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Browne DJ, Crooks P, Smith C, Doolan DL. Differential reactivity of SARS-CoV-2 S-protein T-cell epitopes in vaccinated versus naturally infected individuals. Clin Transl Immunology 2025; 14:e70031. [PMID: 40342296 PMCID: PMC12056234 DOI: 10.1002/cti2.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/20/2025] [Accepted: 03/18/2025] [Indexed: 05/11/2025] Open
Abstract
Objectives Vaccine-induced protective immunity against SARS-CoV-2 has proved difficult to sustain. Robust T-cell responses are thought to play an important role, but T-cell responses against the SARS-CoV-2 spike protein (S-protein), the core vaccine antigen, following vaccination or natural infection are incompletely understood. Methods Herein, the reactivity of 170 putative SARS-CoV-2 S-protein CD8+ and CD4+ T-cell peptide epitopes in the same individuals prior to vaccination, after COVID-19 vaccination, and again following subsequent natural infection was assayed using a high-throughput reverse transcription-quantitative PCR (HTS-RT-qPCR) assay. Results The profile of immunoreactive SARS-CoV-2 S-protein epitopes differed between vaccination and natural infection. Vaccine-induced immunoreactive epitopes were localised primarily into two extra-domanial regions. In contrast, epitopes recognised following natural infection were spread across the antigen. Furthermore, T-cell epitopes in naïve individuals were primarily recognised in association with HLA-A, while natural infection shifted epitope associations towards HLA-B, particularly the B7 supertype. Conclusion This study provides insight into T-cell responses against the SARS-CoV-2 S-protein following vaccination and subsequent natural infection.
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Affiliation(s)
- Daniel J Browne
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and MedicineJames Cook UniversityCairnsQLDAustralia
| | - Pauline Crooks
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory, Department of ImmunologyQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia
| | - Corey Smith
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development and Translational and Human Immunology Laboratory, Department of ImmunologyQIMR Berghofer Medical Research InstituteBrisbaneQLDAustralia
- Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
| | - Denise L Doolan
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and MedicineJames Cook UniversityCairnsQLDAustralia
- Institute for Molecular BioscienceThe University of QueenslandSt LuciaQLDAustralia
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Eslami M, Arjmand N, Mahmoudian F, Babaeizad A, Tahmasebi H, Fattahi F, Oksenych V. Deciphering Host-Virus Interactions and Advancing Therapeutics for Chronic Viral Infection. Viruses 2025; 17:390. [PMID: 40143318 PMCID: PMC11946419 DOI: 10.3390/v17030390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/26/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Chronic viral infections like HIV, HBV, and HCV establish persistent interactions with the host immune system, resulting in immune evasion and long-term immune dysfunction. These viruses use a range of strategies to limit host defenses, such as downregulating MHC class I, disrupting interferon signaling, altering apoptosis pathways, and suppressing cytotoxic T-cell activity. Key viral proteins, including HIV Nef, HBV X protein, and HCV NS5A, interfere with antigen presentation and JAK/STAT signaling, thereby reducing antiviral immune responses. Chronic infections induce immune exhaustion due to persistent antigen exposure, which leads to the expression of inhibitory receptors like PD-1 and CTLA-4 on T cells. Viral epigenetic changes, such as N6-methyladenosine modifications and histone deacetylation, enhance immune evasion by modulating gene expression in infected cells. Viruses further manipulate host cytokine networks by promoting an immunosuppressive environment through IL-10 and TGF-β secretion, which suppress inflammatory responses and inhibit T-cell activation. This review examines the molecular/cellular mechanisms that enable chronic viruses to escape host immunity, focusing on antigenic variation, cytokine disruption, and control of apoptotic pathways. It also addresses how host genetic factors, such as HLA polymorphisms, influence disease progression. Lastly, we discuss host-targeted therapies, including immune checkpoint inhibitors, cytokine treatments, and CRISPR.
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Affiliation(s)
- Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran; (M.E.)
- Department of Bacteriology and Virology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Neda Arjmand
- Department of Obstetrics and Gynecology, Tehran Medical University, Tehran 14167-53955, Iran
| | - Fatemeh Mahmoudian
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran; (M.E.)
| | - Ali Babaeizad
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Hamed Tahmasebi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud 36147-73943, Iran
| | - Fahimeh Fattahi
- Clinical Research Development Unit of Ayatollah-Khansari Hospital, Arak University of Medical Sciences, Arak 38186-49433, Iran
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James LM, Georgopoulos AP. Immunogenetics of longevity and its association with human endogenous retrovirus K. FRONTIERS IN AGING 2025; 6:1471202. [PMID: 39967996 PMCID: PMC11832543 DOI: 10.3389/fragi.2025.1471202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 01/20/2025] [Indexed: 02/20/2025]
Abstract
Introduction The human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality. Methods We utilized high-resolution genotyping to characterize HLA and apolipoprotein E in a large sample (N = 986) of participants (469 men, 517 women) ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. Since each individual carries 12 classical HLA alleles (6 alleles of each Class I and Class II), we determined in silico the median predicted binding affinity for each individual (across the 12 HLA alleles) and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW). Next, we performed a stepwise multiple linear regression where the age of the participant was the dependent variable and the 13 median predicted HLA-virus binding affinities were the independent variables. Results The analyses yielded only one statistically significant effect-namely, a positive association between age and HERVK (P = 0.005). Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses (P < 0.001). ApoE genotypes did not differ significantly between older and younger groups. Discussion Taken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.
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Affiliation(s)
- Lisa M. James
- Department of Veterans Affairs Health Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN, United States
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Apostolos P. Georgopoulos
- Department of Veterans Affairs Health Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN, United States
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States
- Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, MN, United States
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Cameron CM, Raghu V, Richardson B, Zagore LL, Tamilselvan B, Golden J, Cartwright M, Schoen RE, Finn OJ, Benos PV, Cameron MJ. Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention. Front Immunol 2024; 15:1437391. [PMID: 39450169 PMCID: PMC11499122 DOI: 10.3389/fimmu.2024.1437391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Introduction Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Methods Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. Results MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-κB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. Discussion These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
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Affiliation(s)
- Cheryl M. Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Vineet Raghu
- Department of Computer Science, University of Pittsburgh, Pittsburgh, PA, United States
- Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States
| | - Brian Richardson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Leah L. Zagore
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Banumathi Tamilselvan
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, United States
| | - Jackelyn Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Michael Cartwright
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
| | - Robert E. Schoen
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States
| | - Olivera J. Finn
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Panayiotis V. Benos
- Department of Epidemiology, University of Florida, Gainesville, FL, United States
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Mark J. Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
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Dratwa-Kuzmin M, Hadra BA, Oguz F, Ogret Y, Constantinescu I, Apostol D, Talangescu A, Constantinescu AE, Maruntelu I, Kościńska K, Lukanov T, Naumova E, Bogunia-Kubik K. Telomere Length, HLA, and Longevity-Results from a Multicenter Study. Int J Mol Sci 2024; 25:9457. [PMID: 39273401 PMCID: PMC11395078 DOI: 10.3390/ijms25179457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Aging is an exceptionally complex process that depends on genetic, environmental, and lifestyle factors. Previous studies within the International HLA and Immunogenetics Workshop (IHIWS) component "Immunogenetics of Ageing" showed that longevity is associated with positive selection of HLA-DRB1*11- and DRB1*16-associated haplotypes, shown to be protective against diseases. Within the 18th IHIWS, we aimed to investigate the relevance of telomere length for successful aging and its association with classical HLAs. In total 957 individuals from Bulgaria, Turkey, Romania, and Poland in two age groups, elderly individuals (age 65-99 years) and ethnically matched young group (age 18-64 years), were investigated. The obtained results confirmed interpopulation differences in the distribution of HLA alleles, documented the lengths of telomeres in analyzed populations, and demonstrated significant associations of telomere length with aging as well as with the presence of some HLA class I or class II alleles. They suggest that telomere length assessment combined with HLA genotyping may help identify immunogenetic profiles associated with longevity. The associations between HLA and telomeres support the theory that HLA genes influence the aging process. However, further research is needed to clarify the biological basis of the observed relationships.
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Affiliation(s)
- Marta Dratwa-Kuzmin
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfled Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Bushra Al Hadra
- Clinic of Clinical Immunology and Stem Cell Bank, University Hospital Alexandrovska, 1431 Sofia, Bulgaria
- Department of Clinical Immunology, Medical University, 1431 Sofia, Bulgaria
| | - Fatma Oguz
- Department of Medical Biology, Istanbul Medical Faculty, Istanbul University, 34098 Istanbul, Turkey
| | - Yeliz Ogret
- Department of Medical Biology, Istanbul Medical Faculty, Istanbul University, 34098 Istanbul, Turkey
| | - Ileana Constantinescu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 022328 Bucharest, Romania
| | - Dimitri Apostol
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 022328 Bucharest, Romania
| | - Adriana Talangescu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 022328 Bucharest, Romania
| | - Alexandra-Elena Constantinescu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 022328 Bucharest, Romania
| | - Ion Maruntelu
- Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 022328 Bucharest, Romania
| | - Katarzyna Kościńska
- HLA Laboratory, Lower Silesian Oncology, Pulmonology and Hematology Center, 54-049 Wroclaw, Poland
| | - Tsvetelin Lukanov
- Clinic of Clinical Immunology and Stem Cell Bank, University Hospital Alexandrovska, 1431 Sofia, Bulgaria
- Department of Clinical Immunology, Medical University, 1431 Sofia, Bulgaria
| | - Elissaveta Naumova
- Clinic of Clinical Immunology and Stem Cell Bank, University Hospital Alexandrovska, 1431 Sofia, Bulgaria
- Department of Clinical Immunology, Medical University, 1431 Sofia, Bulgaria
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfled Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
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Arnaiz-Villena A, Juarez I, Vaquero-Yuste C, Lledo T, Martin-Villa JM, Suarez-Trujillo F. Complex Interactions between the Human Major Histocompatibility Complex (MHC) and Microbiota: Their Roles in Disease Pathogenesis and Immune System Regulation. Biomedicines 2024; 12:1928. [PMID: 39200390 PMCID: PMC11352054 DOI: 10.3390/biomedicines12081928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/02/2024] Open
Abstract
The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota".
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Affiliation(s)
- Antonio Arnaiz-Villena
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Ignacio Juarez
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Christian Vaquero-Yuste
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Tomás Lledo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - José Manuel Martin-Villa
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
| | - Fabio Suarez-Trujillo
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (I.J.); (C.V.-Y.); (T.L.); (J.M.M.-V.); (F.S.-T.)
- Instituto de Investigacion Sanitaria Gegorio Marañon, 28009 Madrid, Spain
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Bello N, Hudu SA, Alshrari AS, Imam MU, Jimoh AO. Overview of Hepatitis B Vaccine Non-Response and Associated B Cell Amnesia: A Scoping Review. Pathogens 2024; 13:554. [PMID: 39057781 PMCID: PMC11279426 DOI: 10.3390/pathogens13070554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND The advent of the hepatitis B vaccine has achieved tremendous success in eradicating and reducing the burden of hepatitis B infection, which is the main culprit for hepatocellular carcinoma-one of the most fatal malignancies globally. Response to the vaccine is achieved in about 90-95% of healthy individuals and up to only 50% in immunocompromised patients. This review aimed to provide an overview of hepatitis B vaccine non-response, the mechanisms involved, B cell amnesia, and strategies to overcome it. METHODS Databases, including Google Scholar, PubMed, Scopus, Cochrane, and ClinicalTrials.org, were used to search and retrieve articles using keywords on hepatitis B vaccine non-response and B cell amnesia. The PRISMA guideline was followed in identifying studies, screening, selection, and reporting of findings. RESULTS A total of 133 studies on hepatitis B vaccine non-response, mechanisms, and prevention/management strategies were included in the review after screening and final selection. Factors responsible for hepatitis B vaccine non-response were found to include genetic, immunological factors, and B cell amnesia in healthy individuals. The genetic factors were sex, HLA haplotypes, and genetic polymorphisms in immune response markers (cytokines). Non-response was common in conditions of immunodeficiency, such as renal failure, haemodialysis, celiac disease, inflammatory bowel disease, hepatitis C co-infection, and latent hepatitis B infection. Others included diabetes mellitus and HIV infection. The mechanisms involved were impaired immune response by suppression of response (T helper cells) or induced suppression of response (through regulatory B and T cells). DISCUSSION A comprehensive and careful understanding of the patient factors and the nature of the vaccine contributes to developing effective preventive measures. These include revaccination or booster dose, vaccine administration through the intradermal route, and the use of adjuvants in the vaccine.
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Affiliation(s)
- Nura Bello
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria 810107, Nigeria
| | - Shuaibu A. Hudu
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
- Department of Medical Microbiology and Parasitology, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria
| | - Ahmed S. Alshrari
- Medical Laboratory Technology Department, Faculty of Applied Medical Science, Northern Border University, Arar 91431, Saudi Arabia;
| | - Mustapha U. Imam
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
| | - Abdulgafar O. Jimoh
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
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Machraoui S, Errafii K, Oujamaa I, Belghali MY, Hakmaoui A, Lamjadli S, Eddehbi FE, Brahim I, Haida Y, Admou B. Frequency of the Main Human Leukocyte Antigen A, B, DR, and DQ Loci Known to Be Associated with the Clearance or Persistence of Hepatitis C Virus Infection in a Healthy Population from the Southern Region of Morocco: A Preliminary Study. Diseases 2024; 12:106. [PMID: 38785761 PMCID: PMC11120154 DOI: 10.3390/diseases12050106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 05/25/2024] Open
Abstract
Hepatitis C Virus (HCV) infection represents a significant global health challenge, with its natural course largely influenced by the host's immune response. Human Leukocyte Antigen (HLA) molecules, particularly HLA class I and II, play a crucial role in the adaptive immune response against HCV. The polymorphism of HLA molecules contributes to the variability in immune response, affecting the outcomes of HCV infection. This study aims to investigate the frequency of HLA A, B, DR, and DQ alleles known to be associated with HCV clearance or persistence in a healthy Moroccan population. Conducted at the University Hospital Center Mohammed VI, Marrakech, this study spanned from 2015 to 2022 and included 703 healthy Moroccan individuals. HLA class I and II typing was performed using complement-dependent cytotoxicity and polymerase chain reaction-based methodologies. The results revealed the distinct patterns of HLA-A, B, DRB1, and DQB1 alleles in the Moroccan population. Notably, alleles linked to favorable HCV outcomes, such as HLA-DQB1*0301, DQB1*0501, and DRB1*1101, were more prevalent. Conversely, alleles associated with increased HCV susceptibility and persistence, such as HLA-DQB1*02 and DRB1*03, were also prominent. Gender-specific variations in allele frequencies were observed, providing insights into genetic influences on HCV infection outcomes. The findings align with global trends in HLA allele associations with HCV infection outcomes. The study emphasizes the role of host genetics in HCV infection, highlighting the need for further research in the Moroccan community, including HCV-infected individuals. The prevalence of certain HLA alleles, both protective and susceptibility-linked, underscores the potential for a national HLA data bank in Morocco.
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Affiliation(s)
- Safa Machraoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Ider Oujamaa
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Moulay Yassine Belghali
- Department of Biology, Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdellah University, Fez 30003, Morocco;
| | - Abdelmalek Hakmaoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Saad Lamjadli
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Fatima Ezzohra Eddehbi
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Ikram Brahim
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Yasmine Haida
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Brahim Admou
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
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Cameron CM, Raghu V, Richardson B, Zagore LL, Tamilselvan B, Golden J, Cartwright M, Schoen RE, Finn OJ, Benos PV, Cameron MJ. Pre-vaccination transcriptomic profiles of immune responders to the MUC1 peptide vaccine for colon cancer prevention. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.09.24305336. [PMID: 38766010 PMCID: PMC11100921 DOI: 10.1101/2024.05.09.24305336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Self-antigens abnormally expressed on tumors, such as MUC1, have been targeted by therapeutic cancer vaccines. We recently assessed in two clinical trials in a preventative setting whether immunity induced with a MUC1 peptide vaccine could reduce high colon cancer risk in individuals with a history of premalignant colon adenomas. In both trials, there were immune responders and non-responders to the vaccine. Here we used PBMC pre-vaccination and 2 weeks after the first vaccine of responders and non-responders selected from both trials to identify early biomarkers of immune response involved in long-term memory generation and prevention of adenoma recurrence. We performed flow cytometry, phosflow, and differential gene expression analyses on PBMCs collected from MUC1 vaccine responders and non-responders pre-vaccination and two weeks after the first of three vaccine doses. MUC1 vaccine responders had higher frequencies of CD4 cells pre-vaccination, increased expression of CD40L on CD8 and CD4 T-cells, and a greater increase in ICOS expression on CD8 T-cells. Differential gene expression analysis revealed that iCOSL, PI3K AKT MTOR, and B-cell signaling pathways are activated early in response to the MUC1 vaccine. We identified six specific transcripts involved in elevated antigen presentation, B-cell activation, and NF-kB1 activation that were directly linked to finding antibody response at week 12. Finally, a model using these transcripts was able to predict non-responders with accuracy. These findings suggest that individuals who can be predicted to respond to the MUC1 vaccine, and potentially other vaccines, have greater readiness in all immune compartments to present and respond to antigens. Predictive biomarkers of MUC1 vaccine response may lead to more effective vaccines tailored to individuals with high risk for cancer but with varying immune fitness.
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Affiliation(s)
- Cheryl M Cameron
- Department of Nutrition, Case Western Reserve University, Cleveland, OH
| | - Vineet Raghu
- Department of Computer Science, University of Pittsburgh, Pittsburgh, PA
- Massachusetts General Hospital, Harvard Medical School, Cambridge, MA
| | - Brian Richardson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Leah L Zagore
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | | | - Jackelyn Golden
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Michael Cartwright
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
| | - Robert E Schoen
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA
| | - Olivera J Finn
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA
| | - Panayiotis V Benos
- Department of Epidemiology, University of Florida, Gainesville, FL
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Mark J Cameron
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
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10
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Georgopoulos AP, James LM. Association between brain cancer immunogenetic profile and in silico immunogenicities of 11 viruses. Sci Rep 2023; 13:21528. [PMID: 38057480 PMCID: PMC10700375 DOI: 10.1038/s41598-023-48843-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023] Open
Abstract
Several viruses including human herpes viruses (HHVs), human polyomavirus JCV, and human papilloma virus (HPV) have been implicated in brain cancer, albeit inconsistently. Since human leukocyte antigen (HLA) is centrally involved in the human immune response to viruses and has been implicated in brain cancer, we evaluated in silico the immunogenicity between 69 Class I HLA alleles with epitopes of proteins of 9 HHVs, JCV, and HPV with respect to a population-based HLA-brain cancer profile. We found that immunogenicity varied widely across HLA alleles with HLA-C alleles exhibiting the highest immunogenicity, and that immunogenicity scores were negatively associated with the population-based HLA-brain cancer profile, particularly for JCV, HHV6A, HHV5, HHV3, HHV8, and HHV7. Consistent with the role of HLA in foreign antigen elimination, the findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to cause brain cancer; conversely, the absence of highly immunogenic HLA may allow the viral antigens to persist, contributing to cancer.
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Affiliation(s)
- Apostolos P Georgopoulos
- The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis VAMC, One Veterans Drive, Minneapolis, MN, 55417, USA.
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA.
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.
| | - Lisa M James
- The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis VAMC, One Veterans Drive, Minneapolis, MN, 55417, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
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11
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James LM, Georgopoulos AP. Positive Association Between the Immunogenetic Human Leukocyte Antigen (HLA) Profiles of Multiple Sclerosis and Brain Cancer. Neurosci Insights 2023; 18:26331055231214543. [PMID: 38046672 PMCID: PMC10693228 DOI: 10.1177/26331055231214543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 10/31/2023] [Indexed: 12/05/2023] Open
Abstract
Previous research has documented elevated risk of brain cancer in patients with multiple sclerosis (MS). Separately, human leukocyte antigen (HLA) has been implicated in protection or susceptibility for both conditions. The aim of the current study was to assess a possible role of shared immunogenetic influence on risk of MS and brain cancer. We first identified an immunogenetic profile for each condition based on the covariance between the population frequency of 127 high-resolution HLA alleles and the population prevalence of each condition in 14 Continental Western European countries and then evaluated the correspondence between MS and brain cancer immunogenetic profiles. Also, since each individual carries 12 HLA alleles (2 × 6 genes), we estimated HLA protection and susceptibility for MS and brain cancer at the individual level. We found that the immunogenetic profiles of MS and brain cancer were highly correlated overall (P < .001) and across all 6 HLA genes with the strongest association observed for DRB1, followed by DQB1 and HLA-A. These findings of immunogenetic overlap between MS and brain cancer are discussed in light of the role of HLA in the immune system response to viruses and other foreign antigens.
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Affiliation(s)
- Lisa M James
- Department of Veterans Affairs Health Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Apostolos P Georgopoulos
- Department of Veterans Affairs Health Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA
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12
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James LM, Georgopoulos AP. Negative association between multiple sclerosis immunogenetic profile and in silico immunogenicities of 12 viruses. Sci Rep 2023; 13:18654. [PMID: 37907711 PMCID: PMC10618254 DOI: 10.1038/s41598-023-45931-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 10/25/2023] [Indexed: 11/02/2023] Open
Abstract
Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12 viruses implicated in MS with respect to 17 HLA Class I alleles positively associated to MS prevalence in 14 European countries. Overall, higher V-HLA immunogenicity was associated with smaller MS-HLA effect, with human herpes virus 3 (HHV3), JC human polyoma virus (JCV), HHV1, HHV4, HHV7, HHV5 showing the strongest association, followed by HHV8, HHV6A, and HHV6B (moderate association), and human endogenous retrovirus (HERV-W), HHV2, and human papilloma virus (HPV) (weakest association). These findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to be involved in MS.
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Affiliation(s)
- Lisa M James
- The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - Apostolos P Georgopoulos
- The HLA Research Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, 55417, USA.
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
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13
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Kawamura A, Matsuda K, Murakami Y, Saruta M, Kohno T, Shiraishi K. Contribution of an Asian-prevalent HLA haplotype to the risk of HBV-related hepatocellular carcinoma. Sci Rep 2023; 13:12944. [PMID: 37558689 PMCID: PMC10412552 DOI: 10.1038/s41598-023-40000-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 08/03/2023] [Indexed: 08/11/2023] Open
Abstract
Liver cancer, particularly hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), is more common in Asians than in Caucasians. This is due, at least in part, to regional differences in the prevalence of exogenous factors such as HBV; however, endogenous factors specific to Asia might also play a role. Such endogenous factors include HLA (human leukocyte antigen) genes, which are considered candidates due to their high racial diversity. Here, we performed a pancancer association analysis of 147 alleles of HLA-class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) in 31,727 cases of 12 cancer types, including 1684 liver cancer cases and 107,103 controls. HLA alleles comprising a haplotype prevalent in Asia were significantly associated with pancancer risk (e.g., odds ratio [OR] for a DRB1*15:02 allele = 1.12, P = 2.7 × 10-15), and the associations were particularly strong in HBV-related HCC (OR 1.95, P = 2.8 × 10-5). In silico prediction suggested that the DRB1*15:02 molecule encoded by the haplotype does not bind efficiently to HBV-derived peptides. RNA sequencing indicated that HBV-related HCC in carriers of the haplotype shows low infiltration by NK cells. These results indicate that the Asian-prevalent HLA haplotype increases the risk of HBV-related liver cancer risk by attenuating immune activity against HBV infection, and by reducing NK cell infiltration into the tumor.
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Affiliation(s)
- Atsushi Kawamura
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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14
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James LM, Georgopoulos AP. Risk assessment of substance use disorders based on the human leukocyte antigen (HLA). Sci Rep 2023; 13:8545. [PMID: 37237010 DOI: 10.1038/s41598-023-35305-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Substance use disorders (SUDs) are common and costly conditions that are partially attributable to genetic factors. In light of immune system influences on neural and behavioral aspects of addiction, the present study evaluated the influence of genes involved in the human immune response, human leukocyte antigen (HLA), on SUDs. We used an immunogenetic epidemiological approach to evaluate associations between the population frequencies of 127 HLA alleles and the population prevalences of six SUDs (alcohol, amphetamine, cannabis, cocaine, opioid, and "other" dependence) in 14 countries of Continental Western Europe to identify immunogenetic profiles of each SUD and evaluate their associations. The findings revealed two primary groupings of SUDs based on their immunogenetic profiles: one group comprised cannabis and cocaine, whereas the other group comprised alcohol, amphetamines, opioids, and "other" dependence. Since each individual possesses 12 HLA alleles, the population HLA-SUD scores were subsequently used to estimate individual risk for each SUD. Overall, the findings highlight similarities and differences in immunogenetic profiles of SUDs that may influence the prevalence and co-occurrence of problematic SUDs and may contribute to assessment of SUD risk of an individual on the basis of their HLA genetic makeup.
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Affiliation(s)
- Lisa M James
- The HLA Research Group, Brain Sciences Center (11B), Department of Veterans Affairs Health Care System, Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA.
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
| | - Apostolos P Georgopoulos
- The HLA Research Group, Brain Sciences Center (11B), Department of Veterans Affairs Health Care System, Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
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15
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Zongo SV, Djigma FW, Yonli AT, Sorgho PA, Nagalo BM, Traore L, Somda D, Amegnona LJ, Languie E, Some CCB, Sia LMJ, Sourabie IB, Sombie RA, Serme AK, Obiri-Yeboah D, Simpore J. Association of DRB1*11 and DRB1*12 alleles of the HLA system with the evolution of the Hepatitis B virus infection in Burkina Faso. Mol Biol Rep 2023; 50:5039-5047. [PMID: 37101005 DOI: 10.1007/s11033-023-08353-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/22/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Hepatitis B Virus (HBV) infection affect all social strata of humanity and in the absence of any management, this infection has a different outcome from one infected person to another. This suggests that there are specific individual factors that influence the outcome of the pathology. Sex, immunogenetics and age of contraction of the virus have been cited as factors that influence the evolution of the pathology. In this study, we looked at two alleles of the Human Leucocyte Antigen (HLA) system to measure their possible involvement in the evolution of HBV infection. METHOD AND RESULTS We conducted a cohort study involving 144 individuals spread over 04 distinct stages of infection and then compared allelic frequencies in these populations. A multiplex PCR was conducted and the data obtained was analyzed using R and SPSS software. Our study revealed a predominance of HLA-DRB1*12 in our study population without, however, showing a significant difference between HLA-DRB1*11 and HLA-DRB1*12. The HLA-DRB1*12 proportion was significantly higher in chronic hepatitis B (CHB) and resolved hepatitis B (RHB) compared to cirrhosis and hepatocellular carcinoma (HCC) (p-value = 0,002). Carrying HLA-DRB1*12 has been associated with a low risk of complication of infection (CHB → cirrhosis; OR 0,33 p-value 0,017; RHB → HCC OR 0,13; p-value = 0,00,045) whereas the presence of HLA-DRB1*11 in the absence of HLA-DRB1*12 increased the risk of developing severe liver disease. However, a strong interaction of these alleles with the environment could modulate the infection. CONCLUSION Our study shown that HLA-DRB1*12 is the most frequent and it's carriage may be protective in the development of infection.
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Affiliation(s)
- Sidnooma Véronique Zongo
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Florencia Wendkuuni Djigma
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso.
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso.
| | - Albert Théophane Yonli
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Pegdwendé Abel Sorgho
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Bolni Marius Nagalo
- Division of Hematology and Oncology, Mayo Clinic, Arizona, 13400 E. Shea Blvd. , Scottsdale, AZ, 85259, USA
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dogfounianalo Somda
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Lanyo Jospin Amegnona
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Eugène Languie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Couna Christiane Bere Some
- Centre Hospitalier Universitaire Yalgado Ouedraogo (CHU-YO), P.O. Box: 03 BP 7022, Ouagadougou 03, Burkina Faso
| | | | - Issa Boaffi Sourabie
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Roger Arsène Sombie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Abdel Karim Serme
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dorcas Obiri-Yeboah
- Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, PMB, Cape Coast, Cape Coast, Ghana
| | - Jacques Simpore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
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16
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Dudley MZ, Gerber JE, Budigan Ni H, Blunt M, Holroyd TA, Carleton BC, Poland GA, Salmon DA. Vaccinomics: A scoping review. Vaccine 2023; 41:2357-2367. [PMID: 36803903 PMCID: PMC10065969 DOI: 10.1016/j.vaccine.2023.02.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 12/24/2022] [Accepted: 02/03/2023] [Indexed: 02/21/2023]
Abstract
BACKGROUND This scoping review summarizes a key aspect of vaccinomics by collating known associations between heterogeneity in human genetics and vaccine immunogenicity and safety. METHODS We searched PubMed for articles in English using terms covering vaccines routinely recommended to the general US population, their effects, and genetics/genomics. Included studies were controlled and demonstrated statistically significant associations with vaccine immunogenicity or safety. Studies of Pandemrix®, an influenza vaccine previously used in Europe, were also included, due to its widely publicized genetically mediated association with narcolepsy. FINDINGS Of the 2,300 articles manually screened, 214 were included for data extraction. Six included articles examined genetic influences on vaccine safety; the rest examined vaccine immunogenicity. Hepatitis B vaccine immunogenicity was reported in 92 articles and associated with 277 genetic determinants across 117 genes. Thirty-three articles identified 291 genetic determinants across 118 genes associated with measles vaccine immunogenicity, 22 articles identified 311 genetic determinants across 110 genes associated with rubella vaccine immunogenicity, and 25 articles identified 48 genetic determinants across 34 genes associated with influenza vaccine immunogenicity. Other vaccines had fewer than 10 studies each identifying genetic determinants of their immunogenicity. Genetic associations were reported with 4 adverse events following influenza vaccination (narcolepsy, GBS, GCA/PMR, high temperature) and 2 adverse events following measles vaccination (fever, febrile seizure). CONCLUSION This scoping review identified numerous genetic associations with vaccine immunogenicity and several genetic associations with vaccine safety. Most associations were only reported in one study. This illustrates both the potential of and need for investment in vaccinomics. Current research in this field is focused on systems and genetic-based studies designed to identify risk signatures for serious vaccine reactions or diminished vaccine immunogenicity. Such research could bolster our ability to develop safer and more effective vaccines.
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Affiliation(s)
- Matthew Z Dudley
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Institute for Vaccine Safety, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Jennifer E Gerber
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Survey Research Division, RTI International, Washington, DC, USA
| | - Haley Budigan Ni
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Office of Health Equity, California Department of Public Health, Richmond, CA, USA
| | - Madeleine Blunt
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Taylor A Holroyd
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; International Vaccine Access Center, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Bruce C Carleton
- Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Gregory A Poland
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN, USA
| | - Daniel A Salmon
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Institute for Vaccine Safety, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Department of Health, Behavior & Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
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17
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Naderi M, Hosseini SM, Behnampour N, Shahramian I, Moradi A. Association of HLADQ-B1 polymorphisms in three generations of chronic hepatitis B patients. Virus Res 2023; 325:199036. [PMID: 36592642 DOI: 10.1016/j.virusres.2022.199036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
The presence of polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene, along with its expression, has been demonstrated to be correlated with spontaneous clearance and susceptibility to HBV infection. The present study aimed to evaluate the possible role of genetic polymorphisms in HLA-DQB1 in three generations of patients with chronic hepatitis B (CHB). Based on the inclusion criteria, 90 CHB patients, 18 individuals recovered from HBV infection, and 40 healthy subjects were chosen. The DNA contents of the whole blood samples were extracted in order to perform HLA-DQB1 typing by the PCR technique. Besides whole blood samples, sera were applied to measure liver function tests (LFTs), as well as the titers of anti-HDV and anti-HCV. Also, in all CHB patients were measured liver stiffness (LSM) by Fibro Scan. The results of HLA-DQB1 polymorphisms (rs2856718 and rs7453920) demonstrated that the majority of polymorphisms in CHB patients were HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01 that associated with HBV persistence and chronicity. Among the patients who showed these polymorphisms, the mean±SD, LSM was 4±1.57 KPa and most of them, F grade was reported as F2, which was a sign of disease progression towards chronicity. HLA polymorphisms imputation revealed that HLA-DQB1*06:04 (3.4%, P-Value= 0.2) was detected only in healthy subjects as protective polymorphism, while the allele HLA-DQB1*03:03 was reported in both healthy subjects (P-Value= 0.06) and recovered patients (P-Value= 0.1) as suppressor of CHB formation. The allele HLA-DQB1*05:02 was found in both healthy subjects (3.4%) and CHB patients (4.5%) which was associated with risk to liver cirrhosis (P-Value= 0, OR: 0.002 0.95CI: 0.000-0.15). HLA polymorphism analysis indicated that 17.39% of patients who were seropositive for anti-HCV carried the HLA-DQB1*03:01. HBV resistance or infection risk could be assessed by DBQ1 typing. The existence of polymorphisms in HLA gene could influence the clearance (HLA-DQB1*03:03) or susceptibility and persistence of infection (HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01). These results have the potential to improve personalized therapy and prognosis for HBV infection.
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Affiliation(s)
- Malihe Naderi
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran; Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Masoud Hosseini
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
| | - Naser Behnampour
- Biostatistics and Epidemiology Department, Faculty of Health, Health Management and Social Development Research Center, Golestan University of Medical Sciences, Golestan, Iran
| | - Iraj Shahramian
- Department of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolvahab Moradi
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
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18
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James LM, Georgopoulos AP. Immunogenetic Profiles and Associations of Breast, Cervical, Ovarian, and Uterine Cancers. Cancer Inform 2023; 22:11769351221148588. [PMID: 36684415 PMCID: PMC9846304 DOI: 10.1177/11769351221148588] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/13/2022] [Indexed: 01/18/2023] Open
Abstract
It is increasingly recognized that the human immune response influences cancer risk, progression, and survival; consequently, there is growing interest in the role of human leukocyte antigen (HLA), genes that play a critical role in initiating the immune response, on cancer. Recent evidence documented clustering of cancers based on immunogenetic profiles such that breast and ovarian cancers clustered together as did uterine and cervical cancers. Here we extend that line of research to evaluate the HLA profile of those 4 cancers and their associations. Specifically, we evaluated the associations between the frequencies of 127 HLA alleles and the population prevalences of breast, ovarian, cervical, and uterine cancer in 14 countries in Continental Western Europe. Factor analysis and hierarchical clustering were used to evaluate groupings of cancers based on their immunogenetic profiles. The results documented highly similar immunogenetic profiles for breast and ovarian cancers that were characterized predominantly by protective HLA effects. In addition, highly similar immunogenetic profiles for cervical and uterine cancers were observed that were, conversely, characterized by susceptibility effects. In light of the role of HLA in host immune system protection against non-self antigens, these findings suggest that certain cancers may be associated with similar contributory factors such as viral oncoproteins or neoantigens.
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Affiliation(s)
- Lisa M James
- Department of Veterans Affairs Health
Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN,
USA,Department of Neuroscience, University
of Minnesota Medical School, Minneapolis, MN, USA,Department of Psychiatry, University of
Minnesota Medical School, Minneapolis, MN, USA
| | - Apostolos P Georgopoulos
- Department of Veterans Affairs Health
Care System, The HLA Research Group, Brain Sciences Center, Minneapolis, MN,
USA,Department of Neuroscience, University
of Minnesota Medical School, Minneapolis, MN, USA,Department of Psychiatry, University of
Minnesota Medical School, Minneapolis, MN, USA,Department of Neurology, University of
Minnesota Medical School, Minneapolis, MN, USA,Apostolos P Georgopoulos, Department of
Neuroscience, University of Minnesota Medical School, Brain Sciences Center
(11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN 55417, USA.
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19
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Karuppiah B, Chinniah R, Pandi S, Sevak V, Ravi PM, Thadakanathan D. Immunogenetic landscape of COVID-19 infections related neurological complications. COVID-19 IN ALZHEIMER'S DISEASE AND DEMENTIA 2023:133-146. [DOI: 10.1016/b978-0-443-15256-6.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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20
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James LM, Leuthold AC, Georgopoulos AP. Human Leukocyte Antigen (HLA) Modulates the Dependence on Age of the Variability of Synchronous Neural Interactions. Neurosci Insights 2023; 18:26331055231159658. [PMID: 36969700 PMCID: PMC10037734 DOI: 10.1177/26331055231159658] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 02/08/2023] [Indexed: 03/29/2023] Open
Abstract
Recent evidence documented a protective effect of Class II human leukocyte antigen (HLA) DRB1*13 on brain health across the lifespan including evidence of reduced neural network variability relative to non-carriers. Here, in an extension of those findings, we evaluated the influence of a large number of Class I and Class II HLA alleles on aging-related changes in neural network variability. Cognitively healthy women (N = 178) ranging in age from 28 to 99 years old underwent a magnetoencephalography scan from which neural network variability was calculated and provided a blood sample from which HLA and apolipoprotein E (ApoE) genotype were determined. The primary analyses assessed the dependence of network variability on age in carriers of a specific HLA allele compared to non-carriers. Effects were considered protective if there was a significant increase of network variability with age in the absence of a given HLA allele but not in its presence, and were considered to confer susceptibility if the converse was documented; HLA alleles that did not influence the dependence of network variability on age in their presence or absence were considered neutral. Of 50 alleles investigated, 22 were found to be protective, 7 were found to confer susceptibility, and 21 were neutral. The frequencies of those 50 alleles were not associated significantly with ApoE genotype. The findings, which document the influence of HLA on age-related brain changes and highlight the role of HLA in healthy brain function, are discussed in terms of the role of HLA in the human immune response to foreign antigens.
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Affiliation(s)
- Lisa M James
- The HLA Research Group, Brain Sciences
Center, Department of Veterans Affairs Health Care System, Minneapolis, MN,
USA
- Department of Neuroscience, University
of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of
Minnesota Medical School, Minneapolis, MN, USA
- Center for Cognitive Sciences,
University of Minnesota, Minneapolis, MN, USA
- Lisa M James, Department of Neuroscience,
University of Minnesota Medical School, Brain Sciences Center (11B), Minneapolis
VAHCS, 1 Veterans Drive, Minneapolis, MN 55417, USA.
| | - Arthur C Leuthold
- The HLA Research Group, Brain Sciences
Center, Department of Veterans Affairs Health Care System, Minneapolis, MN,
USA
- Department of Neuroscience, University
of Minnesota Medical School, Minneapolis, MN, USA
| | - Apostolos P Georgopoulos
- The HLA Research Group, Brain Sciences
Center, Department of Veterans Affairs Health Care System, Minneapolis, MN,
USA
- Department of Neuroscience, University
of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of
Minnesota Medical School, Minneapolis, MN, USA
- Center for Cognitive Sciences,
University of Minnesota, Minneapolis, MN, USA
- Department of Neurology, University of
Minnesota, Minneapolis, MN, USA
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21
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James LM, Charonis SA, Georgopoulos AP. Schizophrenia, Human Leukocyte Antigen (HLA), and Herpes Viruses: Immunogenetic Associations at the Population Level. Neurosci Insights 2023; 18:26331055231166411. [PMID: 37077512 PMCID: PMC10108429 DOI: 10.1177/26331055231166411] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/13/2023] [Indexed: 04/21/2023] Open
Abstract
Several factors have been implicated in schizophrenia (SZ), including human herpes viruses (HHV) and the adaptive immunity Human Leukocyte Antigen (HLA) genes. Here we investigated these issues in 2 complementary ways. In one analysis, we evaluated SZ-HLA and HHV-HLA associations at the level of a single allele by computing (a) a SZ-HLA protection/susceptibility (P/S) score based on the covariance between SZ and 127 HLA allele prevalences in 14 European countries, (b) estimating in silico HHV-HLA best binding affinities for the 9 HHV strains, and (c) evaluating the dependence of P/S score on HHV-HLA binding affinities. These analyses yielded (a) a set of 127 SZ-HLA P/S scores, varying by >200× (maximum/minimum), which could not be accounted for by chance, (b) a set of 127 alleles × 9 HHV best-estimated affinities, varying by >600×, and (c) a set of correlations between SZ-HLA P/S scores and HHV-HLA binding which indicated a prominent role of HHV1. In a subsequent analysis, we extended these findings to the individual person by taking into account the fact that every individual carries 12 HLA alleles and computed (a) the average SZ-HLA P/S scores of 12 randomly chosen alleles (2 per gene), an indicator of HLA-based SZ P/S for an individual, and (b) the average of the corresponding HHV estimated affinities for those alleles, an indicator of overall effectiveness of HHV-HLA binding. We found (a) that HLA protection for SZ was significantly more prominent than susceptibility, and (b) that protective SZ-HLA scores were associated with higher HHV-HLA binding affinities, indicating that HLA binding and subsequent elimination of several HHV strains may confer protection against schizophrenia.
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Affiliation(s)
- Lisa M James
- The HLA Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
- Lisa M James, Brain Sciences Center (11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN 55417, USA.
| | - Spyros A Charonis
- The HLA Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Apostolos P Georgopoulos
- The HLA Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA
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22
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Immunogenetics of posttraumatic stress disorder (PTSD) in women veterans. Brain Behav Immun Health 2022; 26:100567. [DOI: 10.1016/j.bbih.2022.100567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
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Genetic polymorphism of HLA-DRA and alcohol consumption affect hepatitis development in the Korean population. Genes Genomics 2022; 44:1109-1116. [PMID: 35895219 DOI: 10.1007/s13258-022-01286-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 07/10/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Hepatitis is an inflammation of the liver that has several potential causes; however, the genetic association has recently begun to be studied. OBJECTIVES Human leukocyte antigen (HLA) is an essential component of the immune response, and in this study, we conducted a correlation analysis to determine whether genetic polymorphisms of HLA and drinking habits affect hepatitis development. METHODS Genetic polymorphisms of HLA were investigated using Korean genomic and epidemiological data. A gene association study was performed using PLINK version 1.07. Other statistical analyses and multivariate logistic regression analyses were performed using PASW Statistics version 18.0. RESULTS Thirteen single nucleotide polymorphisms (SNPs) in HLA-DRA showed significant statistical correlations with hepatitis. In particular, rs9268645 showed the highest statistical association with hepatitis (P = 3.97 × 10-5, odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.61-0.84). In multivariate logistic regression analysis, when considering only genetic factors, the A allele of rs9268644 showed a reduced hepatitis OR of approximately 0.52-fold. However, the group carrying the minor A allele (AA + AC) with alcohol consumption had an approximately 1.58-fold OR of hepatitis compared to that of the group carrying the same allele with no alcohol consumption. This implies that the A allele of rs9268644 has a protective effect on hepatitis by genetic factors and shows sensitivity to alcohol. CONCLUSIONS Our results showed that hepatitis is influenced by both genetic and external factors (drinking habits), which can provide new guidelines for the prevention or treatment of hepatitis.
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Howard FHN, Kwan A, Winder N, Mughal A, Collado-Rojas C, Muthana M. Understanding Immune Responses to Viruses-Do Underlying Th1/Th2 Cell Biases Predict Outcome? Viruses 2022; 14:1493. [PMID: 35891472 PMCID: PMC9324514 DOI: 10.3390/v14071493] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Emerging and re-emerging viral diseases have increased in number and geographical extent during the last decades. Examples include the current COVID-19 pandemic and the recent epidemics of the Chikungunya, Ebola, and Zika viruses. Immune responses to viruses have been well-characterised within the innate and adaptive immunity pathways with the outcome following viral infection predominantly attributed to properties of the virus and circumstances of the infection. Perhaps the belief that the immune system is often considered as a reactive component of host defence, springing into action when a threat is detected, has contributed to a poorer understanding of the inherent differences in an individual's immune system in the absence of any pathology. In this review, we focus on how these host factors (age, ethnicity, underlying pathologies) may skew the T helper cell response, thereby influencing the outcome following viral infection but also whether we can use these inherent biases to predict patients at risk of a deviant response and apply strategies to avoid or overcome them.
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Affiliation(s)
- Faith H. N. Howard
- Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK; (A.K.); (N.W.); (A.M.); (C.C.-R.); (M.M.)
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25
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Xu HC, Huang J, Pandyra AA, Pandey P, Wang R, Zhang Z, Zhuang Y, Gertzen CG, Münk C, Herebian D, Borkhardt A, Recher M, Gohlke H, Esposito I, Oberbarnscheidt M, Häussinger D, Lang KS, Lang PA. Single MHC-I Expression Promotes Virus-Induced Liver Immunopathology. Hepatol Commun 2022; 6:1620-1633. [PMID: 35166071 PMCID: PMC9234681 DOI: 10.1002/hep4.1913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Major histocompatibility complex I (MHC-I) molecules present epitopes on the cellular surface of antigen-presenting cells to prime cytotoxic clusters of differentiation 8 (CD8)+ T cells (CTLs), which then identify and eliminate other cells such as virus-infected cells bearing the antigen. Human hepatitis virus cohort studies have previously identified MHC-I molecules as promising predictors of viral clearance. However, the underlying functional significance of these predictions is not fully understood. Here, we show that expression of single MHC-I isomers promotes virus-induced liver immunopathology. Specifically, using the lymphocytic choriomeningitis virus (LCMV) model system, we found MHC-I proteins to be highly up-regulated during infection. Deletion of one of the two MHC-I isomers histocompatibility antigen 2 (H2)-Db or H2-Kb in C57Bl/6 mice resulted in CTL activation recognizing the remaining MHC-I with LCMV epitopes in increased paucity. This increased CTL response resulted in hepatocyte death, increased caspase activation, and severe metabolic changes in liver tissue following infection with LCMV. Moreover, depletion of CTLs abolished LCMV-induced pathology in these mice with resulting viral persistence. In turn, natural killer (NK) cell depletion further increased antiviral CTL immunity and clearance of LCMV even in the presence of a single MHC-I isomer. Conclusion: Our results suggest that uniform MHC-I molecule expression promotes enhanced CTL immunity during viral infection and contributes to increased CTL-mediated liver cell damage that was alleviated by CD8 or NK cell depletion.
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Affiliation(s)
- Haifeng C. Xu
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Jun Huang
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Aleksandra A. Pandyra
- Department of Pediatric Oncology, Hematology and Clinical ImmunologyMedical FacultyCenter of Child and Adolescent HealthHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Piyush Pandey
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Ruifeng Wang
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Zeli Zhang
- Clinic for Gastroenterology, Hepatology, and Infectious DiseasesMedical FacultyHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Yuan Zhuang
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
| | - Christoph G.W. Gertzen
- John von Neumann Institute for ComputingJülich Supercomputing CenterInstitute of Biological Information Processing (Structural Biochemistry) and Institute of Bio‐ and Geosciences (Bioinformatics)Forschungszentrum Jülich GmbHJülichGermany
- Institute for Pharmaceutical and Medicinal ChemistryHeinrich Heine University DüsseldorfDüsseldorfGermany
- Center for Structural StudiesHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Carsten Münk
- Clinic for Gastroenterology, Hepatology, and Infectious DiseasesMedical FacultyHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric CardiologyMedical FacultyHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical ImmunologyMedical FacultyCenter of Child and Adolescent HealthHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Mike Recher
- Immunodeficiency ClinicMedical Outpatient Unit and Immunodeficiency LabDepartment BiomedicineBasel University HospitalBaselSwitzerland
| | - Holger Gohlke
- John von Neumann Institute for ComputingJülich Supercomputing CenterInstitute of Biological Information Processing (Structural Biochemistry) and Institute of Bio‐ and Geosciences (Bioinformatics)Forschungszentrum Jülich GmbHJülichGermany
- Institute for Pharmaceutical and Medicinal ChemistryHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Irene Esposito
- Institute of PathologyMedical FacultyHeinrich‐Heine University and University Hospital of DuesseldorfDüsseldorfGermany
| | | | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious DiseasesMedical FacultyHeinrich Heine University DüsseldorfDüsseldorfGermany
| | - Karl S. Lang
- Institute of ImmunologyMedical FacultyUniversity of Duisburg‐EssenEssenGermany
| | - Philipp A. Lang
- Department of Molecular Medicine II, Medical FacultyHeinrich Heine UniversityDüsseldorfGermany
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26
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Ashouri S, Khor SS, Hitomi Y, Sawai H, Nishida N, Sugiyama M, Kawai Y, Posuwan N, Tangkijvanich P, Komolmit P, Tsuiji M, Shotelersuk V, Poovorawan Y, Mizokami M, Tokunaga K. Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population. Front Genet 2022; 13:887121. [PMID: 35769989 PMCID: PMC9234442 DOI: 10.3389/fgene.2022.887121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
Abstract
To identify novel host genetic variants that predispose to hepatitis B virus (HBV) persistence, we performed the first genome-wide association study in the Thai population involving 318 cases of chronic hepatitis B and 309 healthy controls after quality control measures. We detected the genome-wide significant association of the HLA class II region (HLA-DPA1/DPB1, rs7770370, p-value = 7.71 × 10-10, OR = 0.49) with HBV chronicity. Subsequent HLA allele imputation revealed HLA-DPA1*01:03 (Pc = 1.21 × 10-6, OR = 0.53), HLA-DPB1*02:01 (Pc = 2.17 × 10-3, OR = 0.50), and HLA-DQB1*06:09 (Pc = 2.17 × 10-2, OR = 0.07) as protective alleles, and HLA-DPA1*02:02 (Pc = 6.32 × 10-5, OR = 1.63), HLA-DPB1*05:01 (Pc = 1.13 × 10-4, OR = 1.72), HLA-DPB1*13:01 (Pc = 4.68 × 10-2, OR = 1.60), and HLA-DQB1*03:03 (Pc = 1.11 × 10-3, OR = 1.84) as risk alleles for HBV persistence. We also detected suggestive associations in the PLSCR1 (rs35766154), PDLIM5 (rs62321986), SGPL1 (rs144998273), and MGST1 (rs1828682) loci. Among single-nucleotide polymorphisms in the PLSCR1 locus, rs1061307 was identified as the primary functional variant by in silico/in vitro functional analysis. In addition to replicating the association of the HLA class II region, we detected novel candidate loci that provide new insights into the pathophysiology of chronic hepatitis B.
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Affiliation(s)
- Saeideh Ashouri
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Seik-Soon Khor
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuki Hitomi
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nao Nishida
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Masaya Sugiyama
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nawarat Posuwan
- Chulabhorn International College of Medicine, Thammasat University, Rangsit Campus, Pathum Thani, Thailand
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Liver Fibrosis and Cirrhosis Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Makoto Tsuiji
- Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Vorasuk Shotelersuk
- Department of Pediatrics, Center of Excellence for Medical Genomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Masashi Mizokami
- Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Toyama, Tokyo,Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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27
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Charonis SA, James LM, Georgopoulos AP. SARS-CoV-2 in silico binding affinity to human leukocyte antigen (HLA) Class II molecules predicts vaccine effectiveness across variants of concern (VOC). Sci Rep 2022; 12:8074. [PMID: 35577837 PMCID: PMC9109665 DOI: 10.1038/s41598-022-11956-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/26/2022] [Indexed: 11/08/2022] Open
Abstract
There is widespread concern about the clinical effectiveness of current vaccines in preventing Covid-19 caused by SARS-CoV-2 Variants of Concern (Williams in Lancet Respir Med 29:333-335, 2021; Hayawi in Vaccines 9:1305, 2021), including those identified at present (Alpha, Beta, Gamma, Delta, Omicron) and possibly new ones arising in the future. It would be valuable to be able to predict vaccine effectiveness for any variant. Here we offer such an estimate of predicted vaccine effectiveness for any SARS-CoV-2 variant based on the amount of overlap of in silico high binding affinity of the variant and Wildtype spike glycoproteins to a pool of frequent Human Leukocyte Antigen Class II molecules which are necessary for initiating antibody production (Blum et al. in Annu Rev Immunol 31:443-473, 2013). The predictive model was strong (r = 0.910) and statistically significant (P = 0.013).
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Affiliation(s)
- Spyros A Charonis
- The HLA SARS-CoV-2 Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center (11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - Lisa M James
- The HLA SARS-CoV-2 Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center (11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - Apostolos P Georgopoulos
- The HLA SARS-CoV-2 Research Group, Department of Veterans Affairs Health Care System, Brain Sciences Center (11B), Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA.
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
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28
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James LM, Georgopoulos AP. Immunogenetic clustering of 30 cancers. Sci Rep 2022; 12:7235. [PMID: 35508592 PMCID: PMC9068692 DOI: 10.1038/s41598-022-11366-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 04/15/2022] [Indexed: 11/09/2022] Open
Abstract
Human leukocyte antigen (HLA) genes have been implicated in cancer risk and shared heritability of different types of cancer. In this immunogenetic epidemiological study we first computed a Cancer-HLA profile for 30 cancer types characterized by the correlation between the prevalence of each cancer and the population frequency of 127 HLA alleles, and then used multidimensional scaling to evaluate the possible clustering of those Cancer-HLA associations. The results indicated the presence of three clusters, broadly reflecting digestive-skin-cervical cancers, reproductive and endocrine systems cancers, and brain and androgen-associated cancers. The clustering of cancer types documented here is discussed in terms of mechanisms underlying shared Cancer-HLA associations.
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Affiliation(s)
- Lisa M James
- The HLA Research Group, Brain Sciences Center (11B), Department of Veterans Affairs Health Care System, Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA.,Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.,Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA
| | - Apostolos P Georgopoulos
- The HLA Research Group, Brain Sciences Center (11B), Department of Veterans Affairs Health Care System, Minneapolis VAHCS, One Veterans Drive, Minneapolis, MN, 55417, USA. .,Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, 55455, USA. .,Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, 55455, USA. .,Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
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Astbury S, Reynolds CJ, Butler DK, Muñoz‐Sandoval DC, Lin K, Pieper FP, Otter A, Kouraki A, Cusin L, Nightingale J, Vijay A, Craxford S, Aithal GP, Tighe PJ, Gibbons JM, Pade C, Joy G, Maini M, Chain B, Semper A, Brooks T, Ollivere BJ, McKnight Á, Noursadeghi M, Treibel TA, Manisty C, Moon JC, COVIDsortium Investigators* AbbassHakamAbiodunAderonkeAlfarihMashaelAlldisZoeAltmannDaniel M.AminOliver E.AndiapenMervynArticoJessicaAugustoJoão B.BacaGeorgiana L.BaileySasha N. L.BhuvaAnish N.BoulterAlexBowlesRuthBoytonRosemary J.BrackenOlivia V.O’BrienBenBrooksTimBullockNatalieButlerDavid K.CapturGabriellaChampionNicolaChanCarmenChandranAneeshCollierDavidde SousaJorge CoutoCouto‐ParadaXoseCutino‐MoguelTeresaDaviesRhodri H.DouglasBrookeGenovaCeciliaDieobi‐AneneKeenanDinizMariana O.EllisAnayaFeehanKarenFinlayMalcolmFontanaMariannaForooghiNasimGaierCeliaGibbonsJoseph M.GilroyDerekHamblinMattHarkerGabrielleHewsonJacquelineHicklingLauren M.HingoraniAroon D.HowesLeeHughesAlunHughesGemmaHughesRebeccaItuaIvieJardimVictorLeeWing‐Yiu JasonJensenMelaniepetraJonesJessicaJonesMeleriJoyGeorgeKapilVikasKurdiHibbaLambourneJonathanLinKai‐MinLouthSarahMainiMala K.MandadapuVineelaManistyCharlotteMcKnightÁineMenachoKatiaMfukoCelinaMitchelmoreOliverMoonChristopherMoonJames C.Muñoz‐SandovalDiana C.MurraySam M.NoursadeghiMahdadOtterAshleyPadeCorinnaPalmaSusanaParkerRuthPatelKushPawarovaBabitaPetersenSteffen E.PinieraBrianPieperFranziska P.PopeDanielProssoraMaryRanniganLisaRapalaAlicjaReynoldsCatherine J.RichardsAmyRobathanMatthewRosenheimJoshuaSambileGenineSchmidtNathalie M.SemperAmandaSeraphimAndreasSimionMihaelaSmitAngeliqueSugimotoMichelleSwadlingLeoTaylorStephenTempertonNigelThomasStephenThorntonGeorge D.TreibelThomas A.TuckerArtVeerapenJessryVijayakumarMohitWelchSophieWodehouseTheresaWynneLucindaZahediDanAltmannDaniel MBoytonRosemary J.BrooksTimChainBenjaminMainiMala K.ManistyCharlotteMcKnightÁineMoonJames C.NoursadeghiMahdadTreibelThomas A.AithalGuruprasad P.AshrafWaheedAstburyStuartBallJonathan K.ChappellJoseph G.CraxfordSimonCusinLola M. L.DuncanJoshua D.IkramAdeelIrvingWilliam L.JacksonHannah J.KellyAnthonyLingayaMelanieMarsonBen A.NewhamJayneNightingaleJessicaNorrishAlanNowickaBarbaraOllivereBenjamin J.TarrAlexander W.TighePatrick J.TsoleridisTheocharisUrbanowiczRichard A.ValdesAna M.VijayAmrita, Valdes AM, Boyton RJ, Altmann DM. HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19. Immunology 2022; 166:68-77. [PMID: 35156709 PMCID: PMC9111350 DOI: 10.1111/imm.13450] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 12/15/2022] Open
Abstract
SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.
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Affiliation(s)
- Stuart Astbury
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases CentreSchool of MedicineUniversity of NottinghamNottinghamUK
| | | | - David K. Butler
- Department of Infectious DiseaseImperial College LondonLondonUK
| | | | - Kai‐Min Lin
- Department of Infectious DiseaseImperial College LondonLondonUK
| | | | - Ashley Otter
- National Infection ServicePublic Health EnglandPorton DownUK
| | - Afroditi Kouraki
- Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Lola Cusin
- School of Life SciencesUniversity of NottinghamNottinghamUK
| | - Jessica Nightingale
- Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Amrita Vijay
- Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Simon Craxford
- Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Guruprasad P. Aithal
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Nottingham Digestive Diseases CentreSchool of MedicineUniversity of NottinghamNottinghamUK
| | | | - Joseph M. Gibbons
- Barts and the London School of Medicine and DentistryBlizard InstituteQueen Mary University of LondonLondonUK
| | - Corinna Pade
- Barts and the London School of Medicine and DentistryBlizard InstituteQueen Mary University of LondonLondonUK
| | - George Joy
- Barts Heart CentreSt. Bartholomew's HospitalLondonUK
| | - Mala Maini
- Division of Infection and ImmunityUniversity College LondonLondonUK
| | - Benny Chain
- Division of Infection and ImmunityUniversity College LondonLondonUK
| | - Amanda Semper
- National Infection ServicePublic Health EnglandPorton DownUK
| | - Timothy Brooks
- National Infection ServicePublic Health EnglandPorton DownUK
| | - Benjamin J. Ollivere
- Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Áine McKnight
- Barts and the London School of Medicine and DentistryBlizard InstituteQueen Mary University of LondonLondonUK
| | | | - Thomas A. Treibel
- Barts Heart CentreSt. Bartholomew's HospitalLondonUK,Institute of Cardiovascular SciencesUniversity College LondonLondonUK
| | - Charlotte Manisty
- Barts Heart CentreSt. Bartholomew's HospitalLondonUK,Institute of Cardiovascular SciencesUniversity College LondonLondonUK
| | - James C. Moon
- Barts Heart CentreSt. Bartholomew's HospitalLondonUK,Institute of Cardiovascular SciencesUniversity College LondonLondonUK
| | | | - Ana M. Valdes
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust and the University of NottinghamNottinghamUK,Division of Rheumatology, Orthopaedics and DermatologySchool of MedicineUniversity of NottinghamNottinghamUK
| | - Rosemary J. Boyton
- Department of Infectious DiseaseImperial College LondonLondonUK,Lung DivisionRoyal Brompton and Harefield HospitalsGuy’s and St Thomas’ NHS Foundation TrustLondonUK
| | - Daniel M. Altmann
- Department of Immunology and InflammationImperial College LondonLondonUK
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Hernández-Doño S, Sánchez-González RA, Trujillo-Vizuet MG, Zamudio-Castellanos FY, García-Silva R, Bulos-Rodríguez P, Vazquez-Guzmán CA, Cárdenas-Ramos X, de León Rodríguez D, Elías F, Domínguez-Arevillaga S, Pérez-Tirado JM, Vera-Lastra OL, Granados J, Sepúlveda-Delgado J. Protective HLA alleles against severe COVID-19: HLA-A*68 as an ancestral protection allele in Tapachula-Chiapas, Mexico. Clin Immunol 2022; 238:108990. [PMID: 35395388 PMCID: PMC8982524 DOI: 10.1016/j.clim.2022.108990] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/13/2022] [Accepted: 03/25/2022] [Indexed: 11/03/2022]
Abstract
HLA is a polymorphic antigen presenter which has provided valuable information on the susceptibility of populations to viruses. Therefore, the study of HLA can reveal specific susceptibility or resistance alleles to severe COVID-19 in an ethnically dependent manner. This pilot study investigated HLA alleles associated with COVID-19 severity in Tapachula, Chiapas, Mexico. A total of 146 Mexican Mestizos were typed for HLA class I and II using PCR-SSP. The patients were classified according to the outcome (death or improvement) and the infection's severity (mild or severe). In addition, a group of exposed uninfected individuals was included. HLA-A*68 was found to be a protective allele against the severe infection and fatal outcome; pC = 0.03, OR = 0.4, 95% CI =0.20-0.86, and pC =0.009, OR = 0.3, 95% CI =0.13-0.71 respectively. HLA-DRB1*03 also appears to be a protective factor against fatal outcome pC = 0.009, OR = 0.1, 95%IC = 0.01-0.66; however, the low frequency of this allele in the studied population limits the statistical power. The severity and fatal outcome of COVID-19 patients in Tapachula, Chiapas depend more on the lack of resistance than susceptibility HLA alleles.
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Affiliation(s)
- Susana Hernández-Doño
- Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | | | - Rafael García-Silva
- Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Pedro Bulos-Rodríguez
- Department of Internal Medicine, Hospital Regional de Alta Especialidad Ciudad Salud, Tapachula, Chiapas, Mexico
| | - Carlos A Vazquez-Guzmán
- Department of Internal Medicine, Hospital Regional de Alta Especialidad Ciudad Salud, Tapachula, Chiapas, Mexico
| | | | - Diana de León Rodríguez
- Facultad de Medicina Humana Campus IV, Universidad Autónoma de Chiapas, Mexico; Becario de la Dirección General de Calidad y Educación en Salud, Secretaría de Salud, Mexico
| | - Fabiola Elías
- Facultad de Medicina Humana Campus IV, Universidad Autónoma de Chiapas, Mexico
| | | | | | - Olga Lidia Vera-Lastra
- Department of Internal Medicine, Hospital de Especialidades, Centro Médico la Raza, Chile
| | - Julio Granados
- Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jesús Sepúlveda-Delgado
- Research Division, Hospital Regional de Alta Especialidad Ciudad Salud, Tapachula, Chiapas, Mexico.
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Tandoh KZ, Quaye O. Genetic associations in chronic hepatitis B infection: toward developing polygenic risk scores. Future Microbiol 2022; 17:541-549. [PMID: 35332782 DOI: 10.2217/fmb-2021-0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Chronic hepatitis B (CHB) infection results in multiple clinical phenotypes of varying severity. One of the critical gaps in CHB management is the lack of a genetic-based tool to aid existing hepatocellular carcinoma and cirrhosis risk stratification models for patients with active CHB. Such individual predictive models for CHB are plagued by an inherent limitation of discriminatory power that clearly indicates the need for their improvement. In this article, we highlight genetic association studies in CHB that identified HLA and cytokine genetic susceptibility loci to CHB. We advance the position that translating CHB genetic susceptibility loci into polygenic risk scores will be a welcome addendum to the current arsenal of CHB outcome predictive models. We conclude with comments on hurdles that future research efforts should address within the research enclave of CHB and advocate for increased genetic data representation from sub-Saharan Africa.
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Affiliation(s)
- Kwesi Z Tandoh
- Department of Biochemistry, West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Cell & Molecular Biology, College of Basic & Applied Sciences, University of Ghana, Accra, Ghana
| | - Osbourne Quaye
- Department of Biochemistry, West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Cell & Molecular Biology, College of Basic & Applied Sciences, University of Ghana, Accra, Ghana
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Hovhannisyan A, Madelian V, Avagyan S, Nazaretyan M, Hyussyan A, Sirunyan A, Arakelyan R, Manukyan Z, Yepiskoposyan L, Mayilyan KR, Jordan F. HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity. Front Immunol 2022; 13:769900. [PMID: 35185875 PMCID: PMC8850920 DOI: 10.3389/fimmu.2022.769900] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).
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Affiliation(s)
- Anahit Hovhannisyan
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
- Russian-Armenian University, Yerevan, Armenia
| | - Vergine Madelian
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
| | - Sevak Avagyan
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
| | - Mihran Nazaretyan
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
| | - Armine Hyussyan
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
| | - Alina Sirunyan
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
| | | | | | | | - Karine R. Mayilyan
- Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia
| | - Frieda Jordan
- Armenian Bone Marrow Donor Registry Charitable Trust, Yerevan, Armenia
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Schreiber S, Honz M, Mamozai W, Kurktschiev P, Schiemann M, Witter K, Moore E, Zielinski C, Sette A, Protzer U, Wisskirchen K. Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors. Mol Ther Methods Clin Dev 2021; 23:476-489. [PMID: 34853796 PMCID: PMC8605085 DOI: 10.1016/j.omtm.2021.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/27/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.
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Xue C, Gu X, Li L. Immune classifier-based signatures provide good prognostic stratification and predict the clinical benefits of immune-based therapies for hepatocellular carcinoma. Cancer Cell Int 2021; 21:471. [PMID: 34488768 PMCID: PMC8422634 DOI: 10.1186/s12935-021-02183-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/27/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive cancer with a high rate of death globally. The use of bioinformatics may help to identify immune cell-related genes both as targets for potential immunotherapies and for their value associated with predicting therapy responses. METHODS In this study, mRNA expression profiles of HCC samples from The Cancer Genome Atlas (TCGA) database were subjected to gene enrichment, cell type abundance, immune cell infiltration, and pathway enrichment analyses to determine immune cell gene features, cell type abundance, and functional annotation characteristics. We also evaluated their prognostic values using Cox regression and Kaplan-Meier analyses and assessed potential responses to chemotherapy. Four subgroups (Groups 1-4) were identified. Group 4 was associated with advanced clinical characteristics, high immune cell enrichment scores, and the poorest outcomes. RESULTS Differentially expressed genes (DEGs) in the HCC samples were enriched in the following pathways: antigen binding, cell surface receptor signal transduction of the immune response, and cell surface activated receptor signal transduction of the immune response. Highly expressed genes in Group 4 were enriched in elements of the WNT signalling pathway. We identified five immune-related genes (SEMA3A, TNFRSF11B, GUCA2A, SAA1, and CALCR) that were significantly related to HCC prognosis. A prognostic model based on these five genes exhibited good predictive value, with 1-year and 5-year area under the curve (AUC) values of > 0.66. Group 4 was also potentially more sensitive to EHT 1864, FH535, and lapatinib chemotherapies than the other groups. CONCLUSIONS We identified and validated four HCC subgroups based on immune system-related genes and identified five genes that may be used for an immune-based prognostic model for HCC treatment.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang, China.
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Abstract
Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.
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Umemura T, Joshita S, Saito H, Wakabayashi SI, Kobayashi H, Yamashita Y, Sugiura A, Yamazaki T, Ota M. Investigation of the Effect of KIR-HLA Pairs on Hepatocellular Carcinoma in Hepatitis C Virus Cirrhotic Patients. Cancers (Basel) 2021; 13:cancers13133267. [PMID: 34209910 PMCID: PMC8267716 DOI: 10.3390/cancers13133267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/21/2021] [Accepted: 06/25/2021] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Natural killer (NK) cells normally respond to tumor cells and virally infected cells by killing them via the innate immune system. However, the functional impairment of NK cells has been observed in hepatocellular carcinoma. The NK-cell phenotype is partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This study evaluated the involvement of KIR–HLA pairs in hepatocellular carcinoma development in 211 patients with hepatitis C virus-associated cirrhosis. HLA-Bw4 and the KIR3DL1+HLA-Bw4 pair were significantly associated with hepatocellular carcinoma onset during a median follow-up of 6.6 years, which suggested that functional interactions between KIR and HLA or HLA-Bw4 may influence the risk of cancer development. Abstract Natural killer cells are partially mediated through the binding of killer cell immunoglobulin-like receptors (KIR) with human leukocyte antigen (HLA) class I ligands. This investigation examined the risk of hepatocellular carcinoma (HCC) in relation to KIR–HLA pairs in patients with compensated hepatitis C virus (HCV)-associated cirrhosis. A total of 211 Japanese compensated HCV cirrhotic cases were retrospectively enrolled. After KIR, HLA-A, HLA-Bw, and HLA-C typing, associations between HLA, KIR, and KIR–HLA combinations and HCC development were evaluated using the Cox proportional hazards model with the stepwise method. During a median follow-up period of 6.6 years, 69.7% of patients exhibited HCC. The proportions of HLA-Bw4 and the KIR3DL1 + HLA-Bw4 pair were significantly higher in patients with HCC than in those without (78.9% vs. 64.1%; odds ratio (OR)—2.10, 95% confidence interval (CI)—1.10–4.01; p = 0.023 and 76.2% vs. 60.9%, odds ratio—2.05, p = 0.024, respectively). Multivariate analysis revealed the factors of male gender (hazard ratio (HR)—1.56, 95% CI—1.12–2.17; p = 0.009), α-fetoprotein > 5.6 ng/mL (HR—1.56, 95% CI—1.10–2.10; p = 0.011), and KIR3DL1 + HLA-Bw4 (HR—1.69, 95% CI—1.15–2.48; p = 0.007) as independent risk factors for developing HCC. Furthermore, the cumulative incidence of HCC was significantly higher in patients with KIR3DL1 + HLA-Bw4 than in those without (log-rank test; p = 0.013). The above findings suggest KIR3DL1 + HLA-Bw4, in addition to HLA-Bw4, as a novel KIR–HLA pair possibly associated with HCC development in HCV cirrhosis. HCV-associated cirrhotic patients with the risk factors of male gender, α-fetoprotein > 5.6 ng/mL, and KIR3DL1 + HLA-Bw4 may require careful surveillance for HCC onset.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
- Consultation Center for Liver Diseases, Shinshu University Hospital, Matsumoto 390-8621, Nagano, Japan
- Department of Life Innovation, Shinshu University, Matsumoto 390-8621, Nagano, Japan
- Correspondence: ; Tel.: +81-263-37-2634; Fax: +81-263-32-9412
| | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Hiromi Saito
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Shun-ichi Wakabayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Hiroyuki Kobayashi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Yuki Yamashita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Ayumi Sugiura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Tomoo Yamazaki
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
| | - Masao Ota
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan; (S.J.); (H.S.); (S.-i.W.); (H.K.); (Y.Y.); (A.S.); (T.Y.); (M.O.)
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Cai Y, Yin W. The Multiple Functions of B Cells in Chronic HBV Infection. Front Immunol 2020; 11:582292. [PMID: 33381113 PMCID: PMC7767983 DOI: 10.3389/fimmu.2020.582292] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.
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Affiliation(s)
- Ying Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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38
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Al-Saffar OB, Ad'hiah AH. Genetic variants in IL4RA, IL6, and IL12B genes and susceptibility to hepatitis B and C virus infections among Iraqi patients. J Med Virol 2020; 92:3448-3458. [PMID: 32652594 DOI: 10.1002/jmv.26297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/27/2020] [Accepted: 07/09/2020] [Indexed: 12/18/2022]
Abstract
Hepatitis B and C viruses (HBV and HCV) are common causative pathogens of viral hepatitis. Progression of both infections is determined by virus- and host-related factors. Cytokines are important host genetic factors that may have a predisposing role in HBV and HCV infections. This case-control study evaluated the genetic association of IL4RA+1902 (rs1801275), IL6-174 (rs1800795), IL6-597 (rs1800797), and IL12B-1188 (rs3212227) variants with chronic HBV and HCV infections among Iraqi patients. A total of 220 viral hepatitis patients were enrolled in the study (113 HBV and 107 HCV), together with 141 healthy subjects. Sequence-specific primer polymerase chain reaction assay was the genotyping method. Results revealed that under a dominant genetic model, IL6-174 variant was significantly associated with HBV infection, whereas no association with the HCV risk was reported. However, the risk for both infections was markedly associated with IL6-597 variant under recessive, dominant, and codominant genetic models. Estimation of IL6-174 -IL6-597 haplotypes depicted that G-A haplotype was significantly associated with an increased risk to develop HBV infection, whereas a significantly decreased risk was associated with G-G and C-G haplotypes. For HCV, G-G and C-A haplotypes were significantly associated with risk of HCV infection. IL4RA+1902 and IL12B-1188 variants showed no association with HBV or HCV risk. Analysis of variance revealed no significant association between genotypes of the four determined single-nucleotide polymorphisms and HBV or HCV viral load. In conclusion, the study supports the concept that IL6-597 variant is associated with susceptibility to HBV and HCV infections among Iraqis. The risk of HBV infection is further associated with IL6-174 variant.
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Affiliation(s)
- Osama B Al-Saffar
- Biology Department, Madenat Al-elem University College, Baghdad, Iraq
| | - Ali H Ad'hiah
- Tropical-Biological Research Unit, College of Science, University of Baghdad, Baghdad, Iraq
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Yengo CK, Torimiro J, Kowo M, Lebon PA, Tiedeu BA, Luma H, Njoya O, Rowland-Jones S, Yindom LM. Variation of HLA class I (-A and -C) genes in individuals infected with hepatitis B or hepatitis C virus in Cameroon. Heliyon 2020; 6:e05232. [PMID: 33102855 PMCID: PMC7569220 DOI: 10.1016/j.heliyon.2020.e05232] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/10/2020] [Accepted: 10/08/2020] [Indexed: 12/22/2022] Open
Abstract
The Human Leucocyte Antigens (HLA) work in concert with other immune factors to modulate immunity to viral infections. Extensive variation has been reported in the genetic sequences and functions of classical HLA class I genes in many (mostly Western) populations, and several HLA associations with infectious disease outcomes have been reported. Little is known about their role in the susceptibility or resistance to hepatitis viruses in Central African populations. The aim of this study was to determine variants of two HLA class I genes (HLA-A and -C) in adults infected with hepatitis B (HBV)- or -C (HCV) virus in Cameroon. In this case-control study, a total of 169 unrelated adults comprising 68 HCV-infected, 38 HBV-infected and 63 uninfected (controls) individuals participated. Each consented participant was screened for HBV, HCV, and HIV infections and willingly donated a single blood sample for genomic DNA isolation and some clinical laboratory tests. HLA-A and HLA-C were genotyped using previously described sequence-based techniques (SBT). A total of 54 HLA alleles were identified in the study population (27 HLA-A and 27 HLA-C). HLA-A∗23:01 and HLA-C∗07:01 were the most common alleles with genotype frequencies of 31.4% and 29.3%, respectively. Hepatitis individuals were six times more likely to be HLA-A∗30:01 carriers than uninfected controls (OR = 6.30, p = 0.020 (HBV); OR = 6.21, p = 0.010 (HCV), respectively). Similarly, carriers of HLA-C∗17:01 were over-represented in the HBV-infected compared to the uninfected control group (21.9% vs. 6.4%, respectively) suggesting that this allele could play a role in the susceptibility to HBV infection. These findings demonstrate that carriers of HLA-A∗30:01 were over-represented in the hepatitis group compared to uninfected controls while HLA-C∗17:01 was completely absent in the HCV + group.
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Affiliation(s)
- Clauvis Kunkeng Yengo
- Department of Biochemistry, Faculty of Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Judith Torimiro
- Molecular Biology Laboratory, Chantal Biya International Reference Centre for Research on Prevention and Management of HIV/AIDS (CIRCB), Yaoundé, Cameroon
- Department of Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Mathurin Kowo
- Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Patrick Awoumou Lebon
- Department of Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Barbara Atogho Tiedeu
- Department of Biochemistry, Faculty of Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Henry Luma
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
| | - Oudou Njoya
- Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon
| | - Sarah Rowland-Jones
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Louis-Marie Yindom
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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40
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Liu Q, Shi Z, Liu X, Xiao H. Correlation between the coexpression of zinc finger and SCAN domain-containing protein 31 and transcriptional activator with PDZ-binding motif and prognosis in hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1308. [PMID: 33209888 PMCID: PMC7661889 DOI: 10.21037/atm-20-6373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Transcriptional coactivator with PDZ binding motif (TAZ) regulates multiple biological processes and has been found to be related to hepatocellular carcinoma (HCC). However, common signaling pathways downstream after TAZ knockdown may also be important. Methods TAZ was knocked down in an HCC cell line, and its potential target genes were analyzed. A decrease in the expression of zinc finger and SCAN domain-containing protein 31 (ZSCAN31) was observed. The difference in ZSCAN31 expression was evaluated, and its effect on survival in HCC patients who received surgical resection was determined. Results ZSCAN31 was over-expressed in HCC tissues and was associated with low overall survival (OS) in HCC patients after surgical resection. Analysis of tissue samples from 83 HCC patients who underwent surgical resection in our hospital produced similar results. High ZSCAN31 expression was significantly associated with tumor size. High expression levels of both TAZ and ZSCAN31 were related to poor OS. A positive correlation was identified between ZSCAN31 expression and TAZ expression, and the protein binding of ZSCAN31 and TAZ was confirmed by co-immunoprecipitation (Co-IP) assay using an HCC cell line. Conclusions ZSCAN31 is associated with TAZ expression in HCC cells, and the targeting of ZSCAN31 and TAZ may represent a novel therapeutic approach in HCC.
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Affiliation(s)
- Qiang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengrong Shi
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiongwei Liu
- Department of Hepatobiliary Surgery, North-Kuanren General Hospital, Chongqing, China
| | - Heng Xiao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Andeen NK, Smith KD, Vasilescu ER, Batal I. The Authors Reply. Kidney Int Rep 2020; 5:1841. [PMID: 33102981 PMCID: PMC7569693 DOI: 10.1016/j.ekir.2020.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 11/25/2022] Open
Affiliation(s)
- Nicole K Andeen
- Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA
| | - Kelly D Smith
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Elena-Rodica Vasilescu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
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Mohamed AA, Abd-Elsalam S, Zaghloul M, Attala M, Khattab RA, Khater A, El-damasy DA, El-Sayed E, Hassanin S, Hawash N, Mohamed MR. Association between Human Leukocyte Antigen-DQ Polymorphisms and Treatment Response in Chronic Hepatitis B Egyptian Population: A Prospective Study. THE OPEN BIOMARKERS JOURNAL 2020; 10:55-59. [DOI: 10.2174/1875318302010010055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/03/2020] [Accepted: 05/12/2020] [Indexed: 02/08/2023]
Abstract
Background & Aims:
Several studies, in different populations, have focused on the role of HLA-DQ gene polymorphism in the pathogenesis of HBV infection. However, these findings are still controversial. This study aimed to determine HLA-DQ polymorphism in Chronic HBV patients and its impact on the response to antiviral therapy.
Methods:
This study was carried out on a total number of 188 participants, they were subdivided as follows: Group I (patients’ group): included 97 patients with chronic hepatitis B viral infection that was further subdivided according to response to treatment into responder and non-responder subgroups, Group II (Control group): included 91 normal healthy subjects who were matched to the patient group by sex and age. PCR (Polymerase Chain Reaction) testing, for HBV-DNA, was done for all participants enrolled in the study to measure the viral virus load before and after treatment. HLA- DQ polymorphism allelic discrimination assay was assayed using the Real-time equipment.
Results:
In a general analysis for the SNP rs7453920, the overall genotypes frequencies were 37% for A/A, 60.6% for A/G, and 37% for G/G. The G alleles of HLA-DQ rs7453920 were significantly increased in chronic HBV infection patients. A total of 77 (79.4%) patients were responders. Among this group, 72.7% were male, and the average age was 38.59 ±9.15 years. On evaluation of the association between polymorphisms in HLA-DQ gene and treatment response, the results indicated that response to treatment declined when patients were carrying the more unfavorable rs 7453920 GG with a response rate of 64%. Patients carrying the mutant allele AG, or the wild type allele AA were more likely to achieve a higher rate of response (84.8% and 83.3%, respectively).
Conclusion:
The presence of HLA-DQB2 rs 7453920-G serves as a risk factor for chronic HBV infection and treatment failure in the Egyptian population.
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Can Direct-Acting Antiviral Treatment Change the Immunologic Risk Profile in Patients Infected with Hepatitis C Virus Who Are on the Cadaveric Waiting List? Transplant Proc 2020; 52:97-101. [PMID: 31901328 DOI: 10.1016/j.transproceed.2019.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/11/2019] [Accepted: 10/06/2019] [Indexed: 12/09/2022]
Abstract
BACKGROUND In patients with hepatitis C virus (HCV) infection, the activation of the immune system by the virus or viral proteins leads to the production of numerous autoantibodies and clinical manifestations. The objectives of this study were to investigate the relationship between HCV and anti-HLA antibodies, as well as the effect of viremia on the antibody response and of direct-acting antivirals (DAAs) on anti-HLA antibody persistence in patients on the waiting list for a cadaveric kidney transplant. METHODS A total of 395 patients from the cadaveric renal transplant waiting list were included in the study. The patients were grouped according to the presence of HCV infection, and patients with HCV positivity were further divided into a spontaneous clearance group and a persistent group. Anti-HLA antibodies were examined before and after treatment of the patients in the persistent group. The One Lambda Luminex method (Thermo Fisher Scientific, Waltham, MA, United States) was used to assess both HLA class I and II alleles and the anti-HLA antibody profile. RESULTS Anti-HLA class I and II antibodies were detected in 48.2% and 55.1%, respectively, of the patients infected with HCV and in 21.8% and 20.4%, respectively, of the patients who were not infected. The level of anti-HLA A3, A11, B72, B52, Cw6, Cw16, DR3, and DQ4 antibodies was significantly higher in the patients infected with HCV. There was no statistically significant difference in class I and II antibody titration between the HCV-infected spontaneous clearance group and the persistent group (class I mean fluorescence intensity [MFI] ± SD: 13,583 ± 6224, 13,450 ± 9540, P = .808; Class II MFI ± SD: 13,000 ± 8673, 8440 ± 8302, P = .317, respectively). There was no significant difference in the class I and class II anti-HLA antibody profile and titration in the persistent group after treatment with DAAs (P > .05). CONCLUSIONS The results of this study demonstrated that hepatitis C DAA treatment did not change the anti-HLA antibody profile and titration.
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HLA-DQB1/ DRB1 Alleles Associate with Traditional Chinese Medicine Syndrome of Chronic Hepatitis B: A Potential Predictor of Progression. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8146937. [PMID: 31871943 PMCID: PMC6906876 DOI: 10.1155/2019/8146937] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/11/2019] [Accepted: 10/26/2019] [Indexed: 12/28/2022]
Abstract
Background and Aims Traditional Chinese medicine (TCM) has been widely applied in chronic hepatitis B (CHB) supplementary treatment in China. Kidney yang deficiency syndrome (KYDS), one of the most common TCM syndromes of CHB, is more likely to progress to liver cirrhosis or hepatocellular carcinoma than other syndromes. Polymorphisms in the human leucocyte antigen- (HLA-) DQB1 and -DRB1 genes were reported to be associated with hepatitis B virus infection outcomes. Here, we investigated whether HLA-DQB1 and HLA-DRB1 are associated with the classification of CHB TCM syndromes. Methods We genotyped HLA-DQB1 and HLA-DRB1 alleles in a total of 105 subjects, including 74 CHB patients (28 KYDS and 46 non-KYDS) and 31 healthy individuals from Sichuan Province of Southwest China, by polymerase chain reaction sequence-based typing (PCR-SBT). Moreover, a meta-analysis was carried out for further verification. Results The proportion of patients with high HBV DNA load (≥2000 IU/ml) in the KYDS group is higher than that in the non-KYDS group (60.70% [17/28] vs. 28.30% [13/46]); P=0.01). The frequencies of HLA-DQB1∗02:01 (P=0.04) and HLA-DRB1∗03:01 (P=0.04) in the KYDS group were significantly increased compared to the non-KYDS group. The gene test and meta-analysis showed that HLA-DRB1∗08:03 confers susceptibility to CHB (odds ratio = 1.57). Conclusion We found an association between HLA-DRB1/DQB1 polymorphisms and KYDS of CHB. Moreover, KYDS patients of CHB are characteristic with high HBV DNA loads. These findings help to reveal the biological mechanism of KYDS in high risk of CHB progression and suggest a potential prognostic value for disease outcome evaluation.
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Udomkarnjananun S, Takkavatakarn K, Praditpornsilpa K, Nader C, Eiam-Ong S, Jaber BL, Susantitaphong P. Hepatitis B virus vaccine immune response and mortality in dialysis patients: a meta-analysis. J Nephrol 2019; 33:343-354. [DOI: 10.1007/s40620-019-00668-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 10/31/2019] [Indexed: 12/11/2022]
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46
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Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host Genetic Determinants of Hepatitis B Virus Infection. Front Genet 2019; 10:696. [PMID: 31475028 PMCID: PMC6702792 DOI: 10.3389/fgene.2019.00696] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.
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Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Changtai Wang
- Department of Infectious Diseases, the Affiliated Anqing Hospital of Anhui Medical University, Anqing, China
| | - Zhongping Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guizhou Zou
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Duisburg-Essen, Essen, Germany
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Ivanova M, Creary LE, Al Hadra B, Lukanov T, Mazzocco M, Sacchi N, Ameen R, Al-Shemmari S, Moise A, Ursu LD, Constantinescu I, Vayntrub T, Fernández-Viňa MA, Shivarov V, Naumova E. 17th IHIW component "Immunogenetics of Ageing" - New NGS data. Hum Immunol 2019; 80:703-713. [PMID: 31331679 DOI: 10.1016/j.humimm.2019.07.287] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/08/2019] [Accepted: 07/12/2019] [Indexed: 12/14/2022]
Abstract
The 'Immunogenetics of Aging' project is a component introduced in the 14th International HLA and Immunogenetics Workshop (IHIW) and developed further within subsequent workshops. The aim was to determine the relevance of immunogenetic markers, focusing on HLA, cytokine genes, and some innate immunity genes, for successful aging and an increased capacity to reach the extreme limits of life-span. Within the 17th IHIW we applied Next Generation Sequencing methods to refine further HLA associations at allele level in longevity, and to extend our knowledge to additional loci such as HLA-DQA1, HLA-DPB1 and HLA-DPA1. Analysis of relatively small number of healthy elderly and young controls from four populations showed that some HLA class I and class II alleles were significantly positively associated with healthy aging. Additionally we observed statistically significant differences in HLA allele distribution when the analysis was performed separately in elderly females and males compared to sex-matched young controls. Haplotypes, probably associated with better control of viral and malignant diseases were increased in the elderly sample. These preliminary NGS data could confirm our hypotheses that survival and longevity might be associated with selection of HLA alleles and haplotypes conferring disease resistance or susceptibility. Therefore HLA alleles and haplotypes could be informative immunogenetic markers for successful ageing.
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Affiliation(s)
- Milena Ivanova
- Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria.
| | - Lisa E Creary
- Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA
| | - Bushra Al Hadra
- Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria
| | - Tsvetelin Lukanov
- Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria
| | - Michela Mazzocco
- Italian Bone Marrow Donor Registry Tissue Typing Laboratory, E.O. Ospedali Galliera, Genova, Italy
| | - Nicoletta Sacchi
- Italian Bone Marrow Donor Registry Tissue Typing Laboratory, E.O. Ospedali Galliera, Genova, Italy
| | - Reem Ameen
- Medical Laboratory Sciences Department, Health Sciences Center, Kuwait University, Jabriya, Kuwait
| | - Salem Al-Shemmari
- Medical Laboratory Sciences Department, Health Sciences Center, Kuwait University, Jabriya, Kuwait
| | - Ana Moise
- Carol Davila University of Medicine and Pharmacy, Bucharest, Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania
| | - Larisa Denisa Ursu
- Carol Davila University of Medicine and Pharmacy, Bucharest, Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania
| | - Ileana Constantinescu
- Carol Davila University of Medicine and Pharmacy, Bucharest, Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania
| | - Tamara Vayntrub
- Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA
| | - Marcelo A Fernández-Viňa
- Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA; Histocompatibility, Immunogenetics and Disease Profiling Laboratory, Stanford Blood Center, Palo Alto, CA, USA
| | - Velizar Shivarov
- Laboratory of Clinical Immunology, University Hospital Sofiamed, Sofia, Bulgaria; Department of Genetics, Faculty of Biology, Sofia University "St. Kliment Ohridski", Sofia, Bulgaria
| | - Elissaveta Naumova
- Department of Clinical Immunology, University Hospital Alexandrovska, Medical University, Sofia, Bulgaria
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Identifying immunologically-vulnerable regions of the HCV E2 glycoprotein and broadly neutralizing antibodies that target them. Nat Commun 2019; 10:2073. [PMID: 31061402 PMCID: PMC6502829 DOI: 10.1038/s41467-019-09819-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 04/02/2019] [Indexed: 02/06/2023] Open
Abstract
Isolation of broadly neutralizing human monoclonal antibodies (HmAbs) targeting the E2 glycoprotein of Hepatitis C virus (HCV) has sparked hope for effective vaccine development. Nonetheless, escape mutations have been reported. Ideally, a potent vaccine should elicit HmAbs that target regions of E2 that are most difficult to escape. Here, aimed at addressing this challenge, we develop a predictive in-silico evolutionary model for E2 that identifies one such region, a specific antigenic domain, making it an attractive target for a robust antibody response. Specific broadly neutralizing HmAbs that appear difficult to escape from are also identified. By providing a framework for identifying vulnerable regions of E2 and for assessing the potency of specific antibodies, our results can aid the rational design of an effective prophylactic HCV vaccine. A good vaccine should direct the immune response to virus regions that are most difficult to escape. Here, Quadeer et al. develop a predictive in-silico evolutionary model for HCV E2 which identifies one such antigenic region and identifies multiple broadly neutralizing human antibodies that appear difficult to escape from.
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James LM, Georgopoulos AP. Human Leukocyte Antigen as a Key Factor in Preventing Dementia and Associated Apolipoprotein E4 Risk. Front Aging Neurosci 2019; 11:82. [PMID: 31031617 PMCID: PMC6473084 DOI: 10.3389/fnagi.2019.00082] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 03/22/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
- Lisa M. James
- Department of Veterans Affairs Health Care System, Brain Sciences Center, Minneapolis, MN, United States
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Apostolos P. Georgopoulos
- Department of Veterans Affairs Health Care System, Brain Sciences Center, Minneapolis, MN, United States
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States
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50
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Bavaro DF, Saracino A, Fiordelisi D, Bruno G, Ladisa N, Monno L, Angarano G. Influence of HLA-B18 on liver fibrosis progression in a cohort of HIV/HCV coinfected individuals. J Med Virol 2019; 91:751-757. [PMID: 30578670 DOI: 10.1002/jmv.25385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is accelerated in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected compared with HCV monoinfected patients, due to multiple cofactors. Recently, HLA-B18 haplotype has been associated with short-term liver disease progression in this population. Our aim was to assess the influence of HLA-B18 on the fibrosis process in HIV/HCV coinfected individuals, untreated for HCV, during a long-term follow-up. All consecutive HIV/HCV co-infectedcoinfected patients followed in our center, with positive HCV-RNA and available human leukocyte antigen (HLA) haplotypes (determined by sequence-specific oligonucleotide primed polymerase chain reaction and simple sequence repeats polymerase chain reaction using Luminex Technology) were included. Liver fibrosis progression was assessed by means of fibrosis-4 index for liver fibrosis (FIB-4) and AST to platelet ratio index. The association between FIB-4 score over time and laboratory and clinical parameters, including HLA, was evaluated by univariate and multivariate multilevel generalized linear models. A total of 29 out of 148 screened patients were excluded because of spontaneous HCV clearance (27% were HLA-B18+). Among the remaining 119 individuals (82% males; median age at first visit = 30 years [interquartile range, IQR, 26-35]; median follow-up = 21.5 years [IQR, 15-25]), 26% were HLA-B18+. No baseline differences were evidenced between HLA-B18+ and B18- patients. Fibrosis progression was significantly faster in HLA-B18+ than in HLA-B18- patients ( P < 0.001) (Figure 1). At univariate analysis, age ( P < 0.001), HLA-B18 haplotype ( P = 0.02) and HIV-RNA viral load overtime ( P < 0.001) were associated with liver disease progression. At multivariate analysis, only age ( P < 0.001) remained independently associated with liver fibrosis progression. Our data suggest a possible association between HLA-B18 and an accelerated liver fibrosis in HIV/HCV coinfected with a long-term follow-up.
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Affiliation(s)
- Davide Fiore Bavaro
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Annalisa Saracino
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Deborah Fiordelisi
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Giuseppe Bruno
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Nicoletta Ladisa
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Laura Monno
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
| | - Gioacchino Angarano
- Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari "Aldo Moro,", Bari, Italy
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