Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo.
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ABSTRACT:
SUBMITTER: Heinemann FM
PROVIDER: S-EPMC5673998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aim: The objective of this study was to evaluate the association of the human leukocyte antigen (HLA) class II genes HLA-DRB1, HLA-DPB1, and HLA-DQB1 with the humoral immune response elicited by inactivated Japanese encephalitis (JE) vaccine (IJEV). Methods: A total of 373 individuals aged 3-12 years in the Inner Mongolia Autonomous Region in China, who received two doses of IJEV at 0 and 7 days, were enrolled in the current study. Based on the individuals' specific JE virus (JEV)-neutralizing antibodies (NAbs), they were divided into a seropositive and a seronegative group. HLA-DRB1, HLA-DPB1, and HLA-DQB1 were genotyped using a sequencing-based typing method. Next, the association of the HLA class II genes and their haplotypes with antibody response was evaluated. Results: Based on NAbs, a total of 161 individuals were classified as seropositive and 212 as seronegative. DQB1 * 02:01 was significantly associated with JEV seropositivity (P < 0.001, OR = 0.364, 95% CI: 0.221-0.600), while DQB1 * 02:02 was significantly associated with JEV seronegativity (P = 5.03 × 10-6, OR = 7.341, 95% CI: 2.876-18.736). The haplotypes DRB1 * 07:01-DPB1 * 04:01-DQB1 * 02:01, DRB1 * 15:01-DPB1 * 02:01-DQB1 * 06:02, DRB1 * 07:01-DQB1 * 02:01, and DPB1 * 02:01-DQB1 * 06:02 were very frequent in the seropositive group, while DRB1 * 07:01-DPB1 * 17:01-DQB1 * 02:02, DRB1 * 07:01-DQB1 * 02:02, and DPB1 * 17:01-DQB1 * 02:02 were very frequent in the seronegative group. The presence of DRB1 * 01:01, DRB1 * 04:05, DRB1 * 09:01, DRB1 * 12:02, DRB1 * 13:02, and DRB1 * 14:01 was associated with a higher geometric mean titer (GMT) of NAbs than that of DRB1 * 11:01 at the DRB1 locus (P < 0.05). At the DPB1 locus, the presence of DPB1 * 05:01 was associated with higher GMTs than that of DPB1 * 02:01 and DPB1 * 13:01 (P < 0.05), and the presence of DPB1 * 04:01 and DPB1 * 09:01 was associated with higher GMTs than that of DPB1 * 13:01 (P < 0.05). Conclusions: The present study suggests that HLA class II genes may influence the antibody response to IJEV.
| S-EPMC6418001 | biostudies-literature
Project description:Antibodies reactive to human leukocyte antigens (HLA) represent a barrier for patients awaiting transplantation. Based on reactivity patterns in single-antigen bead (SAB) assays, various epitope matching algorithms have been proposed to improve transplant outcomes. However, some antibody reactivities cannot be explained by amino acid motifs, leading to uncertainty about their clinical relevance. Antibodies against the HLA class II molecule, DQβ0603:DQα0103, present in some candidates, represent one such example. Here, we show that peptides derived from amino acids 119-148 of the HLA class I heavy chain are bound to DQβ0603:DQα0103 proteins and contribute to antibody reactivity through an HLA-DM-dependent process. Moreover, antibody reactivity is impacted by the specific amino acid sequence presented. In summary, we demonstrate that polymorphic HLA class I peptides, bound to HLA class II proteins, can directly or indirectly be part of the antibody binding epitope. Our findings have potential important implications for the field of transplant immunology and for our understanding of adaptive immunity.
| S-EPMC10798988 | biostudies-literature
Project description:While donor specific antibody (DSA) against HLA class II could frequently cause chronic antibody-mediated rejection (ABMR) in organ transplantation, anti-A/B antibody would not do so, because blood group ABO-incompatible transplantation has shown favorable graft outcome. Recently, an increasing attention has been paid to the importance of direct allorecognition of CD4 T-cells against HLA-class II expressed on graft endothelial cells. However, the effect of allo-antibody binding on its allorecognition remains unclear. Microarray analysis and molecular profiling demonstrated that CD275 (PD-L1) expression was increased by anti-A/B ligation-mediated ERK inactivation in endothelial cells despite IFNγ stimulation.
2018-09-28 | GSE120545 | GEO
Project description:Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.
| S-EPMC10143129 | biostudies-literature
Project description:In the RV144 vaccine trial, two antibody responses were found to correlate with HIV-1 acquisition. Because human leukocyte antigen (HLA) class II-restricted CD4(+) T cells are involved in antibody production, we tested whether HLA class II genotypes affected HIV-1-specific antibody levels and HIV-1 acquisition in 760 individuals. Indeed, antibody responses correlated with acquisition only in the presence of single host HLA alleles. Envelope (Env)-specific immunoglobulin A (IgA) antibodies were associated with increased risk of acquisition specifically in individuals with DQB1*06. IgG antibody responses to Env amino acid positions 120 to 204 were higher and were associated with decreased risk of acquisition and increased vaccine efficacy only in the presence of DPB1*13. Screening IgG responses to overlapping peptides spanning Env 120-204 and viral sequence analysis of infected individuals defined differences in vaccine response that were associated with the presence of DPB1*13 and could be responsible for the protection observed. Overall, the underlying genetic findings indicate that HLA class II modulated the quantity, quality, and efficacy of antibody responses in the RV144 trial.
| S-EPMC4911012 | biostudies-literature
Project description:The human leukocyte antigen (HLA)-bound viral antigens serve as an immunological signature that can be selectively recognized by T cells. As viruses evolve by acquiring mutations, it is essential to identify a range of presented viral antigens. Using HLA peptidomics, we are able to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides presented by highly prevalent HLA class I (HLA-I) molecules by using infected cells as well as overexpression of SARS-CoV-2 genes. We find 26 HLA-I peptides and 36 HLA class II (HLA-II) peptides. Among the identified peptides, some are shared between different cells and some are derived from out-of-frame open reading frames (ORFs). Seven of these peptides were previously shown to be immunogenic, and we identify two additional immunoreactive peptides by using HLA multimer staining. These results may aid the development of the next generation of SARS-CoV-2 vaccines based on presented viral-specific antigens that span several of the viral genes.
| S-EPMC8185308 | biostudies-literature
Project description:Identification of the specific HLA locus and allele presenting an epitope for recognition by specific TCRs (HLA restriction) is necessary to fully characterize the immune response to Ags. Experimental determination of HLA restriction is complex and technically challenging. As an alternative, the restricting HLA locus and allele can be inferred by genetic association, using response data in an HLA-typed population. However, simple odds ratio (OR) calculations can be problematic when dealing with large numbers of subjects and Ags, and because the same epitope can be presented by multiple alleles (epitope promiscuity). In this study, we develop a tool, denominated Restrictor Analysis Tool for Epitopes, to extract inferred restriction from HLA class II-typed epitope responses. This automated method infers HLA class II restriction from large datasets of T cell responses in HLA class II-typed subjects by calculating ORs and relative frequencies from simple data tables. The program is validated by: 1) analyzing data of previously determined HLA restrictions; 2) experimentally determining in selected individuals new HLA restrictions using HLA-transfected cell lines; and 3) predicting HLA restriction of particular peptides and showing that corresponding HLA class II tetramers efficiently bind to epitope-specific T cells. We further design a specific iterative algorithm to account for promiscuous recognition by calculation of OR values for combinations of different HLA molecules while incorporating predicted HLA binding affinity. The Restrictor Analysis Tool for Epitopes program streamlines the prediction of HLA class II restriction across multiple T cell epitopes and HLA types.
| S-EPMC4458389 | biostudies-literature
Project description:BackgroundBevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients.MethodsThe study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized NanoString platform covering 800 genes. Candidate gene predictors associated with response were analyzed by multivariate logistic and Cox regression analysis.ResultsTwo genes were independently associated with response: Low expression of angiotensinogen (2-fold decrease in AGT; OR = 2.44; 95% CI: 1.45-4.17; P = 0.0009) and high expression of a HLA class II gene (2-fold increase in HLA-DQA1; OR = 1.22; 95% CI: 1.01-1.47; P = 0.04). These two genes were included in a model that is able predict response to bevacizumab combination therapy in clinical practice. When stratified for a validated prognostic index, the predictive model for response was significantly associated with improved overall survival.ConclusionTwo genes (low angiotensinogen and high HLA-class II expression) were predictive for bevacizumab response and were included in a predictive model for response. This model can be used in clinical practice to identify patients who will benefit from bevacizumab combination therapy.
| S-EPMC5423207 | biostudies-literature
Project description:CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ("A," "B," and "C") improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
| S-EPMC6057471 | biostudies-literature
Project description:BackgroundWhereas human leukocyte antigen (HLA) class I mutation-associated neoantigen burden has been linked with response to immune checkpoint blockade (ICB), the role of HLA class II-restricted neoantigens in clinical responses to ICB is less studied. We used computational approaches to assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB.Patients and methodsWe analyzed whole-exome sequence data from four cohorts of ICB-treated patients with melanoma (n = 110) and non-small-cell lung cancer (NSCLC) (n = 123). MHCnuggets, a neural network-based model, was applied to estimate HLA class II IMM burdens and cellular fractions of IMMs were calculated to assess mutation clonality. We evaluated the combined impact of HLA class II germline genetic variation and class II IMM burden on clinical outcomes. Correlations between HLA class II IMM burden and density of tumor-infiltrating lymphocytes were computed from expression data.ResultsResponding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and NSCLC (P ≤ 9.6e-3). HLA class II IMM burden was correlated with longer survival, particularly in the NSCLC cohort and in the context of low intratumoral IMM heterogeneity (P < 0.001). HLA class I and II IMM landscapes were largely distinct suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration and programmed death-ligand 1 expression. Transcriptomic analyses revealed an inflamed tumor microenvironment for tumors harboring a high HLA class II IMM burden.ConclusionsHLA class II IMM burden identified patients with NSCLC and melanoma that attained longer survival after ICB treatment. Our findings suggest that HLA class II IMMs may impact responses to ICB in a manner that is distinct and complementary to HLA class I-mediated responses.
| S-EPMC10621650 | biostudies-literature