07:05:01:01 or B*07:06:01 results in a novel allele, HLA-B*07:269., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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- View/download PDF
32. Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus.
- Author
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Chen D, Enroth S, Liu H, Sun Y, Wang H, Yu M, Deng L, Xu S, and Gyllensten U
- Subjects
- Alleles, Case-Control Studies, Female, Genome, Human, Genotype, HLA-B Antigens genetics, HLA-B7 Antigen genetics, HLA-DQ alpha-Chains genetics, HLA-DQ beta-Chains genetics, HLA-DRB1 Chains genetics, Humans, Polymorphism, Single Nucleotide, Risk, Genetic Predisposition to Disease, Genome-Wide Association Study, Uterine Cervical Neoplasms genetics, Uterine Cervical Dysplasia genetics
- Abstract
Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 × 10-24; rs2516448, 1.1 × 10-15; and rs3130196, 2.3 × 10-9, respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54-0.67, P = 3.0 × 10-19), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3., Competing Interests: Conflicts of Interest: None declared.
- Published
- 2016
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33. Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers.
- Author
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Baía D, Pou J, Jones D, Mandelboim O, Trowsdale J, Muntasell A, and López-Botet M
- Subjects
- Alleles, Amino Acid Sequence, Cell Line, Gene Expression, HLA-A Antigens chemistry, HLA-A Antigens genetics, HLA-A Antigens immunology, HLA-B7 Antigen chemistry, HLA-B7 Antigen genetics, HLA-B7 Antigen immunology, HLA-B7 Antigen metabolism, Humans, Interferon Type I metabolism, Interferon Type I pharmacology, Leukocyte Immunoglobulin-like Receptor B1, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Monocytes drug effects, Monocytes immunology, Monocytes metabolism, Protein Binding, Antigens, CD metabolism, HLA-A Antigens metabolism, Protein Multimerization, Receptors, Immunologic metabolism
- Abstract
Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) has been reported to interact with a wide spectrum of HLA class I (HLA-I) molecules, albeit with different affinities determined by allelic polymorphisms and conformational features. HLA-G dimerization and the presence of intracellular Cys residues in HLA-B7 have been shown to be critical for their recognition by LILRB1. We hypothesized that dimerization of classical HLA class Ia molecules, previously detected in exosomes, might enhance their interaction with LILRB1. A soluble LILRB1-Fc fusion protein and a sensitive cellular reporter system expressing a LILRB1-ζ chimera were employed to assess receptor interaction with different HLA class Ia molecules transfected in the human lymphoblastoid 721.221 cell line. Under these conditions, intracellular Cys residues and HLA-I dimerization appeared associated with increased LILRB1 recognition. On the other hand, a marginal interaction of LILRB1 with primary monocytic cells, irrespective of their high HLA-I expression, was enhanced by type I interferon (IFN). This effect appeared disproportionate to the cytokine-induced increase of surface HLA-I expression and was accompanied by detection of HLA class Ia dimers. Altogether, the results support that a regulated assembly of these noncanonical HLA-I conformers during the immune response may enhance the avidity of their interaction with LILRB1., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
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34. Identification of the novel HLA-B*07:261 allele.
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Brunet L, Mouron D, Villard J, Tiercy JM, and Buhler S
- Subjects
- Humans, Alleles, HLA-B7 Antigen genetics
- Published
- 2016
- Full Text
- View/download PDF
35. Developments in Intralesional Therapy for Metastatic Melanoma.
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Sloot S, Rashid OM, Sarnaik AA, and Zager JS
- Subjects
- Administration, Cutaneous, BCG Vaccine administration & dosage, BCG Vaccine adverse effects, BCG Vaccine therapeutic use, DNA, Recombinant administration & dosage, DNA, Recombinant therapeutic use, Electrochemotherapy methods, Fluorescent Dyes administration & dosage, Fluorescent Dyes therapeutic use, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, HLA-B7 Antigen genetics, Herpesvirus 1, Human, Humans, Interleukin-2 administration & dosage, Interleukin-2 therapeutic use, Lipids administration & dosage, Lipids therapeutic use, Melanoma genetics, Rose Bengal administration & dosage, Rose Bengal therapeutic use, Skin Neoplasms genetics, Genetic Therapy, Immunotherapy, Injections, Intralesional methods, Melanoma therapy, Oncolytic Viruses, Skin Neoplasms therapy
- Abstract
Background: Locoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing., Methods: The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents., Results: Intralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary., Conclusions: Due to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.
- Published
- 2016
- Full Text
- View/download PDF
36. Detection of a novel variant of HLA-B*07, HLA-B*07:249, in a Taiwanese unrelated hematopoietic stem cell donor.
- Author
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Yang KL, Hung JH, and Lin PY
- Subjects
- Base Sequence, Codon, Exons, HLA-B7 Antigen immunology, Hematopoietic Stem Cell Transplantation, Histocompatibility Testing, Humans, Molecular Sequence Data, Sequence Alignment, Sequence Analysis, DNA, Taiwan, Unrelated Donors, Alleles, HLA-B7 Antigen genetics, Point Mutation
- Abstract
One nucleotide replacement at residue 398 of HLA-B*07:05:01 or HLA-B*07:06 results in a novel allele, HLA-B*07:249., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
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37. Cell surface expression level variation between two common Human Leukocyte Antigen alleles, HLA-A2 and HLA-B8, is dependent on the structure of the C terminal part of the alpha 2 and the alpha 3 domains.
- Author
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Dellgren C, Nehlin JO, and Barington T
- Subjects
- Alleles, Amino Acid Sequence, Gene Expression Regulation, HEK293 Cells, HLA-A2 Antigen chemistry, HLA-A2 Antigen immunology, HLA-A3 Antigen chemistry, HLA-A3 Antigen immunology, HLA-B7 Antigen chemistry, HLA-B7 Antigen immunology, HLA-B8 Antigen chemistry, HLA-B8 Antigen immunology, Histocompatibility Testing, Humans, Interferon-gamma, Molecular Sequence Data, Plasmids chemistry, Plasmids metabolism, Protein Structure, Tertiary, RNA, Messenger immunology, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins immunology, Transfection, HLA-A2 Antigen genetics, HLA-A3 Antigen genetics, HLA-B7 Antigen genetics, HLA-B8 Antigen genetics, RNA, Messenger genetics, Recombinant Fusion Proteins genetics
- Abstract
Constitutive cell surface expression of Human Leukocyte Antigen (HLA) class I antigens vary extremely from tissue to tissue and individual antigens may differ widely in expression levels. Down-regulation of class I expression is a known immune evasive mechanism used by cancer cells and viruses. Moreover, recent observations suggest that even minor differences in expression levels may influence the course of viral infections and the frequency of complications to stem cell transplantation. We have shown that some human multipotent stem cells have high expression of HLA-A while HLA-B is only weakly expressed, and demonstrate here that this is also the case for the human embryonic kidney cell line HEK293T. Using quantitative flow cytometry and quantitative polymerase chain reaction we found expression levels of endogenous HLA-A3 (median 71,204 molecules per cell) 9.2-fold higher than the expression of-B7 (P = 0.002). Transfection experiments with full-length HLA-A2 and -B8 encoding plasmids confirmed this (54,031 molecules per cell vs. 2,466, respectively, P = 0.001) independently of transcript levels suggesting a post-transcriptional regulation. Using chimeric constructs we found that the cytoplasmic tail and the transmembrane region had no impact on the differential cell surface expression. In contrast, ~65% of the difference could be mapped to the six C-terminal amino acids of the alpha 2 domain and the alpha 3 domain (amino acids 176-284), i.e. amino acids not previously shown to be of importance for differential expression levels of HLA class I molecules. We suggest that the differential cell surface expression of two common HLA-A and-B alleles is regulated by a post-translational mechanism that may involve hitherto unrecognized molecules.
- Published
- 2015
- Full Text
- View/download PDF
38. Association Between HLA Haplotypes and Increased Serum Levels of IgG4 in Patients With Primary Sclerosing Cholangitis.
- Author
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Berntsen NL, Klingenberg O, Juran BD, Benito de Valle M, Lindkvist B, Lazaridis KN, Boberg KM, Karlsen TH, and Hov JR
- Subjects
- Biomarkers blood, Cholangitis, Sclerosing blood, Cholangitis, Sclerosing diagnosis, Gene Frequency, Genetic Predisposition to Disease, HLA-B7 Antigen genetics, HLA-B8 Antigen genetics, HLA-DRB1 Chains genetics, Humans, Norway, Phenotype, Sweden, United States, Up-Regulation, Cholangitis, Sclerosing genetics, Cholangitis, Sclerosing immunology, HLA Antigens genetics, Haplotypes, Immunoglobulin G blood
- Abstract
Increased serum levels of IgG4 have been reported in 9%-15% of patients with primary sclerosing cholangitis (PSC); it is not clear whether this increase contributes to pathogenesis. We performed genetic analyses of the HLA complex in patients with PSC from Norway, Sweden, and from the United States. We found an association between levels of IgG4 above the upper reference limit and specific HLA haplotypes. These patients had a significantly lower frequency of the strongest PSC risk factor, HLA-B*08, than patients without increased IgG4, and significantly higher frequencies of HLA-B*07 and HLA-DRB1*15. HLA genotype therefore might affect the serum concentration of IgG4, and increased IgG4 might be a marker of a distinct phenotype of PSC., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
39. Human herpesvirus 6B immediate-early I protein contains functional HLA-A*02, HLA-A*03, and HLA-B*07 class I restricted CD8(+) T-cell epitopes.
- Author
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Iampietro M, Morissette G, Gravel A, Dubuc I, Rousseau M, Hasan A, O'Reilly RJ, and Flamand L
- Subjects
- Adolescent, Adoptive Transfer, Adult, Animals, CD8-Positive T-Lymphocytes pathology, Cell Proliferation genetics, Epitopes, T-Lymphocyte genetics, Female, HLA-A2 Antigen genetics, HLA-A3 Antigen genetics, HLA-B7 Antigen genetics, Herpesvirus 6, Human genetics, Humans, Immediate-Early Proteins genetics, Immunity, Cellular genetics, Male, Mice, Mice, Transgenic, Middle Aged, Roseolovirus Infections genetics, Roseolovirus Infections immunology, Roseolovirus Infections pathology, Roseolovirus Infections therapy, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, HLA-A2 Antigen immunology, HLA-A3 Antigen immunology, HLA-B7 Antigen immunology, Herpesvirus 6, Human immunology, Immediate-Early Proteins immunology
- Abstract
Human herpesvirus 6B (HHV-6B) is a ubiquitous pathogen with frequent reactivation observed in immunocompromised patients such as BM transplant (BMT) recipients. Adoptive immunotherapy is a promising therapeutic avenue for the treatment of opportunistic infections, including herpesviruses. While T-cell immunotherapy can successfully control CMV and EBV reactivations in BMT recipients, such therapy is not available for HHV-6 infections, in part due to a lack of identified protective CD8(+) T-cell epitopes. Our goal was to identify CD8(+) T-cell viral epitopes derived from the HHV-6B immediate-early protein I and presented by common human leukocyte Ag (HLA) class I alleles including HLA-A*02, HLA-A*03, and HLA-B*07. These epitopes were functionally tested for their ability to induce CD8(+) T-cell expansion and kill HHV-6-infected autologous cells. Cross-reactivity of specific HHV-6B-expanded T cells against HHV-6A-infected cells was also confirmed for a conserved epitope presented by HLA-A*02 molecule. Our findings will help push forward the field of adoptive immunotherapy for the treatment and/or the prevention of HHV-6 reactivation in BMT recipients., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
- Full Text
- View/download PDF
40. HLA-B27, but not HLA-B7, immunodominance to influenza is ERAP dependent.
- Author
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Akram A, Lin A, Gracey E, Streutker CJ, and Inman RD
- Subjects
- Aminopeptidases genetics, Animals, Gene Expression Regulation genetics, Gene Expression Regulation immunology, Genetic Predisposition to Disease, HLA-B27 Antigen genetics, HLA-B7 Antigen genetics, Humans, Influenza A Virus, H3N2 Subtype genetics, Mice, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections pathology, Spondylitis, Ankylosing genetics, Spondylitis, Ankylosing immunology, Spondylitis, Ankylosing pathology, Alleles, Aminopeptidases immunology, HLA-B27 Antigen immunology, HLA-B7 Antigen immunology, Influenza A Virus, H3N2 Subtype immunology, Orthomyxoviridae Infections immunology
- Abstract
Endoplasmic reticulum-associated aminopeptidase-1 (ERAP1) plays a critical role in the processing of peptides prior to binding to MHC class I molecules. In this article, we show for the first time, to our knowledge, that the HLA-B27 immunodominant influenza nucleoprotein (NP) 383-391 epitope is made as an N-terminally extended 14-mer before it is trimmed by ERAP. In the absence of ERAP, there is a significant reduction in the CTL response to the B27/NP383-391 epitope in influenza A (flu)-infected B27/ERAP(-/-) mice. With the use of tetramer staining, the number of naive CD8(+) T cells expressing TCR Vβ8.1 in B27/ERAP(-/-) transgenic mice is significantly lower than that seen in B27/ERAP(+/+) mice. HLA-B27 surface expression in naive and flu-infected B27/ERAP(-/-) mice is also lower than the expression seen for the same allele in naive and flu-infected B27/ERAP(+/+) mice. In contrast, surface expression of HLA-B7 was unaffected by the absence of ERAP in B7/ERAP(-/-) transgenic mice. The B7-restricted NP418-426 CTL response in flu-infected B7/ERAP(-/-) and B7/ERAP(+/+) mice was also similar. These results provide, to our knowledge, the first in vivo demonstration of ERAP functionally influencing host immune response in an HLA allele-specific manner. This principle has relevance to diseases such as ankylosing spondylitis, in which HLA-B27 and ERAP jointly contribute to disease predisposition., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
41. HIV subtype influences HLA-B*07:02-associated HIV disease outcome.
- Author
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Kløverpris HN, Adland E, Koyanagi M, Stryhn A, Harndahl M, Matthews PC, Shapiro R, Walker BD, Ndung'u T, Brander C, Takiguchi M, Buus S, and Goulder P
- Subjects
- Adult, Cohort Studies, Disease Progression, Genotype, HIV Infections genetics, HIV-1 genetics, HLA-B7 Antigen metabolism, Humans, gag Gene Products, Human Immunodeficiency Virus genetics, Epitopes, T-Lymphocyte immunology, HIV Infections immunology, HIV-1 immunology, HLA-B7 Antigen genetics, Polymorphism, Genetic, gag Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Genetic polymorphisms within the MHC encoding region have the strongest impact on HIV disease progression of any in the human genome and provide important clues to the mechanisms of HIV immune control. Few analyses have been undertaken of HLA alleles associated with rapid disease progression. HLA-B*07:02 is an HLA class I molecule that is prevalent in most populations worldwide and that has previously been consistently linked to accelerated disease progression in B-clade infection. This study investigates the observation that HLA-B*07:02 is not associated with a high viral setpoint in C-clade infection. We examine the hypothesis that this clade-specific difference in association with disease outcome may be related to distinct targeting of CD8(+) T cell epitopes. We observed that C-clade-infected individuals with HLA-B*07:02 target a broader range of Gag epitopes, and to higher magnitudes, than do individuals infected with B-clade infection. In particular, a novel p17-Gag (Gag22-30, RPGGKKHYM) epitope is targeted in >50% of HLA-B*07:02-positive C-clade-infected individuals but clade-specific differences in this epitope result in nonimmunogenicity in B-clade infection. Only the C-clade p24-Gag "GL9" (Gag355-363, GPSHKARVL) epitope-specific CD8(+) T cell response out of 16 studied was associated with a low viral setpoint. Although this epitope was also targeted in B-clade infection, the escape mutant S357S is present at higher frequency in B-clade infection than in C-clade infection (70% versus 43% in HLA-B*07:02-negative subjects). These data support earlier studies suggesting that increased breadth of the Gag-specific CD8(+) T cell response may contribute to improved HIV immune control irrespective of the particular HLA molecules expressed.
- Published
- 2014
- Full Text
- View/download PDF
42. HLA class I alleles are associated with peptide-binding repertoires of different size, affinity, and immunogenicity.
- Author
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Paul S, Weiskopf D, Angelo MA, Sidney J, Peters B, and Sette A
- Subjects
- Algorithms, Alleles, Animals, Antigens, Viral chemistry, Antigens, Viral immunology, Dengue Virus immunology, Epitopes, T-Lymphocyte metabolism, HLA-A1 Antigen genetics, HLA-A1 Antigen metabolism, HLA-A2 Antigen genetics, HLA-A2 Antigen metabolism, HLA-B7 Antigen genetics, HLA-B7 Antigen metabolism, Immunization, Inhibitory Concentration 50, Mice, Mice, Transgenic, Peptide Fragments chemistry, Peptide Fragments immunology, Peptide Fragments metabolism, Protein Binding, Antigen Presentation, Epitopes, T-Lymphocyte immunology, Genes, MHC Class I, HLA-A1 Antigen immunology, HLA-A2 Antigen immunology, HLA-B7 Antigen immunology
- Abstract
Prediction of HLA binding affinity is widely used to identify candidate T cell epitopes, and an affinity of 500 nM is routinely used as a threshold for peptide selection. However, the fraction (percentage) of peptides predicted to bind with affinities of 500 nM varies by allele. For example, of a large collection of ~30,000 dengue virus-derived peptides only 0.3% were predicted to bind HLA A*0101, whereas nearly 5% were predicted for A*0201. This striking difference could not be ascribed to variation in accuracy of the algorithms used, as predicted values closely correlated with affinity measured in vitro with purified HLA molecules. These data raised the question whether different alleles would also vary in terms of epitope repertoire size, defined as the number of associated epitopes or, alternatively, whether alleles vary drastically in terms of the affinity threshold associated with immunogenicity. To address this issue, strains of HLA transgenic mice with wide (A*0201), intermediate (B*0702), or narrow (A*0101) repertoires were immunized with peptides of varying binding affinity and relative percentile ranking. The results show that absolute binding capacity is a better predictor of immunogenicity, and analysis of epitopes from the Immune Epitope Database revealed that predictive efficacy is increased using allele-specific affinity thresholds. Finally, we investigated the genetic and structural basis of the phenomenon. Although no stringent correlate was defined, on average HLA B alleles are associated with significantly narrower repertoires than are HLA A alleles.
- Published
- 2013
- Full Text
- View/download PDF
43. The novel HLA-B allele, HLA-B*07:110, was identified by sequencing genomic DNA.
- Author
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Li JP, Li XF, Zhang X, Lin FQ, and Zhang KL
- Subjects
- Base Sequence, China, DNA genetics, Genome, Histocompatibility Testing, Humans, Molecular Sequence Data, Polymorphism, Genetic, Sequence Alignment, Sequence Analysis, DNA, Tissue Donors, HLA-B7 Antigen genetics
- Published
- 2013
- Full Text
- View/download PDF
44. Identification of a novel HLA-B allele HLA-B*07:185 in a Japanese individual.
- Author
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Maekawa K, Futagami T, Kusunoki Y, Matsuzaki Y, and Takikawa H
- Subjects
- Base Sequence, Gene Frequency, Genetic Predisposition to Disease, Histocompatibility Testing, Humans, Japan, Molecular Sequence Data, Polymorphism, Single Nucleotide, Sequence Alignment, Chemical and Drug Induced Liver Injury genetics, HLA-B7 Antigen genetics
- Published
- 2013
- Full Text
- View/download PDF
45. Co-expression of HLA-B7 and HLA-B27 alleles is associated with B7-restricted immunodominant responses following influenza infection.
- Author
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Akram A and Inman RD
- Subjects
- Animals, Antigens, Viral genetics, Antigens, Viral metabolism, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Gene Expression, HLA-B27 Antigen biosynthesis, HLA-B27 Antigen genetics, HLA-B7 Antigen biosynthesis, HLA-B7 Antigen genetics, Humans, Immunity, Cellular genetics, Immunodominant Epitopes genetics, Immunodominant Epitopes metabolism, Influenza A Virus, H3N2 Subtype genetics, Influenza A Virus, H3N2 Subtype metabolism, Mice, Mice, Knockout, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections metabolism, Orthomyxoviridae Infections pathology, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell, alpha-beta metabolism, Antigens, Viral immunology, CD8-Positive T-Lymphocytes immunology, HLA-B27 Antigen immunology, HLA-B7 Antigen immunology, Immunodominant Epitopes immunology, Influenza A Virus, H3N2 Subtype immunology, Orthomyxoviridae Infections immunology
- Abstract
It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K(-/-)/D(-/-) double-knockout transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted matrix I.58-66, the B7-restricted NP418-426 or the B27-restricted NP383-391 influenza A (flu) epitopes, we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice, a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1(+) NP383/B27-restricted CD8(+) T cells, and a diminished Vβ12(+) CD8(+) T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice, we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens., (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
46. Atopic dermatitis complicated by eczema herpeticum is associated with HLA B7 and reduced interferon-γ-producing CD8+ T cells.
- Author
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Mathias RA, Weinberg A, Boguniewicz M, Zaccaro DJ, Armstrong B, Schneider LC, Hata TR, Hanifin JM, Beck LA, Barnes KC, and Leung DY
- Subjects
- CD8-Positive T-Lymphocytes metabolism, Case-Control Studies, Dermatitis, Atopic complications, Gene Frequency, HLA-B7 Antigen genetics, Humans, Kaposi Varicelliform Eruption complications, Leukocytes, Mononuclear immunology, Phenotype, CD8-Positive T-Lymphocytes immunology, Dermatitis, Atopic immunology, HLA-B7 Antigen immunology, Immunity, Cellular physiology, Interferon-gamma biosynthesis, Kaposi Varicelliform Eruption immunology
- Abstract
Background: The increased susceptibility of patients with atopic dermatitis (AD) to disseminated viral skin infections such as eczema herpeticum (ADEH+) is poorly understood., Objectives: The primary goal of the current study was to determine whether ADEH+ subjects have identifiable defects in cell-mediated immunity that reduce their ability to control viral infections., Materials and Methods: In this study, we evaluated cytokine expression by various subsets of peripheral blood mononuclear cells from ADEH+ (n = 24) compared with AD without a history of viral infections (ADEH-) (n = 20) before and after treatment with herpes simplex virus (HSV)., Results: We found that interferon (IFN)-γ expression after HSV treatment was lower in the CD8+ T cells and monocytes from patients with ADEH+ compared with patients who are ADEH- or nonatopic. Given the induction of CD8+ T cells as the result of antigen presentation by human leucocyte antigen (HLA) class I, consistent with the findings described above we also found that the HLA B7 allele was significantly associated with risk of the ADEH+ phenotype (odds ratio = 1·91, P = 0·02, 125 ADEH+ and 161 ADEH- subjects)., Conclusions: These data suggest that defects in viral-induced IFN-γ from CD8+ T cells contribute to the ADEH+ phenotype., (© 2013 British Association of Dermatologists.)
- Published
- 2013
- Full Text
- View/download PDF
47. The frequency of HLA alleles in a population of Inuit women of northern Quebec.
- Author
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Metcalfe S, Roger M, Faucher MC, Coutlée F, Franco EL, and Brassard P
- Subjects
- Adolescent, Adult, Aged, Female, HLA-B7 Antigen genetics, HLA-DQ beta-Chains genetics, Haplotypes genetics, Heterozygote, Homozygote, Humans, Middle Aged, Quebec epidemiology, Young Adult, Gene Frequency genetics, HLA Antigens genetics, Inuit genetics
- Abstract
Background: Human leukocyte antigen (HLA) alleles code for proteins that are involved in the recognition of foreign antigens and activation of the immune system. The frequency of HLA alleles varies across different populations., Objective: To describe the frequency of HLA alleles in a population of Inuit women of Nunavik, Quebec, Canada., Design: A cohort of women was recruited from 4 different communities between January 2002 and December 2007. HLA-B*07, HLA-DQB1*03, DQB1*06:02, DRB1*13 and DRB1*15:01 alleles were typed by PCR sequence-specific primers (PCR-SSP) and HLA-E and G alleles were type by DNA-sequencing procedures., Results: We obtained data on 524 participants. The most frequent HLA alleles in this population were HLA-E*01:03, HLA-G*01:04:01 and HLA-DQB1*03, and they were found in 89, 75 and 94% of the population, respectively., Conclusions: The distribution of HLA alleles in Nunavik, Quebec is unique when compared to other populations in Canada or around the world.
- Published
- 2013
- Full Text
- View/download PDF
48. Identification of a novel HLA-B allele, B*07:162, in a Taiwanese individual.
- Author
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Chen PL, Lai SK, Yang WS, Chang TC, and Chu CC
- Subjects
- Base Sequence, Exons genetics, Humans, Molecular Sequence Data, Sequence Alignment, Taiwan ethnology, Alleles, Asian People genetics, HLA-B7 Antigen genetics
- Abstract
The new allele, HLA-B*07:162, is identical to HLA-B*07:12 in exon 2 but has a non-synonymous substitution at position 419 (A to C) in exon 3., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
49. A novel HLA-B allele, B*07:55, identified by sequence-based typing.
- Author
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Liu N, Zhang Z, Shan X, Wang L, and Cui S
- Subjects
- Base Sequence, Exons genetics, Humans, Molecular Sequence Data, Sequence Alignment, Alleles, HLA-B7 Antigen genetics, Histocompatibility Testing
- Abstract
The novel allele differs from HLA-B*07:02:01 by a single nucleotide substitution at position 538 in exon 3., (© 2013 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
50. B*07:156, revealed by sequence-based typing of a leukemia patient and confirmed by allele-specific amplification.
- Author
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Witter K, Albert T, Spannagl M, and Dick A
- Subjects
- Alleles, Humans, Molecular Sequence Data, HLA-B7 Antigen genetics, Leukemia genetics, Leukemia immunology
- Abstract
We present the full-length sequence of the novel allele HLA-B*07:156, closely related to B*07:02:01., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
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