1,109 results
Search Results
2. Genetic variants associated with T cell–mediated cutaneous adverse drug reactions: A PRISMA‐compliant systematic review—An EAACI position paper.
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Oussalah, Abderrahim, Yip, Vincent, Mayorga, Cristobalina, Blanca, Miguel, Barbaud, Annick, Nakonechna, Alla, Cernadas, Josefina, Gotua, Maia, Brockow, Knut, Caubet, Jean‐Christoph, Bircher, Andreas, Atanaskovic‐Markovic, Marina, Demoly, Pascal, Kase‐Tanno, Luciana, Terreehorst, Ingrid, Laguna, José Julio, Romano, Antonino, Guéant, Jean‐Louis, and Pirmohamed, Munir
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TOXIC epidermal necrolysis , *DRUG side effects , *HLA histocompatibility antigens , *META-analysis , *PATHOLOGY , *DRUG metabolism , *STEVENS-Johnson Syndrome ,SIDE effects of anticonvulsants - Abstract
Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell–mediated reactions classically occur more than 6 hours after drug administration and include life‐threatening conditions such as toxic epidermal necrolysis, Stevens‐Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA‐B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA‐compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim‐sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future. [ABSTRACT FROM AUTHOR]
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- 2020
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3. Systematic review of associations between HLA and renal function.
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Lowe, Marcus, Jervis, Steven, Payton, Antony, Poulton, Kay, Worthington, Judith, Gemmell, Isla, and Verma, Arpana
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KIDNEY physiology ,FALSE positive error ,KIDNEY diseases ,KIDNEY failure ,HISTOCOMPATIBILITY antigens ,HLA histocompatibility antigens ,META-analysis - Abstract
Introduction: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations. Methods: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study. Results: A total of 95 HLA types and 14 three‐locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies. Discussion: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine.
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Bechtold, Viviane, Smolen, Kinga K., Burny, Wivine, de Angelis, Simone P., Delandre, Simon, Essaghir, Ahmed, Marchant, Arnaud, Ndour, Cheikh, Taton, Martin, van der Most, Robbert, Willems, Fabienne, and Didierlaurent, Arnaud M.
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HEPATITIS associated antigen ,INTERFERON regulatory factors ,HEPATITIS B vaccines ,IMMUNOLOGIC memory ,HLA histocompatibility antigens - Abstract
The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)–DR, which correlated with the magnitude of the memory CD4
+ T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (AP-1), GATA, C/EBP, and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14+ monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection. Editor's summary: Most vaccines based on recombinant antigens rely on coadministration with an adjuvant to elicit a robust immune response. Although adjuvants are needed for many vaccines, it is less clear which adjuvant(s) should be paired with each immunogen. In two papers, Bechtold et al. and Arunachalam et al. performed comparative analyses to assess the effect of different adjuvants on the immune response. Bechtold et al. showed that an AS01-adjuvanted hepatitis B virus vaccine, which induces robust CD4+ T cell responses against the vaccine antigen, also elicited trained immunity in human recipients, which was not observed in an Alum-adjuvanted vaccine. Arunachalam et al. found that Matrix-M and 3M-052 + Alum adjuvantation induced robust immune responses to the R21 malaria vaccine in nonhuman primates, but a third comparator, GLA-LSQ, elicited a lower magnitude of response that was short lived. Although Matrix-M and 3M-052 + Alum induced robust and durable antibody responses, they elicited distinct innate immune responses, demonstrating that multiple innate immune mechanisms can program durable vaccine-induced immunity. These head-to-head comparisons in both humans and nonhuman primates demonstrate that selecting an adjuvant should be done carefully and that different adjuvants have distinct effects on both innate and adaptive immunity. —Courtney Malo [ABSTRACT FROM AUTHOR]- Published
- 2024
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5. HLA and amyotrophic lateral sclerosis: a systematic review and meta-analysis.
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Nona, R. J., Greer, J. M., Henderson, R. D., and McCombe, P. A.
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AMYOTROPHIC lateral sclerosis ,HLA histocompatibility antigens ,FIXED effects model ,GENOME-wide association studies ,NEURODEGENERATION - Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of upper and lower motor neurones. It leads to death by respiratory failure and has a typical prognosis of 2–3 years. The immune system has been shown to play a role in the pathophysiology of ALS. Some of the most important immune genes are within the human leukocyte antigen (HLA) region, and a recent genome-wide association study (GWAS) has identified a risk allele for ALS within the HLA region. Older studies have also suggested an HLA association with ALS, with certain HLA alleles showing differing expression between patients and controls. This systematic review and meta-analysis examines the previous studies performed in this field. Methods: We used established publication search engines. Findings were excluded if they did not meet the selection criteria. We then undertook statistical meta-analysis on the eligible papers, using a fixed effects model. Results: There were eight eligible papers. There were three statistically significant meta-analysis findings, although these would not be significant after correction for multiple comparisons. The frequencies of HLA-A9 and HLA-DR4 genotypes were lower in ALS subjects than controls, and HLA-B35 was higher in ALS subjects. Discussion: This systematic review and meta-analysis do not confirm all the previously reported associations of HLA with ALS, but shows three alleles of interest. However, there are limitations to the studies, which include the use of older serotyping methodology and the small numbers of subjects. Given the recent GWAS association with HLA, further modern HLA studies are warranted. [ABSTRACT FROM AUTHOR]
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- 2023
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6. The Role of the Duffy Blood Group Antigens in Renal Transplantation and Rejection. A Mini Review.
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Hariri, Dana, Bordas, Jozsef, Elkins, Matthew, Gallay, Brian, Spektor, Zhanna, and Hod-Dvorai, Reut
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BLOOD group antigens ,KIDNEY transplantation ,HISTOCOMPATIBILITY antigens ,CHRONIC kidney failure ,HLA histocompatibility antigens - Abstract
Finding a compatible donor for kidney transplant candidates requires overcoming immunological barriers such as human leukocyte antigens (HLA) compatibility and ABO compatibility. Emerging data suggest a role for red blood cell antigens (RCA) in renal transplant outcomes. The incidence of RCA alloimmunization is high in chronically transfused individuals, such as end stage renal disease patients, but whether antibodies to RCA can mediate renal graft rejection remains debatable. The Duffy blood group antigens (Fy) has been shown to be expressed in the kidney, among other tissues. There are some data to suggest that donor-recipient Fy mismatches may increase the risk for chronic allograft damage and that anti-Fy antibodies may be involved in renal graft rejection, however, while it is routine to screen renal transplant candidates for ABO antigens, detailed RCA phenotyping of the donor kidney is not routinely tested. In this paper, we review the current data on the role of Fy in renal transplantation and discuss the potential mechanisms of its biological function. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Immunogenetics of Alzheimer’s disease: the human leukocyte antigen.
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Costescu, Carla-Ramona, Vică, LauraMihaela, Bâlici, Silvia-Ștefana, Nicula, GheorgheZsolt, Nemeș, Bogdan, Coman, Horia-George, and Matei, HoreaVladi
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HLA histocompatibility antigens ,ALZHEIMER'S disease ,IMMUNOGENETICS ,EARLY death - Abstract
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- 2023
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8. Decision trees to evaluate the risk of developing multiple sclerosis.
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Pasella, Manuela, Pisano, Fabio, Cannas, Barbara, Fanni, Alessandra, Cocco, Eleonora, Frau, Jessica, Lai, Francesco, Mocci, Stefano, Littera, Roberto, and Giglio, Sabrina Rita
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DECISION trees ,MULTIPLE sclerosis ,CEREBROSPINAL fluid examination ,NATALIZUMAB ,HLA histocompatibility antigens ,NEUROLOGICAL disorders ,MAGNETIC resonance imaging - Abstract
Introduction: Multiple sclerosis (MS) is a persistent neurological condition impacting the central nervous system (CNS). The precise cause of multiple sclerosis is still uncertain; however, it is thought to arise from a blend of genetic and environmental factors. MS diagnosis includes assessing medical history, conducting neurological exams, performing magnetic resonance imaging (MRI) scans, and analyzing cerebrospinal fluid. While there is currently no cure for MS, numerous treatments exist to address symptoms, decelerate disease progression, and enhance the quality of life for individuals with MS. Methods: This paper introduces a novel machine learning (ML) algorithm utilizing decision trees to address a key objective: creating a predictive tool for assessing the likelihood of MS development. It achieves this by combining prevalent demographic risk factors, specifically gender, with crucial immunogenetic risk markers, such as the alleles responsible for human leukocyte antigen (HLA) class I molecules and the killer immunoglobulin-like receptors (KIR) genes responsible for natural killer lymphocyte receptors. Results: The study included 619 healthy controls and 299 patients affected by MS, all of whom originated from Sardinia. The gender feature has been disregarded due to its substantial bias in influencing the classification outcomes. By solely considering immunogenetic risk markers, the algorithm demonstrates an ability to accurately identify 73.24% of MS patients and 66.07% of individuals without the disease. Discussion: Given its notable performance, this system has the potential to support clinicians in monitoring the relatives of MS patients and identifying individuals who are at an increased risk of developing the disease. [ABSTRACT FROM AUTHOR]
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- 2023
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9. DECIPHERING THE INTRICATE NETWORK: IMMUNOLOGIC FACTORS IN INFERTILITY AND THEIR IMPACT ON REPRODUCTIVE HEALTH.
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MANUELA, GRIJINCU, LAURIANA, ZBARCEA, ROXANA, BUZAN, SIMONA, ANGHEL, ALEXANDRA, IVAN, ADA, TELEA, and FLORINA, BOJIN
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IMMUNOMODULATORS , *TH2 cells , *KILLER cell receptors , *KILLER cells , *T helper cells , *REPRODUCTIVE health , *INFERTILITY , *HLA histocompatibility antigens , *COMPREHENSION in children - Abstract
This paper investigates the intricate interplay of fetal human leukocyte antigen (HLA) and maternal killer cell immunoglobulin-like receptor (KIR) interactions, focusing on their implications for pregnancy outcomes. The study explores the impact of HLA mismatches, particularly in the context of the HY immunity system, on the maternal immune response. The presence of HLA antibodies is assessed, with consideration given to the correlation with total immunoglobulin levels, aiming to discern associations with potential pregnancy complications. Complement activity is examined, adding a layer of understanding to the dynamics of fetal HLA and maternal KIR interactions. Furthermore, the paper delves into the delicate balance between Th1 and Th2 helper T cells, crucial components of the immune system, and their potential influence on maternal-fetal immune tolerance. Natural Killer Cell Cytotoxic Activity (NKa) is investigated, providing insights into the cytotoxicity of these immune cells and their role in the context of maternal-fetal interactions. The findings presented contribute to a nuanced comprehension of the immunological factors shaping pregnancy outcomes and may inform future research and clinical approaches aimed at optimizing maternal and fetal health. [ABSTRACT FROM AUTHOR]
- Published
- 2023
10. Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch.
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Cao, Rui, Schladt, David P., Dorr, Casey, Matas, Arthur J., Oetting, William S., Jacobson, Pamala A., Israni, Ajay, Chen, Jinbo, and Guan, Weihua
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GENETIC risk score ,SINGLE nucleotide polymorphisms ,DEAD ,HLA histocompatibility antigens ,GENOTYPES ,DNA mismatch repair ,KIDNEY transplantation - Abstract
Background: Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications. Methods: We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry. An AR polygenic risk score (PRS) was constructed with the non-HLA single nucleotide polymorphisms (SNPs) filtered by independence (r
2 < 0.2) and P-value (< 1×10−3 ) criteria. The PRS was validated in an independent cohort of 352 living donor-recipient pairs. Results: By the genome-wide scan, we identified one significant SNP rs6749137 with HR = 2.49 and P-value = 2.15×10−8 . 1,307 non-HLA PRS SNPs passed the clumping plus thresholding and the PRS exhibited significant association with the AR in the validation cohort (HR = 1.54, 95% CI = (1.07, 2.22), p = 0.019). Further pathway analysis attributed the PRS genes into 13 categories, and the over-representation test identified 42 significant biological processes, the most significant of which is the cell morphogenesis (GO:0000902), with 4.08 fold of the percentage from homo species reference and FDR-adjusted P-value = 8.6×10−4 . Conclusions: Our results show the importance of donor-recipient mismatching in non-HLA regions. Additional work will be needed to understand the role of SNPs included in the PRS and to further improve donor-recipient genetic matching algorithms. Trial registry: Deterioration of Kidney Allograft Function Genomics (NCT00270712) and Genomics of Kidney Transplantation (NCT01714440) are registered on ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]- Published
- 2024
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11. TripHLApan: predicting HLA molecules binding peptides based on triple coding matrix and transfer learning.
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Wang, Meng, Lei, Chuqi, Wang, Jianxin, Li, Yaohang, and Li, Min
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TWO-dimensional bar codes , *TRANSFER matrix , *HLA histocompatibility antigens , *PEPTIDES , *CANCER vaccines , *T cells , *PEPTIDE synthesis - Abstract
Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Ready for polygenic risk scores? An analysis of regulation of preimplantation genetic testing in European countries.
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Siermann, M, Schoot, V van der, Bunnik, E M, and Borry, P
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GENETIC testing , *GENETIC regulation , *HLA histocompatibility antigens , *GOVERNMENT websites , *HUMAN experimentation , *MEDICAL personnel - Abstract
STUDY QUESTION Would the different regulatory approaches for preimplantation genetic testing (PGT) in Europe permit the implementation of preimplantation genetic testing using polygenic risk scores (PGT-P)? SUMMARY ANSWER While the regulatory approaches for PGT differ between countries, the space provided for potential implementation of PGT-P seems limited in all three regulatory models. WHAT IS KNOWN ALREADY PGT is a reproductive genetic technology that allows the testing for hereditary genetic disorders and chromosome abnormalities in embryos before implantation. Throughout its history, PGT has largely been regarded as an ethically sensitive technology. For example, ethical questions have been raised regarding the use of PGT for adult-onset conditions, non-medical sex selection, and human leukocyte antigen typing for the benefit of existing siblings. Countries in which PGT is offered each have their own approach of regulating the clinical application of PGT, and a clear overview of legal and practical regulation of PGT in Europe is lacking. An emerging development within the field of PGT, namely PGT-P, is currently bringing new ethical tensions to the forefront. It is unclear whether PGT-P may be applied within the current regulatory frameworks in Europe. Therefore, it is important to investigate current regulatory frameworks in Europe and determine whether PGT-P fits within these frameworks. STUDY DESIGN, SIZE, DURATION The aim of this study was to provide an overview of the legal and practical regulation of the use of PGT in seven selected European countries (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK) and critically analyse the different approaches with regards to regulatory possibilities for PGT-P. Between July and September 2023, we performed a thorough and extensive search of websites of governments and governmental agencies, websites of scientific and professional organizations, and academic articles in which laws and regulations are described. PARTICIPANTS/MATERIALS, SETTING, METHODS We investigated the legal and regulatory aspects of PGT by analysing legal documents, regulatory frameworks, scientific articles, and guidelines from scientific organizations and regulatory bodies to gather relevant information about each included country. The main sources of information were national laws relating to PGT. MAIN RESULTS AND THE ROLE OF CHANCE We divided the PGT regulation approaches into three models. The regulation of PGT differs per country, with some countries requiring central approval of PGT for each new indication (the medical indication model: the UK, the Netherlands), other countries evaluating each individual PGT request at the local level (the individual requests model: France, Germany), and countries largely leaving decision-making about clinical application of PGT to healthcare professionals (the clinical assessment model: Belgium, Italy, Spain). In the countries surveyed that use the medical indication model and the individual requests model, current legal frameworks and PGT criteria seem to exclude PGT-P. In countries using the clinical assessment model, the fact that healthcare professionals and scientific organizations in Europe are generally negative about implementation of PGT-P due to scientific and socio-ethical concerns, implies that, even if it were legally possible, the chance that PGT-P would be offered in the near future might be low. LIMITATIONS, REASONS FOR CAUTION The results are based on our interpretation of publicly available written information and documents, therefore not all potential discrepancies between law and practice might have been identified. In addition, our analysis focuses on seven—and not all—European countries. However, since these countries are relevant players within PGT in Europe and since they have distinct PGT regulations, the insights gathered give relevant insights into diverse ways of PGT regulation. WIDER IMPLICATIONS OF THE FINDINGS To the best of our knowledge, this is the first paper that provides a thorough overview of the legal and practical regulation of PGT in Europe. Our analysis of how PGT-P fits within current regulation models provides guidance for healthcare professionals and policymakers in navigating the possible future implementation of PGT-P within Europe. STUDY FUNDING/COMPETING INTEREST(s) This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 813707. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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13. HLA-Clus: HLA class I clustering based on 3D structure.
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Shen, Yue, Parks, Jerry M., and Smith, Jeremy C.
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PEPTIDES ,HIERARCHICAL clustering (Cluster analysis) ,DEEP learning ,HLA histocompatibility antigens ,STRUCTURAL models ,K-nearest neighbor classification ,SPACE frame structures - Abstract
Background: In a previous paper, we classified populated HLA class I alleles into supertypes and subtypes based on the similarity of 3D landscape of peptide binding grooves, using newly defined structure distance metric and hierarchical clustering approach. Compared to other approaches, our method achieves higher correlation with peptide binding specificity, intra-cluster similarity (cohesion), and robustness. Here we introduce HLA-Clus, a Python package for clustering HLA Class I alleles using the method we developed recently and describe additional features including a new nearest neighbor clustering method that facilitates clustering based on user-defined criteria. Results: The HLA-Clus pipeline includes three stages: First, HLA Class I structural models are coarse grained and transformed into clouds of labeled points. Second, similarities between alleles are determined using a newly defined structure distance metric that accounts for spatial and physicochemical similarities. Finally, alleles are clustered via hierarchical or nearest-neighbor approaches. We also interfaced HLA-Clus with the peptide:HLA affinity predictor MHCnuggets. By using the nearest neighbor clustering method to select optimal allele-specific deep learning models in MHCnuggets, the average accuracy of peptide binding prediction of rare alleles was improved. Conclusions: The HLA-Clus package offers a solution for characterizing the peptide binding specificities of a large number of HLA alleles. This method can be applied in HLA functional studies, such as the development of peptide affinity predictors, disease association studies, and HLA matching for grafting. HLA-Clus is freely available at our GitHub repository (https://github.com/yshen25/HLA-Clus). [ABSTRACT FROM AUTHOR]
- Published
- 2023
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14. Prevalence and risk factors of antibodies towards HLA Class I and Class II in Malaysian renal transplant candidates.
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Khairul-Fahmy, Norfarhana, Ismail, Jamiila, Koay, Bee Tee, Md-Zakariah, Muhammad Zhafri, Mansor, Salawati, Zulkifli, Nordalila, Mat-Ali, Siti Fatimah, Mohamed, Rozinah, Mustafa, Norhazlin, and Arip, Masita
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KIDNEY transplantation ,IMMUNOGLOBULINS ,HLA histocompatibility antigens ,CHINESE people ,GRAFT rejection ,BLOOD group incompatibility - Abstract
Antibody-mediated rejection (AMR) still persists as the major hurdle towards successful renal allograft survival. This paper aims to report on the HLA antibody landscape of renal transplant candidates in Malaysia. A total of 2,219 adult samples from 2016 to 2019 were analysed for anti-HLA antibodies using solid-phase assay. Our findings highlight the prevalence and risk factors for antibodies against HLA antigens in renal transplant settings, which could be beneficial for selecting compatible recipients from deceased organ donors. To the best of our knowledge, this study is the first to demonstrate that ethnic Malay and Chinese showed significantly higher prevalence of anti-HLA antibodies. Based on our multivariate analysis: (i) female gender was associated with higher risk for panel reactive antibodies (PRAs) against Class I, Class II, and Class I and II (p < 0.001); (ii) older patients (≥ 38 years old) were associated with higher risk of positivity against Class I, Class II and Class I and II (p < 0.001); (iii) Malays showed significant association with Class II antibodies (p = 0.035); Chinese patients presented with higher risk of PRA positivity against Class II (p < 0.001) and Class I and II (p = 0.01); Indians were significantly associated with higher risk of HLA antibody sensitization against Class I (p = 0.022), Class II (p = 0.026) and Class I and II (p = 0.05). Thus, our findings suggested that female gender, older age (≥ 38 years old) and ethnicity may serve as independent risk factors for HLA antibody sensitization in adult renal transplant candidates. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Integration of the immune memory into the pathogen‐driven MHC polymorphism hypothesis.
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Radwan, Jacek, Kohi, Chirine, Ejsmond, Maciej, Paganini, Julien, and Pontarotti, Pierre
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IMMUNOLOGIC memory , *HLA histocompatibility antigens , *MAJOR histocompatibility complex , *COVID-19 pandemic , *T cell receptors , *T cells - Abstract
Major histocompatibility complex (MHC) genes (referred to as human leukocyte antigen or HLA in humans) are a key component of vertebrate immune systems, coding for proteins which present antigens to T‐cells. These genes are outstanding in their degree of polymorphism, with important consequences for human and animal health. The polymorphism is thought to arise from selection pressures imposed by pathogens on MHC allomorphs, which differ in their antigen‐binding capacity. However, the existing theory has not considered MHC selection in relation to the formation of immune memory. In this paper, we argue that this omission limits our understanding of the evolution of MHC polymorphism and its role in disease. We review recent evidence that has emerged from the massive research effort related to the SARS‐CoV‐2 pandemics, and which provides new evidence for the role of MHC in shaping immune memory. We then discuss why the inclusion of immune memory within the existing theory may have non‐trivial consequence for our understanding of the evolution of MHC polymorphism. Finally, we will argue that neglecting immune memory hinders our interpretation of empirical findings, and postulate that future studies focusing on pathogen‐driven MHC selection would benefit from stratifying the available data according to the history of infection (and vaccination, if relevant). [ABSTRACT FROM AUTHOR]
- Published
- 2023
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16. Pharmacogenomics in Psychiatric Disorders.
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Tauser, Roxana-Georgiana
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PHARMACOGENOMICS ,HLA histocompatibility antigens ,MENTAL illness ,SEROTONIN ,PATIENTS' rights ,NEUROTRANSMITTER receptors ,EXPERIMENTAL design ,DOPAMINE antagonists - Abstract
The broad arsenal of psychotropic medications is characterised by significant interindividual variability in clinical response and adverse effects, stringent monitoring requirements, potential drug-drug interactions, difficult long-term adherence and high costs. Pharmacogenomics investigates the correlation between genetic polymorphisms and responsiveness to drugs and could provide a valuable guide to fulfill the promise of personalized therapy in the context of the genomic medicine era, by tailoring treatment based on the patient's specific genetic markers. The present paper overviews the current advances in the clinical applications of pharmacogenomics to individualized psychotropic therapy. Material and methods. The relevant recent pharmacogenomics literature is selected and analysed in order to illustrate the impact on the clinical outcomes and quality of life in psychiatric patients of the genetic variants in the neurotransmitter receptors (dopamine and serotonin), metabolic pathways of drugs (cytochrome CYP450 2D6 and 2C19) and the human leukocyte antigen system. The paper focuses on some of the major psychotropic drug classes, such as: antipsychotics, antidepressants and mood stabilizers. Validation of statistically significant pharmacogenomics relationships has enabled the development and market approval of some predictive tests which are already integrated into some psychotropic drugs label. Results and discussions. Predictive pharmacogenomics tests have changed the classical approach of prescription "trial-and error" and "one dose fits all patients" towards personalized therapy. In addition, in new therapeutic candidates' clinical development, pharmacogenomics practically guides the clinical studies design, by substantially reducing the failure rates, costs and exposure risks of non-responders patients to new drugs. Current translation barriers of predictive pharmacogenomic tests from bench to clinical practice are also discussed. Conclusion. The paper emphasizes the current progress and future prospects in the field of pharmacogenomics as a guide to personalized therapy of psychiatric disorders, by: a) pretreatment selection of the right drug, prescribed in its optimized dose, to the right patient, according to one's specific genetic biomarkers; b) by improved clinical trials design based on genetic stratification of patients' population into responders versus nonresponders, especially in the costly phases III and IV. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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17. Therapeutic Applications of Adeno-Associated Virus (AAV) Gene Transfer of HLA-G in the Eye.
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Gilger, Brian C. and Hirsch, Matthew L.
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HISTOCOMPATIBILITY class I antigens ,GENETIC transformation ,ADENO-associated virus ,HLA histocompatibility antigens ,DRY eye syndromes ,CHOROID ,EYE - Abstract
The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that demonstrate efficacy in animal models of disease, including intracorneal delivery of AAV-HLA-G to treat corneal inflammation and prevent corneal graft rejection, subconjunctival injection of AAV-HLA-G for ocular graft vs. host disease and potentially dry eye disease, and intravitreal injection of AAV-HLA-G to inhibit uveitis. Furthermore, due to the anti-vascular function of HLA-G, AAV-HLA-G may be an effective therapy for posterior ocular diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization. Therefore, AAV-mediated gene transfer of HLA-G may be an effective treatment for common immune-mediated, inflammatory, and neovascular diseases of the eye. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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18. Case Report: Pathological Complete Response in a Lung Metastasis of Phyllodes Tumor Patient Following Treatment Containing Peptide Neoantigen Nano-Vaccine.
- Author
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Sha, Huizi, Liu, Qin, Xie, Li, Shao, Jie, Yu, Lixia, Cen, Lanqi, Li, Lin, Liu, Fangcen, Qian, Hanqing, Wei, Jia, and Liu, Baorui
- Subjects
PHYLLODES tumors ,PEPTIDES ,TUMOR markers ,ANTIGENS ,FEBRILE neutropenia ,GRANULOCYTE-macrophage colony-stimulating factor ,HLA histocompatibility antigens ,METASTASIS - Abstract
Some of the mutant peptides produced by gene mutation transcription and translation have the ability to induce specific T cells, which are called new antigens. Neoantigen-based peptide, DNA, RNA, and dendritic cell vaccines have been used in the clinic. In this paper, we describe a lung metastasis of a phyllodes tumor patient demonstrating pathological complete response following treatment containing personalized multi-epitope peptide neoantigen nano-vaccine. Based on whole-exome sequencing (WES), RNA sequencing, and new antigen prediction, several mutated peptide fragments were predicted to bind to the patient's human leukocyte antigen (HLA) allotypes, including ten peptides with high predicted binding affinity for six genes. The pulmonary metastases remained stable after the four cycles of anti-PD1 and anlotinib. After the addition of the multi-epitope peptide neoantigen nano-vaccine, the tumor began to collapse and contracture developed, accompanied by a decrease of tumor markers to normal, and complete pathological remission was achieved. With the use of the vaccination, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was used every time, and low-dose cyclophosphamide was injected every 3 weeks to improve efficacy. Peripheral blood immune monitoring demonstrated immune reactivity against a series of peptides, with the most robust post-vaccine T-cell response detected against the HLA-DRB1*0901-restricted SLC44A5 V54F peptide. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
19. Process Modeling of a HLA Research Lab.
- Author
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Ribeiro, Bruna G. C., Sena, Alexandre C., Silva, Dilson, and Marzulo, Leandro A. J.
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BIOINFORMATICS ,HLA histocompatibility antigens ,NUCLEOTIDE sequencing ,MOLECULAR biology ,GENOTYPES - Abstract
Bioinformatics has provided tremendous breakthroughs in the field of molecular biology. All this evolution has generated a large volume of biological data that increasingly require the use of computing for analysis and storage of this information. The identification of the human leukocyte antigen (HLA) genotypes is critical to the success of organ transplants in humans. HLA typing involves not only laboratory tests but also DNA sequencing, with the participation of several professionals responsible for different stages of the process. Thus, the objective of this paper is to map the main steps in HLA typing in a laboratory specialized in performing such procedures, analyzing each process and proposing solutions to speed up the these steps, avoiding mistakes. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
20. Pharmacogenetics‐Guided Advances in Antipsychotic Treatment.
- Author
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Islam, Farhana, Men, Xiaoyu, Yoshida, Kazunari, Zai, Clement C., and Müller, Daniel J.
- Subjects
ARIPIPRAZOLE ,GENETIC variation ,HLA histocompatibility antigens ,CYTOCHROME P-450 CYP2D6 ,TARDIVE dyskinesia ,PHENOTYPES - Abstract
Pharmacogenetics (PGx) research over the past 2 decades has produced extensive evidence for the influence of genetic factors on the efficacy and tolerability of antipsychotic treatment. However, the application of these findings to optimize treatment outcomes for patients in clinical practice has been limited. This paper presents a meta‐review of key PGx findings related to antipsychotic response and common adverse effects, including antipsychotic‐induced weight gain, tardive dyskinesia (TD), and clozapine‐induced agranulocytosis (CIAG), and highlights advances and challenges in clinical implementation. Most robust findings from candidate gene and genomewide association studies were reported for associations between polymorphisms in CYP2D6 and exposure and response to specific antipsychotics. As a result, product labels and guidelines from various PGx expert groups have provided selection and dosing recommendations based on CYP2D6 metabolizer phenotypes for commonly prescribed antipsychotics. Other interesting genetic targets include DRD2 for antipsychotic response, SLC18A2 for TD, and the human leukocyte antigen (HLA) genes, HLA‐DQB1 and HLA‐B, for CIAG. Well‐designed studies using large, well‐characterized samples that leverages international collaborations are needed to validate previous findings, as well as discover new genetic variants involved in antipsychotic response and adverse effects. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
21. A novel privacy-preserving federated genome-wide association study framework and its application in identifying potential risk variants in ankylosing spondylitis.
- Author
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Wu, Xin, Zheng, Hao, Dou, Zuochao, Chen, Feng, Deng, Jieren, Chen, Xiang, Xu, Shengqian, Gao, Guanmin, Li, Mengmeng, Wang, Zhen, Xiao, Yuhui, Xie, Kang, Wang, Shuang, and Xu, Huji
- Subjects
GENOME-wide association studies ,ANKYLOSING spondylitis ,HLA histocompatibility antigens ,SINGLE nucleotide polymorphisms ,INFORMATION sharing - Abstract
Genome-wide association studies (GWAS) have been widely used for identifying potential risk variants in various diseases. A statistically meaningful GWAS typically requires a large sample size to detect disease-associated single nucleotide polymorphisms (SNPs). However, a single institution usually only possesses a limited number of samples. Therefore, cross-institutional partnerships are required to increase sample size and statistical power. However, cross-institutional partnerships offer significant challenges, a major one being data privacy. For example, the privacy awareness of people, the impact of data privacy leakages and the privacy-related risks are becoming increasingly important, while there is no de-identification standard available to safeguard genomic data sharing. In this paper, we introduce a novel privacy-preserving federated GWAS framework (iPRIVATES). Equipped with privacy-preserving federated analysis, iPRIVATES enables multiple institutions to jointly perform GWAS analysis without leaking patient-level genotyping data. Only aggregated local statistics are exchanged within the study network. In addition, we evaluate the performance of iPRIVATES through both simulated data and a real-world application for identifying potential risk variants in ankylosing spondylitis (AS). The experimental results showed that the strongest signal of AS-associated SNPs reside mostly around the human leukocyte antigen (HLA) regions. The proposed iPRIVATES framework achieved equivalent results as traditional centralized implementation, demonstrating its great potential in driving collaborative genomic research for different diseases while preserving data privacy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. You may have a higher risk of MS and other diseases if you're descended from these ancient people.
- Author
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Curry, Andrew
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MULTIPLE sclerosis ,NATALIZUMAB ,HLA histocompatibility antigens ,FOSSIL DNA - Abstract
New research using ancient DNA has found a link between the risk of multiple sclerosis (MS) and the migration of the Yamnaya people from the steppes near the Black Sea to central and Northern Europe around 5000 years ago. The study, led by University of Copenhagen paleogeneticist Eske Willerslev, analyzed the genomes of over 1000 ancient individuals and compared them with modern British DNA. The researchers found that the proportion of ancestry from ancient populations predicted differences in disease risk and physical attributes in present-day Europeans. The findings suggest that the legacy of ancient populations still has a significant impact on modern people. [Extracted from the article]
- Published
- 2024
23. Immunosuppression trends in solid organ transplantation: The future of individualization, monitoring, and management.
- Author
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Pilch, Nicole A., Bowman, Lyndsey J., and Taber, David J.
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TRANSPLANTATION of organs, tissues, etc. ,HLA histocompatibility antigens ,IMMUNOSUPPRESSION ,CORAL reef restoration - Abstract
Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1‐year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under‐ and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long‐term outcomes during the next era of immunosuppression, which will move from universal protocols to patient‐specific optimization. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
24. MICA and NKG2D: Is There an Impact on Kidney Transplant Outcome?
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Risti, Matilde and Graça Bicalho, Maria da
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KIDNEY transplantation ,KILLER cells ,HLA histocompatibility antigens - Abstract
This paper aims to present an overview of MICA and natural killer group 2 member D (NKG2D) genetic and functional interactions and their impact on kidney transplant outcome. Organ transplantation has gone from what can accurately be called a "clinical experiment" to a routine and reliable practice, which has proven to be clinically relevant, life-saving and cost-effective when compared with non-transplantation management strategies of both chronic and acute end-stage organ failures. The kidney is the most frequently transplanted organ in the world (transplant-observatory
1 ). The two treatment options for end-stage renal disease (ESRD) are dialysis and/or transplantation. Compared with dialysis, transplantation is associated with significant improvements in quality of life and overall longevity. A strong relationship exists between allograft loss and human leukocyte antigens (HLA) antibodies (Abs). HLA Abs are not the only factor involved in graft loss, as multiple studies have shown that non-HLA antigens are also involved, even when a patient has a good HLA matche and receives standard immunosuppressive therapy. A deeper understanding of other biomarkers is therefore important, as it is likely to lead to better monitoring (and consequent success) of organ transplants. The objective is to fill the void left by extensive reviews that do not often dive this deep into the importance of MICA and NKG2D in allograft acceptance and their partnership in the immune response. There are few papers that explore the relationship between these two protagonists when it comes to kidney transplantation. This is especially true for the role of NKG2D in kidney transplantation. These reasons give a special importance to this review, which aims to be a helpful tool in the hands of researchers in this field. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
25. Indonesians Human Leukocyte Antigen (HLA) Distributions and Correlations with Global Diseases.
- Author
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Pradana, Krisnawan Andy, Widjaya, Michael Anekson, and Wahjudi, Mariana
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HLA histocompatibility antigens ,CROHN'S disease ,MYCOBACTERIAL diseases ,MAJOR histocompatibility complex ,SYSTEMIC lupus erythematosus - Abstract
In Human, Major Histocompatibility Complex known as Human Leukocyte Antigen (HLA). The HLA grouped into three subclasses regions: the class I region, the class II region, and the class III region. There are thousands of polymorphic HLAs, many of them are proven to have correlations with diseases. Indonesia consists of diverse ethnicity people and populations. It carries a unique genetic diversity between one and another geographical positions. This paper aims to extract Indonesians HLA allele data, mapping the data, and correlating them with global diseases. From the study, it is found that global diseases, like Crohn's disease, rheumatoid arthritis, Graves' disease, gelatin allergy, T1D, HIV, systemic lupus erythematosus, juvenile chronic arthritis, and Mycobacterial disease (tuberculosis and leprosy) suspected associated with the Indonesian HLA profiles. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
26. Human Leucocyte Antigens in blood transfusion.
- Author
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Grubic, Zorana
- Subjects
BLOOD transfusion reaction ,GRAFT versus host disease ,BLOOD transfusion ,HLA histocompatibility antigens ,ANTIGENS ,GENETIC polymorphisms - Abstract
Human Leucocyte Antigen (HLA) genes and molecules have an important role in transplantation, aetiology of many autoimmune, non-autoimmune and infection diseases. Due to the extremely high polymorphism of HLA genes and their different frequency distributions in various populations, an increasing probability of HLA non-compatible blood products, tissues or organs usage exists. For that reason, the aim of this paper was to give a concise overview of the role of HLA antigens and antibodies in adverse reactions caused by administration of transfusion products. The HLA system can cause detrimental immune reactions in transfusion therapy (platelet immune refractoriness, febrile transfusion reaction, transfusion-related acute lung injury and transfusion-associated graft versus host disease). Anti-HLA antibodies present in the patient are responsible for some of these reactions, while anti-HLA antibodies or HLA reactive cells present in the transfused product are accountable for immune-reactivity in other cases. In order to avoid or reduce the development of these transfusion-related events, anti-HLA antibody-negative or compatible products should be used. This is increasingly facilitated by introduction of more sensitive and specific techniques to determine anti-HLA antibodies and gene polymorphisms. In conclusion, the most common adverse reactions related to administration of incompatible HLA transfusion products are discussed. Basic information about HLA genes and antibodies as well as methods for their detection is also provided in order to give sufficient data for safe and efficient administration of transfusion products. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
27. Update 2020: nomenclature and listing of celiac disease–relevant gluten epitopes recognized by CD4+ T cells.
- Author
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Sollid, Ludvig M., Tye-Din, Jason A., Qiao, Shuo-Wang, Anderson, Robert P., Gianfrani, Carmen, and Koning, Frits
- Subjects
HLA histocompatibility antigens ,EPITOPES ,GLUTEN ,GLUTELINS ,CELIAC disease ,T cells ,T cell receptors - Abstract
Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4
+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
28. Can the Decreased Expression of Human Leukocyte Antigen Class I and II by Spermatozoa Lead to Recurrent Spontaneous Abortion?
- Author
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Sereshki, Nasrin, Andalib, Alireza, Ghahiri, Ataollah, Mehrabian, Ferdos, Sherkat, Roya, and Rezaei, Abbas
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HISTOCOMPATIBILITY class I antigens ,MISCARRIAGE ,GENITALIA ,HLA histocompatibility antigens ,SPERMATOZOA ,SEMEN - Abstract
Background & Objective: Unexplained recurrent spontaneous abortion (URSA) is defined as an unknown cause of occurrence of three or more clinically detectable pregnancy losses before 20 weeks of gestation, but it occurs presumably as a result of the immune system dysfunctions. We supposed that the disruption of semen or spermatozoa might be responsible for the dysfunction of the immune system in women with URSA. Semen and spermatozoa (as antigens) induce female reproductive tract (FRT) immunity. This stimulated immunity is necessary for pregnancy occurrence. The disruption of semen or spermatozoa can be a result of altering a variety of surface molecules on spermatozoa, especially polymorphic human leukocyte antigen (HLA) molecules or antigens. Despite the importance of HLA antigens in reproduction, to the best of our knowledge, no one has studied the relation of HLA expression between spermatozoa and URSA. Therefore, this paper aims to assess this relation. Methods: Semen samples were collected from 15 URSA couples and 20 normal couples. After purification of normal spermatozoa, the HLA class I and II expressions were evaluated by flow cytometry methods. Results: Results showed that the expression of both HLA class I and II by spermatozoa, in URSA couples, was significantly less than the control couples. Conclusion: The decreased expression of polymorphic HLA class I and II by spermatozoa can be related to URSA occurrence. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
29. Epigenetics and Behçet's Disease: DNA Methylation Specially Highlighted.
- Author
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Farhadi, Jafar, Nouri, Mohammad, Sakhinia, Ebrahim, Samadi, Nasser, Babaloo, Zohreh, Alipour, Shahriar, Jadideslam, Golamreza, Pouremamali, Farhad, and Khabbazi, Alireza
- Subjects
BEHCET'S disease ,DNA methylation ,HLA histocompatibility antigens ,EPIGENETICS ,EPIGENOMICS ,DEMETHYLATION - Abstract
Behçet's disease (BD) is a multisystem inflammatory disease with unknown etiology. Although evidence about the pathogenesis of BD is growing, the actual cause of this disease is unclear. Both genetic and epigenetic factors are claimed to play significant roles in BD. Epigenetic factors such as age, gender, smoking as well as exogenous factors like diet, infection, stress are related to the onset and clinical manifestations of BD. DNA methylation refers to a major epigenetic element which influences gene activities with catalyzing DNA using a set of DNA methyltransferases (Dnmts). DNA methylation status of many genes in patients with BD is different from that of healthy people. For example, cytoskeletal gene, Human Leukocyte Antigen (HLA) loci, Long interspersed nuclear element (LINE-1), and Arthrobacter luteus (Alu) repetitive sequences are different in the DNA methylation status in patients with BD and healthy controls. In this paper we reviewed, according to previous studies, the mechanisms of epigenetic, the epigenetic factors involved in the BD, and especially the effect of DNA methylation in the Behcet's disease. Future studies are needed to identify the capability of specific DNA methylation alterations in BD in order to predict disease manifestations, medical course, and response to treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2019
30. A novel hypothesis on mechanisms and potential role of host cell membrane proteins incorporated into the viral envelope in alloreactivity.
- Author
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García-Peñarrubia, Pilar
- Subjects
VIRAL envelope proteins ,MEMBRANE proteins ,VIRAL envelopes ,GRAFT rejection ,HLA histocompatibility antigens - Abstract
• Preexisting alloreactivity may result from exposure to HLA proteins displayed on viral envelopes. • A new role of HLA molecules incorporated on viral envelope. • An advance in understanding the preexistence of alloreactivity. Despite significant advances in transplantation medicine, allograft rejection remains a major challenge in clinical practice. The preexistence of alloreactive lymphocytes is a primary cause of allograft rejection. The forthcoming challenges in clinical transplantation will involve the suppression or eradication of allospecific memory T cells. Viral infections and allograft rejection interact in multiple ways that can compromise the survival of transplanted organs. Evidence is currently accumulating on the incorporation of HLA antigens and other host cell plasma membrane molecules into the viral envelope. A consequence of the viral envelope displaying the HLA signature acquired from the plasma membrane of infected cells is that when virions are transmitted to the next host, the newly infected person became exposed to allogeneic molecules stimulating alloimmunity and generating memory to alloantigens. Thus, successive exposure to viral infections throughout life could potentially contribute to the development of alloimmunity and the generation of numerous clones of memory alloreactive lymphocytes. In this paper a novel hypothesis is developed on the potential role and mechanisms of alloresponse induced by human spread of enveloped viruses. As this hypothesis could aid in the knowledge of preexisting alloreactivity, additional research into the intricacies of virion-incorporated host cell proteins is necessary. A deeper understanding of this dynamic interaction will help promote advances in the long-term acceptance of transplants. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
31. Multi-omics analysis of overexpressed tumor-associated proteins: gene expression, immunopeptide presentation, and antibody response in oropharyngeal squamous cell carcinoma, with a focus on cancer-testis antigens.
- Author
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Kors, Tsima Abou, Meier, Matthias, Mühlenbruch, Lena, Betzler, Annika C., Oliveri, Franziska, Bens, Martin, Thomas, Jaya, Kraus, Johann M., Doescher, Johannes, von Witzleben, Adrian, Hofmann, Linda, Ezic, Jasmin, Huber, Diana, Benckendorff, Julian, Barth, Thomas F. E., Greve, Jens, Schuler, Patrick J., Brunner, Cornelia, Blackburn, Jonathan M., and Hoffmann, Thomas K.
- Subjects
TUMOR antigens ,HLA histocompatibility antigens ,LIGANDS (Biochemistry) ,SQUAMOUS cell carcinoma ,TESTICULAR cancer - Abstract
Introduction: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets. Materials and methods: Snap-frozen tumor (N
Ligand/RNA =40), healthy mucosa (NRNA =6), and healthy tonsils (NLigand =5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb =27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins). Results: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels. Discussion: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
32. Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.
- Author
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Neuner-Jehle, Nadia, Zeeb, Marius, Thorball, Christian W., Fellay, Jacques, Metzner, Karin J., Frischknecht, Paul, Neumann, Kathrin, Leeman, Christine, Rauch, Andri, Stöckle, Marcel, Huber, Michael, Perreau, Matthieu, Bernasconi, Enos, Notter, Julia, Hoffmann, Matthias, Leuzinger, Karoline, Günthard, Huldrych F., Pasin, Chloé, and Kouyos, Roger D.
- Subjects
HLA histocompatibility antigens ,WHOLE genome sequencing ,VIRAL load ,IMMUNE recognition ,VIRAL mutation - Abstract
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis. Author summary: The intricate interplay between viruses and the human immune system is reflected in dynamic associations between the viral and the human genomes. These often take the form of escape dynamics, in which the virus acquires mutations that allow it to evade immune recognition. We developed a novel viral diversity-based method to screen for such interactions across the viral genome systematically and applied it to a unique dataset of HIV-1 sequences and human leukocyte antigen (HLA) variants. We could identify time-dependent interactions between 98 pairs of HLA and viral variants. Among these pairs, 12 were associated with the concentration of viral RNA, longitudinal time-to-event analyses confirmed 28, and 48 were consistent with computational predictions of viral peptide binding to HLA molecules. Our results highlight how the highly dynamic interaction between the viral genome and the immune system shapes viral evolution, and our approach offers new opportunities to systematically study such interactions from real-world cross-sectional data. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
33. The influence of HLA genetic variation on plasma protein expression.
- Author
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Krishna, Chirag, Chiou, Joshua, Sakaue, Saori, Kang, Joyce B., Christensen, Stephen M., Lee, Isac, Aksit, Melis Atalar, Kim, Hye In, von Schack, David, Raychaudhuri, Soumya, Ziemek, Daniel, and Hu, Xinli
- Subjects
HUMAN genetic variation ,GENE expression ,GENETIC variation ,HLA histocompatibility antigens ,BLOOD proteins - Abstract
Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases. Genetic variation in the HLA locus is associated with many traits, including autoimmune diseases. Here, the authors show that HLA genetic variation exerts widespread trans effects on plasma protein expression, aiding interpretation of associations between HLA alleles and immune mediated diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
34. HLA-C expression in extravillous trophoblasts is determined by an ELF3-NLRP2/NLRP7 regulatory axis.
- Author
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Bowen Gu, Gia-Han Le, Herrera, Sebastian, Blair, Steven J., Meissner, Torsten B., and Strominger, Jack L.
- Subjects
HLA histocompatibility antigens ,FETAL growth retardation ,GENE expression ,TRANSCRIPTION factors ,GENETIC regulation - Abstract
The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal-fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3-NLRP2/NLRP7-HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
35. GIHP: Graph convolutional neural network based interpretable pan-specific HLA-peptide binding affinity prediction.
- Author
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Lingtao Su, Yan Yan, Bo Ma, Shiwei Zhao, and Zhenyu Cui
- Subjects
CONVOLUTIONAL neural networks ,BREAST ,HLA histocompatibility antigens ,TREATMENT effectiveness ,VACCINE effectiveness ,VACCINE development - Abstract
Accurately predicting the binding affinities between Human Leukocyte Antigen (HLA) molecules and peptides is a crucial step in understanding the adaptive immune response. This knowledge can have important implications for the development of effective vaccines and the design of targeted immunotherapies. Existing sequence-based methods are insufficient to capture the structure information. Besides, the current methods lack model interpretability, which hinder revealing the key binding amino acids between the two molecules. To address these limitations, we proposed an interpretable graph convolutional neural network (GCNN) based prediction method named GIHP. Considering the size differences between HLA and short peptides, GIHP represent HLA structure as amino acid-level graph while represent peptide SMILE string as atom-level graph. For interpretation, we design a novel visual explanation method, gradient weighted activation mapping (Grad-WAM), for identifying key binding residues. GIHP achieved better prediction accuracy than state-of-the-art methods across various datasets. According to current research findings, key HLA-peptide binding residues mutations directly impact immunotherapy efficacy. Therefore, we verified those highlighted key residues to see whether they can significantly distinguish immunotherapy patient groups. We have verified that the identified functional residues can successfully separate patient survival groups across breast, bladder, and pan-cancer datasets. Results demonstrate that GIHP improves the accuracy and interpretation capabilities of HLA-peptide prediction, and the findings of this study can be used to guide personalized cancer immunotherapy treatment. Codes and datasets are publicly accessible at: https://github.com/sdustSu/GIHP. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
36. Environmental and Genetic Determinants of Ankylosing Spondylitis.
- Author
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Bilski, Rafał, Kamiński, Piotr, Kupczyk, Daria, Jeka, Sławomir, Baszyński, Jędrzej, Tkaczenko, Halina, and Kurhaluk, Natalia
- Subjects
ANKYLOSING spondylitis ,OXIDANT status ,HLA histocompatibility antigens ,SMOKING ,METABOLIC disorders - Abstract
Exposure to heavy metals and lifestyle factors like smoking contribute to the production of free oxygen radicals. This fact, combined with a lowered total antioxidant status, can induce even more damage in the development of ankylosing spondylitis (AS). Despite the fact that some researchers are looking for more genetic factors underlying AS, most studies focus on polymorphisms within the genes encoding the human leukocyte antigen (HLA) system. The biggest challenge is finding the effective treatment of the disease. Genetic factors and the influence of oxidative stress, mineral metabolism disorders, microbiota, and tobacco smoking seem to be of great importance for the development of AS. The data contained in this review constitute valuable information and encourage the initiation and development of research in this area, showing connections between inflammatory disorders leading to the pathogenesis of AS and selected environmental and genetic factors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
37. Orthanq: transparent and uncertainty-aware haplotype quantification with application in HLA-typing.
- Author
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Uzuner, Hamdiye, Paschen, Annette, Schadendorf, Dirk, and Köster, Johannes
- Subjects
HAPLOTYPES ,HLA histocompatibility antigens ,PAN-genome ,ALLELES ,GENOMES ,TRANSPLANTATION of organs, tissues, etc. - Abstract
Background: Identification of human leukocyte antigen (HLA) types from DNA-sequenced human samples is important in organ transplantation and cancer immunotherapy and remains a challenging task considering sequence homology and extreme polymorphism of HLA genes. Results: We present Orthanq, a novel statistical model and corresponding application for transparent and uncertainty-aware quantification of haplotypes. We utilize our approach to perform HLA typing while, for the first time, reporting uncertainty of predictions and transparently observing mutations beyond reported HLA types. Using 99 gold standard samples from 1000 Genomes, Illumina Platinum Genomes and Genome In a Bottle projects, we show that Orthanq can provide overall superior accuracy and shorter runtimes than state-of-the-art HLA typers. Conclusions: Orthanq is the first approach that allows to directly utilize existing pangenome alignments and type all HLA loci. Moreover, it can be generalized for usages beyond HLA typing, e.g. for virus lineage quantification. Orthanq is available under https://orthanq.github.io. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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38. Breast cancer, viruses, and human leukocyte antigen (HLA).
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James, Lisa M. and Georgopoulos, Apostolos P.
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HLA histocompatibility antigens ,MOUSE mammary tumor virus ,BREAST cancer ,BOVINE leukemia virus ,HUMAN papillomavirus ,RETROVIRUSES ,POLYOMAVIRUSES - Abstract
Several viruses have been implicated in breast cancer, including human herpes virus 4 (HHV4), human herpes virus 5 (HHV5), human papilloma virus (HPV), human JC polyoma virus (JCV), human endogenous retrovirus group K (HERVK), bovine leukemia virus (BLV) and mouse mammary tumor virus (MMTV). Human leukocyte antigen (HLA) is involved in virus elimination and has been shown to influence breast cancer protection/susceptibility. Here we investigated the hypothesis that the contribution of a virus to development of breast cancer would depend on the presence of the virus, which, in turn, would be inversely related to the success of its elimination. For that purpose, we estimated in silico predicted binding affinities (PBA) of proteins of the 7 viruses above to 127 common HLA alleles (69 Class I [HLA-I] and 58 Class II HLA-II]) and investigated the association of these binding affinities to the breast cancer—HLA (BC-HLA) immunogenetic profile of the same alleles. Using hierarchical tree clustering, we found that, for HLA-I, viruses BLV, JCV and MMTV were grouped with the BC-HLA, whereas, for HLA-II, viruses BLV, HERVK, HPV, JCV, and MMTV were grouped with BC-HLA. Finally, for both HLA classes, the average PBAs of the viruses grouped with the BC-HLA profile were significantly lower than those of the other, non BC-HLA associated viruses. Assuming that low PBAs are likely associated with slower viral elimination, these findings support the hypothesis that a defective/slower elimination and, hence, longer persistence and inefficient/delayed production of antibodies against them underlies the observed association of the low-PBA group with breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
39. Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities.
- Author
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Mog, Brian J., Marcou, Nikita, DiNapoli, Sarah R., Pearlman, Alexander H., Nichakawade, Tushar D., Hwang, Michael S., Douglass, Jacqueline, Hsiue, Emily Han-Chung, Glavaris, Stephanie, Wright, Katharine M., Konig, Maximilian F., Paul, Suman, Wyhs, Nicolas, Ge, Jiaxin, Miller, Michelle S., Azurmendi, Aitana, Watson, Evangeline, Pardoll, Drew M., Gabelli, Sandra B., and Bettegowda, Chetan
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CHIMERIC antigen receptors ,TUMOR antigens ,TUMOR treatment ,T cell receptors ,HLA histocompatibility antigens - Abstract
Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells. Editor's summary: Commonly used T cell therapies such as engineered T cell receptors (TCRs) and chimeric antigen receptors (CARs) have greatly improved outcomes for many patients; however, both still have their associated drawbacks. To overcome some of these limitations, Mog et al. have developed high-affinity antibody–expressing T cells that use a receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. They further show in vivo that these Co-STARs induce T cell expansion and induce long-term regression in mouse models with low densities of antigen, representing a promising strategy that requires further evaluation. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]
- Published
- 2024
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40. Epistatic interaction between ERAP2 and HLA modulates HIV-1 adaptation and disease outcome in an Australian population.
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Al-kaabi, Marwah, Deshpande, Pooja, Firth, Martin, Pavlos, Rebecca, Chopra, Abha, Basiri, Hamed, Currenti, Jennifer, Alves, Eric, Kalams, Spyros, Fellay, Jacques, Phillips, Elizabeth, Mallal, Simon, John, Mina, and Gaudieri, Silvana
- Subjects
T cells ,HIV ,HIV infections ,HLA histocompatibility antigens ,VIRAL load ,SINGLE nucleotide polymorphisms ,AUSTRALIANS - Abstract
A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation. We investigated whether ERAP variants influence HLA-associated HIV-1 adaptation with demonstrable effects on overall HIV-1 disease outcome. Utilizing host and viral data of 249 West Australian individuals with HIV-1 subtype B infection, we identified a novel association between two linked ERAP2 single nucleotide polymorphisms (SNPs; rs2248374 and rs2549782) with plasma HIV RNA concentration (viral load) (P adjusted = 0.0024 for both SNPs). Greater HLA-associated HIV-1 adaptation in the HIV-1 Gag gene correlated significantly with higher viral load, lower CD4
+ T cell count and proportion; P = 0.0103, P = 0.0061, P = 0.0061, respectively). When considered together, there was a significant interaction between the two ERAP2 SNPs and HLA-associated HIV-1 adaptation on viral load (P = 0.0111). In a comprehensive multivariate model, addition of ERAP2 haplotypes and HLA associated adaptation as an interaction term to known HLA and CCR5 determinants and demographic factors, increased the explanatory variance of population viral load from 17.67% to 45.1% in this dataset. These effects were not replicated in publicly available datasets with comparably sized cohorts, suggesting that any true global epistasis may be dependent on specific HLA-ERAP allelic combinations. Our data raises the possibility that ERAP2 variants may shape peptide repertoires presented to HLA class I-restricted T cells to modulate the degree of viral adaptation within individuals, in turn contributing to disease variability at the population level. Analyses of other populations and experimental studies, ideally with locally derived ERAP genotyping and HLA-specific viral adaptations are needed to elucidate this further. Author summary: HIV infection outcome is variable between individuals and understanding the factors that impact this variation is important for efforts towards a HIV cure or vaccine. Here, we found that the level of HIV in the blood is affected by whether an individual carries a specific form of ERAP2, a molecule that influences processing and presentation of the virus to the immune system, as well as the degree to which HIV has mutated to adapt to immune responses. We also show that the interaction of ERAP2 and other known genetic factors explains greater variation in infection outcome than these factors alone. These findings expand our knowledge of the potential importance of viral processing and presentation in the immune response to HIV. [ABSTRACT FROM AUTHOR]- Published
- 2024
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41. Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity.
- Author
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Tsuneyoshi, Norihiro, Hosoya, Tomonori, Takeno, Yuriko, Saitoh, Kodai, Murai, Hidetaka, Amimoto, Naoki, Tatsumi, Rie, Watanabe, Sono, Hasegawa, Yudai, Kikkawa, Eri, Goto, Kumiko, Nishigaki, Fusako, Tamura, Kouichi, and Kimura, Hironobu
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HISTOCOMPATIBILITY class I antigens ,IMMUNE checkpoint proteins ,INDUCED pluripotent stem cells ,HLA histocompatibility antigens ,STEM cell transplantation - Abstract
Background: The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch. Methods: First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous β-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed. Results: We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45
+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo. Conclusion: The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation. [ABSTRACT FROM AUTHOR]- Published
- 2024
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42. Anthrax Vaccination, Gulf War Illness, and Human Leukocyte Antigen (HLA).
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James, Lisa M., Carpenter, Adam F., Engdahl, Brian E., Johnson, Rachel A., Lewis, Scott M., and Georgopoulos, Apostolos P.
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ANTHRAX vaccines ,PERSIAN Gulf syndrome ,HLA histocompatibility antigens ,ANTIBODY formation ,PEPTIDES ,BCG vaccines - Abstract
We report on a highly significant, positive association between anthrax vaccination and occurrence of Gulf War Illness (GWI) in 111 Gulf War veterans (42 with GWI and 69 controls). GWI was diagnosed in 47.1% of vaccinated veterans but only in 17.2% of non-vaccinated veterans (Pearson χ
2 = 7.08, p = 0.008; odds ratio = 3.947; relative risk = 2.617), with 1.6x higher GWI symptom severity in vaccinated veterans (p = 0.007, F-test in analysis of covariance). Next, we tested the hypothesis that the susceptibility to GWI following anthrax vaccination could be due to inability to make antibodies against the anthrax protective antigen (PA), the key protein contained in the vaccine. Since the first step in initiating antibody production would be the binding of PA peptide fragments (typically 15-amino acid long [15-mer]) to peptide-binding motifs of human leukocyte antigen (HLA) Class II molecules, we assessed the binding-motif affinities of such HLA specific molecules to all linear 15-mer peptide fragments of the anthrax PA. We identified a total of 58 HLA Class II alleles carried by the veterans in our sample and found that, of those, 18 (31%) were present in the vaccinated group that did not develop GWI but were absent from the vaccinated group who developed GWI. Remarkably, in silico analyses revealed very high binding affinities of peptide-binding motifs of those 18 HLA alleles with fragments of anthrax vaccine PA, leading to the successful production of anti-PA antibodies. Conversely, the absence of these protective HLA alleles points to a reduced ability to develop antibodies against PA, thus resulting in harmful PA persistence and development of GWI. [ABSTRACT FROM AUTHOR]- Published
- 2024
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43. Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study.
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Arhire, Amalia Ioana, Ioacara, Sorin, Papuc, Teodora, Chiper, Miruna Sânziana, Dutescu, Irina Monica, Moise, Ana, Badea, Ioana Roxana, Florea, Suzana, Vlad, Adelina, and Fica, Simona
- Subjects
TYPE 1 diabetes ,VITAMIN D deficiency ,VITAMIN D receptors ,HLA histocompatibility antigens ,CELIAC disease ,CROSS-sectional method ,HAPLOTYPES - Abstract
Background: The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. Methods: A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. Results: The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). Conclusions: The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. Ocular Manifestations in Juvenile Behçet's Disease: A Registry-Based Analysis from the AIDA Network.
- Author
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Gaggiano, Carla, Tufan, Abdurrahman, Guerriero, Silvana, Ragab, Gaafar, Sota, Jurgen, Gentileschi, Stefano, Costi, Stefania, Almaghlouth, Ibrahim A., Hinojosa-Azaola, Andrea, Tharwat, Samar, Sfikakis, Petros P., Lopalco, Giuseppe, Piga, Matteo, Conti, Giovanni, Fragoulis, George, Mauro, Angela, Batu, Ezgi D., Ozen, Seza, Tarsia, Maria, and La Torre, Francesco
- Subjects
BEHCET'S disease ,OCULAR manifestations of general diseases ,IRIDOCYCLITIS ,HLA histocompatibility antigens ,FLUORESCENCE angiography ,AUTOINFLAMMATORY diseases - Abstract
Introduction: This study aims to characterize ocular manifestations of juvenile Behçet's disease (jBD). Methods: This was a registry-based observational prospective study. All subjects with jBD from the Autoinflammatory Diseases Alliance (AIDA) Network BD Registry showing ocular manifestations before 18 years were enrolled. Results: We included 27 of 1000 subjects enrolled in the registry (66.7% male patients, 45 affected eyes). The median (interquartile range [IQR]) age at ocular involvement was 14.2 (4.7) years. Uveitis affected 91.1% of eyes (anterior 11.1%, posterior 40.0%, panuveitis 40.0%), retinal vasculitis 37.8% and other manifestations 19.8%. Later onset (p = 0.01) and male predominance (p = 0.04) characterized posterior involvement. Ocular complications occurred in 51.1% of eyes. Patients with complications had earlier onset (p < 0.01), more relapses (p = 0.02) and more prolonged steroidal treatment (p = 0.02). The mean (standard deviation [SD]) central macular thickness (CMT) at the enrolment and last visit was 302.2 (58.4) and 293.3 (78.2) μm, respectively. Fluorescein angiography was pathological in 63.2% of procedures, with a mean (SD) Angiography Scoring for Uveitis Working Group (ASUWOG) of 17.9 (15.5). At the last visit, ocular damage according to the BD Overall Damage Index (BODI) was documented in 73.3% of eyes. The final mean (SD) best corrected visual acuity (BCVA) logMAR was 0.17 (0.47) and blindness (BCVA logMAR < 1.00 or central visual field ≤ 10°) occurred in 15.6% of eyes. At multivariate regression analysis, human leukocyte antigen (HLA)-B51 + independently predicted a + 0.35 change in the final BCVA logMAR (p = 0.01), while a higher BCVA logMAR at the first assessment (odds ratio [OR] 5.80; p = 0.02) independently predicted blindness. Conclusions: The results of this study may be leveraged to guide clinical practice and future research on this rare sight-threatening condition. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
45. The Relationship of HLA-DQ Alleles with Tuberculosis Risk: A Meta-analysis.
- Author
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Li, Cuiping, Zhou, Ying, Xiang, Xue, Zhou, Yang, and He, Min
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HLA histocompatibility antigens ,PATHOGENIC microorganisms ,TUBERCULOSIS ,META-analysis ,PATIENTS - Abstract
Background: The human leukocyte antigen (HLA) system plays an important role in regulating immune response because it takes part in the defense against pathogens. Some individual research studies have demonstrated that HLA class II genes play an important role in tuberculosis (TB) in several populations. However, the results were controversial. A meta-analysis was performed to examine the associations between HLA alleles and TB risk. Methods: Relevant studies on the association of HLA-DQA1 and DQB1 alleles with TB were included in the analyses. We examined papers published in the PubMed and EMBASE databases up to June 10, 2014. The odds ratios (ORs) and 95 % confidence intervals (CI) were analyzed from fixed-effects or random-effects models. Subgroup analyses were conducted by ethnicity. Results: This meta-analysis included 12 studies with DQB1 (1290 TB patients and 1471 controls) and 6 studies with DQA1 (453 TB patients and 648 controls). Only DQB1*0601 was found to have a significant association with an increased risk for TB [OR (95 % CI) = 1.68 (1.32-2.14), P = 0.000]. No significant association with TB risk was found in any HLA-DQA1 allele or in other HLA-DQB1 alleles. DQB1*0601 was significantly related to an increased risk of TB in Asian group, whereas no evidence was found in the non-Asian group. Conclusion: Our meta-analysis supports the hypothesis that the specific HLA-DQB1 may be regarded as a marker of real worth for predicting the risk of developing TB. The same result was shown in Asian population. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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46. Characterization of Three Generations of Transgenic Pigs Expressing the HLA-E Gene.
- Author
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Hryhorowicz, Magdalena, Zeyland, Joanna, Nowak-Terpiłowska, Agnieszka, Jura, Jacek, Juzwa, Wojciech, Słomski, Ryszard, Bocianowski, Jan, Smorąg, Zdzisław, Woźniak, Anna, and Lipiński, Daniel
- Subjects
HLA histocompatibility antigens ,XENOGRAFTS ,ORGAN donors ,MICROINJECTION (Cytology) ,LABORATORY swine - Abstract
The use of pigs as a source of organs and tissues for xenotransplantation can overcome the growing shortage of human donors. Human NK cells play an important role in the cell-mediated rejection of pig-to-human xenografts. In this paper we report the generation and extensive characterization of three generations of transgenic pigs with HLA-E gene encoding the antigen which can inhibit the human NK cell-mediated response. The gene construct pHLAE-GFPBsd containing the human gene encoding the human leukocyte antigen under the promoter of the EF-1α elongation factor ensuring systemic expression was introduced by microinjection into a pronucleus of the fertilized porcine oocyte. PCR analysis revealed and FISH analysis confirmed that the pHLAE-GFPBsd gene construct was present in the genome of the founder female pig. As a result of inter-breeding, an additional 7 transgenic animals were obtained (one individual from F1 generation and six individuals from F2 generation). The transgene expression was shown by RT-PCR and flow cytometry. Real Time PCR analysis estimated the approximate number of transgene copies at 16–34. Karyotype analysis did not show any changes in the structure or the number of chromosomes. The expression level of the transgene was stable in the next generation of genetically modified pigs. An NK cell-mediated cytotoxicity assay showed the increased viability of the transgenic cells in comparison with the wild-type, which confirmed the protective influence of HLA-E expression. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
47. Autoimmune diseases and 8.1 ancestral haplotype: An update.
- Author
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Gambino, C. M., Aiello, A., Accardi, G., Caruso, C., and Candore, G.
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GENETICS of autoimmune diseases ,HAPLOTYPES ,HLA histocompatibility antigens ,AUTOANTIBODIES ,ALLELES ,PHENOTYPES ,HUMAN genome - Abstract
The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA‐B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome‐wide‐association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA‐DRB1 gene, the most polymorphic sequence within the HLA II region. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
48. Defective HLA class I antigen processing machinery in cancer.
- Author
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Cai, Lei, Michelakos, Theodoros, Yamada, Teppei, Fan, Song, Wang, Xinhui, Schwab, Joseph H., Ferrone, Cristina R., and Ferrone, Soldano
- Subjects
HLA histocompatibility antigens ,TUMOR immunology ,CANCER immunotherapy ,RENAL cancer ,THYROID cancer - Abstract
Malignant transformation of cells is frequently associated with defective HLA class I antigen processing machinery (APM) component expression. This abnormality may have functional relevance, since it may have a negative impact on tumor cell recognition by cognate T cells. Furthermore, HLA class I APM abnormalities appear to have clinical significance, since they are associated with poor prognosis in several malignant diseases and may play a role in the resistance to immune checkpoint inhibitor-based immunotherapy. In this paper, we have reviewed the literature describing abnormalities in HLA class I APM component expression in many types of cancer. These abnormalities have been reported in all types of cancer analyzed with a frequency ranging between a minimum of 35.8% in renal cancer and a maximum of 87.9% in thyroid cancer for HLA class I heavy chains. In addition, we have described the molecular mechanisms underlying defects in HLA class I APM component expression and function by malignant cells. Lastly, we have discussed the clinical significance of HLA class I APM component abnormalities in malignant tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
49. Role of Human Leukocyte Antigens (HLA) in Autoimmune Diseases.
- Author
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Bodis, Gergely, Toth, Victoria, and Schwarting, Andreas
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AUTOIMMUNE diseases ,HLA histocompatibility antigens ,T cells ,ARTHRITIS ,TRANSPLANTATION of organs, tissues, etc. - Abstract
Since the discovery of HLA 60 years ago, it has contributed to the understanding of the immune system as well as of the pathogenesis of several diseases. Aside from its essential role in determining donor-recipient immune compatibility in organ transplantation, HLA genotyping is meanwhile performed routinely as part of the diagnostic work-up of certain autoimmune diseases. Considering the ability of HLA to influence thymic selection as well as peripheral anergy of T cells, its role in the pathogenesis of autoimmunity is understandable. The aim of this paper is to provide a brief overview of the role and current clinical relevance of HLA-B27 in spondyloarthritis and HLA-B51 in Behçet's disease as well as HLA-DQ2/DQ8 in celiac disease and HLA-DRB1 in rheumatoid arthritis and to discuss possible future implications. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
50. Human leucocyte antigens coeliac haplotypes and primary autoimmune hypophysitis in caucasian patients.
- Author
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Chiloiro, Sabrina, Capoluongo, Ettore D., Tartaglione, Tommaso, Bianchi, Antonio, Giampietro, Antonella, Angelini, Flavia, Arena, Vincenzo, Pontecorvi, Alfredo, and De Marinis, Laura
- Subjects
HUMAN leucocytes ,CELIAC disease ,HAPLOTYPES ,GENETICS of autoimmune diseases ,HLA histocompatibility antigens - Abstract
Summary: Purpose: Primary hypophysitis is a rare disease, with an autoimmune aetiology. As few papers have investigated genetic of hypophysitis, our aim was to evaluate HLA status in a single‐centre series of patients. Patients and method: A retrospective, longitudinal and cross‐sectional study was conducted. In consecutive Caucasian patients, clinically or histologically diagnosed for primary autoimmune hypophysitis (PAH), the HLA genotype having been determined. This cohort was compared with a control group. Anti‐pituitary and anti‐hypothalamus auto‐antibodies evaluation was included. Results: 16 patients were enrolled. Fourteen patients were female (87.5%). According to HLA‐DR status, we found the following: 9 of 16 patients (56.3%) haplotypes that were associated with coeliac disease (CD). Among these, 5 carried the DR7‐DQ2 heterozygote haplotype (55.5%) while the remaining ones only the following haplotypes: DR3‐DQ2 homozygote (25%), DR4‐DQ2 heterozygote (25%), DR4‐DQ8 heterozygote (50%) and DR4‐DQ8 homozygote (25%), respectively. A total of 12 CD‐associated haplotypes were identified. In PAH, we found a significantly higher frequency of patients carrying CD‐associated HLA haplotypes as compared to the control group (respectively, 75% vs 48%
P = .03; OR: 3.25 95%IC:1.1‐10.3), particularly, for DQ2 and DQ8 haplotypes. DQ2 haplotype was detected in 50% of PAH and 38.4% of the control group (P = .3), while DQ8 haplotype in 25% of PAH and 7.2% of the control group (P = .01 OR:4.3 95%IC:1.3‐14.7). Conclusion: Our data suggest that PAH and CD share some HLA haplotypes, reinforcing the knowledge of their association. HLA haplotypes, particularly DQ8, may play a role in PAH management and diagnosis, also suggesting the predisposition to other autoimmune diseases. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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