Antiglomerular basement membrane disease

2018 ◽  
Author(s):  
Zhao Cui ◽  
Neil Turner ◽  
Ming-hui Zhao
Keyword(s):  
T Cell ◽  
Animal Models ◽  
Basement Membrane ◽  
Oxygen Toxicity ◽  
Pulmonary Haemorrhage ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Predisposing Genes ◽  
Antibody Titres ◽  
Pulmonary Damage

Individuals appear to be predisposed to antiglomerular basement membrane (anti-GBM) disease by carrying a predisposing human leucocyte antigen type, DRB1*1501 being identified as the highest risk factor, and there are likely to be other predisposing genes or influences on top of which a relatively rare ‘second hit’ leads to the development of autoimmunity. In anti-GBM disease this appears to have a self-perpetuating, accelerating component, that may be to do with antibodies and altered antigen presentation. Lymphocyte depletion may also predispose to the disease. A number of second hits have been identified and they seem to share a theme of damage to the glomerulus. There may be a prolonged (months to years) and usually subclinical phase in anti-GBM disease in which usually relatively low level antibody titres are associated with variable haematuria, sometimes minor pulmonary haemorrhage, but often no symptoms. Damage to the lung seems to determine whether there is a pulmonary component to the disease. Without pulmonary damage caused typically by smoking, inhalation of other fumes, and potentially infection or oxygen toxicity, the disease remains an isolated kidney disease. Antibodies appear to be an important component of the disease, but cell-mediated immunity is also critical to the clinical picture. In animal models, cell-mediated immunity triggered by the GBM antigen can cause severe renal damage in the absence of pathogenic antibody. The development of specific antibody also requires T-cell sensitization and help, and suppressing the response is likely to require suppressing both antibody and cell-mediated immunity. Antibodies recognize one major and some other epitopes, which are now well described. T-cell epitopes are becoming better understood. Evidence from animal models also suggests that the damage in anti-GBM disease is dependent on complement, macrophages, and neutrophils.

scholarly journals NS1 DNA vaccination protects against Zika infection through T cell–mediated immunity in immunocompetent mice

2019 ◽  
Vol 5 (12) ◽  
pp. eaax2388 ◽  
Author(s):  
B. Grubor-Bauk ◽  
D. K. Wijesundara ◽  
M. Masavuli ◽  
P. Abbink ◽  
R. L. Peterson ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Response ◽  
Viral Envelope ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Vaccine Immunogen ◽  
Zikv Infection ◽  
Cell Responses ◽  
Immunocompetent Mice

The causal association of Zika virus (ZIKV) with microcephaly, congenital malformations in infants, and Guillain-Barré syndrome in adults highlights the need for effective vaccines. Thus far, efforts to develop ZIKV vaccines have focused on the viral envelope. ZIKV NS1 as a vaccine immunogen has not been fully explored, although it can circumvent the risk of antibody-dependent enhancement of ZIKV infection, associated with envelope antibodies. Here, we describe a novel DNA vaccine encoding a secreted ZIKV NS1, that confers rapid protection from systemic ZIKV infection in immunocompetent mice. We identify novel NS1 T cell epitopes in vivo and show that functional NS1-specific T cell responses are critical for protection against ZIKV infection. We demonstrate that vaccine-induced anti-NS1 antibodies fail to confer protection in the absence of a functional T cell response. This highlights the importance of using NS1 as a target for T cell–based ZIKV vaccines.

Identification of Multiple HLA Class II Epitopes of Aspergillus Fumigatus by Generation of CD4+ T Cell Clones Recognizing the A. Fumigatus proteins Crf1 and Catalase1

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2332-2332
Author(s):  
Hetty Jolink ◽  
Els van Oorschot ◽  
Ed J Kuijper ◽  
Jan Willem Drijfhout ◽  
Jaap T van Dissel ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Peptide Pool ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
T Cell Clones ◽  
Cell Clones

Abstract Abstract 2332 Invasive aspergillosis is a common and life-threatening complication in recipients of allogeneic stem cell transplantation. Patients are at risk in the neutropenic phase, but also after recovery of the neutrophil count there is an increased risk of developing invasive aspergillosis, probably caused by other defects in the innate immune system, or by impaired T cell mediated immunity after stem cell transplantation. In healthy individuals and in patients lymphoproliferative responses to crude Aspergillus extracts and recombinant antigens have been shown. Furthermore, patients after haploidentical stem cell transplantation were less susceptible to aspergillus infection when transferred with T cell lines generated against Aspergillus fumigatus. To facilitate the study of the role of T cell mediated immunity in aspergillus infection and develop new therapeutic strategies to prevent or treat invasive aspergillosis we aimed to identify T cell epitopes of Aspergillus fumigatus. Peripheral blood mononuclear cells (PBMC) of healthy individuals were stimulated with overlapping 15mer peptides of the Aspergillus fumigatus proteins Crf1 and Catalase1. Directly after stimulation no antigen specific T cells could be detected, however after stimulation with the complete peptide pool, IL-2 and IL-15 for 7 days and subsequent restimulation with peptide pulsed autologous PBMC an increase of activated T cells could be detected in half of the healthy donors, based on IFNγ production, CD154 (CD40 ligand) and CD137 expression. From 6 donors antigen specific CD4+ T cells were single cell sorted 4 hours after restimulation with the complete peptide pool using the IFNγ capture assay or by sorting the CD137+ CD4+ T cells 48 hours after restimulation with the complete peptide pool and cells were clonally expanded. The generated T cell clones were tested for Aspergillus peptide specificity against the complete peptide pool using ELISA to determine the IFNy and IL-4 production. Aspergillus peptide specific clones were further analyzed with subpools of the overlapping peptides, to identify the specific T cell epitope. These subpools are organized in a matrix to enable us to identify the recognized epitope directly from this analysis. Subsequently, the T cell clones were stimulated with the single recognized peptides to confirm the identified epitopes. Five different T cell epitopes of Crf1 were identified: one epitope at position 161–171, which was previously described, and four novel epitopes. For the Catalase1 protein we identified 7 different epitopes, which have not been described before. By using HLA-blocking monoclonal antibodies and an HLA-typed EBV-LCL panel we determined the HLA-restriction of the different T cell epitopes. Two Crf1 epitopes and three Catalase1 epitopes were HLA-DR restricted, and one of the Crf1 epitopes was presented by HLA-DP. The HLA-restriction of the other 6 identified epitopes has not yet been characterized. The T cell clones showed 3 different patterns of cytokine production. Some clones only produced IFNγ, some clones only IL-4 and others produced both IFNγ and IL-4. Twelve T cell epitopes in two different proteins of Aspergillus fumigatus, presented by various HLA class II molecules, were identified. The generated T cell clones showed a variable pattern of cytokine production. To evaluate whether all these epitopes are relevant for the immune response against aspergillosis, the specificity against Aspergillus fumigatus will be tested by incubating T cells and dendritic cells with inactivated fungus. If Aspergillus-specificity is demonstrated, these epitopes can be used to study T cell mediated immunity in patients with aspergillosis and be a first step towards new therapeutic options for invasive aspergillosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Development of Peptide Vaccines in Dengue

2018 ◽  
Vol 24 (11) ◽  
pp. 1157-1173 ◽  
Author(s):  
Kavita Reginald ◽  
Yanqi Chan ◽  
Magdalena Plebanski ◽  
Chit Laa Poh
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Peptide Vaccine ◽  
Human Leukocyte ◽  
Cost Effective ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Peptide Vaccines ◽  
Dengue Vaccine ◽  
Region Data

Dengue is one of the most important arboviral infections worldwide, infecting up to 390 million people and causing 25,000 deaths annually. Although a licensed dengue vaccine is available, it is not efficacious against dengue serotypes that infect people living in South East Asia, where dengue is an endemic disease. Hence, there is an urgent need to develop an efficient dengue vaccine for this region. Data from different clinical trials indicate that a successful dengue vaccine must elicit both neutralizing antibodies and cell mediated immunity. This can be achieved by designing a multi-epitope peptide vaccine comprising B, CD8+ and CD4+ T cell epitopes. As recognition of T cell epitopes are restricted by human leukocyte antigens (HLA), T cell epitopes which are able to recognize several major HLAs will be preferentially included in the vaccine design. While peptide vaccines are safe, biocompatible and cost-effective, it is poorly immunogenic. Strategies to improve its immunogenicity by the use of long peptides, adjuvants and nanoparticle delivery mechanisms are discussed.

scholarly journals Antigenic Properties and Processing Requirements of 65-Kilodalton Mannoprotein, a Major Antigen Target of Anti-Candida Human T-Cell Response, as Disclosed by Specific Human T-Cell Clones

2001 ◽  
Vol 69 (6) ◽  
pp. 3728-3736 ◽  
Author(s):  
Roberto Nisini ◽  
Giulia Romagnoli ◽  
Maria Jesus Gomez ◽  
Roberto La Valle ◽  
Antonella Torosantucci ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Antigenic Properties

ABSTRACT T-cell-mediated immunity is known to play a central role in the host response to Candida albicans. T-cell clones are useful tools for the exact identification of fungal T-cell epitopes and the processing requirements of C. albicans antigens. We isolated human T-cell clones from an HLA-DRB1*1101 healthy donor by using an antigenic extract (MP-F2) of the fungus. Specific clones were T-cell receptor α/β and CD4+/CD8−and showed a T-helper type 1 cytokine profile (production of gamma interferon and not interleukin-4). The large majority of these clones recognized both the natural (highly glycosylated) and the recombinant (nonglycosylated) 65-kDa mannoprotein (MP65), an MP-F2 minor constituent that was confirmed to be an immunodominant antigen of the human T-cell response. Surprisingly, most of the clones recognized two synthetic peptides of different MP65 regions. However, the peptides shared the amino acid motif IXSXIXXL, which may be envisaged as a motif sequence representing the minimal epitope recognized by these clones. Three clones recognized natural and pronase-treated MP65 but did not detect nonglycosylated, recombinant MP65 or the peptides, suggesting a possible role for polysaccharides in T-cell recognition ofC. albicans. Finally, lymphoblastoid B-cell lines were efficient antigen-presenting cells (APC) for recombinant MP65 and peptides but failed to present natural, glycosylated antigens, suggesting that nonprofessional APC might be defective in processing highly glycosylated yeast proteins. In conclusion, this study provides the first characterization of C. albicans-specific human T-cell clones and provides new clues for the definition of the cellular immune response against C. albicans.

scholarly journals Target Structures of the CD8+-T-Cell Response to Human Cytomegalovirus: the 72-Kilodalton Major Immediate-Early Protein Revisited

1999 ◽  
Vol 73 (10) ◽  
pp. 8179-8184 ◽  
Author(s):  
Florian Kern ◽  
Ingolf Pascal Surel ◽  
Nicole Faulhaber ◽  
Claudia Frömmel ◽  
Jens Schneider-Mergener ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Cell Response ◽  
Mononuclear Cells ◽  
T Cell Response ◽  
Immediate Early ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Early Protein

ABSTRACT Cell-mediated immunity plays an essential role in the control of infection with the human cytomegalovirus (HCMV). However, only a few CD8+-T-cell epitopes are known, with the majority being contained in the pp65 phosphoprotein, which is believed to dominate the CD8+-T-cell response to HCMV. Here, we have readdressed the issue of CD8+ T cells specific for the 72-kDa major immediate-early protein (IE-1), which is nonstructural but is found very early and throughout the replicative cycle. Using a novel flow-cytometric assay, we were able to identify CD8+-T-cell epitopes (by IE-1 peptide-specific induction of cytokine synthesis) and simultaneously measure the frequency of cells directed against them. For this purpose, 81 pentadecamer peptides covering the complete 491-amino-acid sequence of IE-1 were tested on peripheral blood mononuclear cells of anti-HCMV immunoglobulin G-seropositive donors. At least 10 new epitopes were identified, and the fine specificity and presenting HLA molecule of the first of them was determined. The frequencies of CD8+ T cells directed against IE-1 were similar to those directed against pp65 in donors tested with known pp65-derived peptides. Importantly, additional testing of a corresponding set of peptides covering the complete sequence of pp65 on 10 of these donors identified individuals whose CD8+ T cells recognized IE-1 but not pp65 and vice versa, clearly illustrating that either protein may be a major target. In summary, our results suggest that IE-1 is far more important as a CD8+-T-cell target than current opinion suggests.

scholarly journals Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Boni ◽  
Davide Cavazzini ◽  
Angelo Bolchi ◽  
Marzia Rossi ◽  
Andrea Vecchi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Viral Escape ◽  
Cell Mediated Immunity ◽  
Structural Constraints ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Hla Class I Molecules

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these “hot” concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.

scholarly journals Analysis of CD8+T cell response during the 2013–2016 Ebola epidemic in West Africa

2018 ◽  
Vol 115 (32) ◽  
pp. E7578-E7586 ◽  
Author(s):  
Saori Sakabe ◽  
Brian M. Sullivan ◽  
Jessica N. Hartnett ◽  
Refugio Robles-Sikisaka ◽  
Karthik Gangavarapu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
West Africa ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Cell Responses

The recent Ebola epidemic exemplified the importance of understanding and controlling emerging infections. Despite the importance of T cells in clearing virus during acute infection, little is known about Ebola-specific CD8+T cell responses. We investigated immune responses of individuals infected with Ebola virus (EBOV) during the 2013–2016 West Africa epidemic in Sierra Leone, where the majority of the >28,000 EBOV disease (EVD) cases occurred. We examined T cell memory responses to seven of the eight Ebola proteins (GP, sGP, NP, VP24, VP30, VP35, and VP40) and associated HLA expression in survivors. Of the 30 subjects included in our analysis, CD8+T cells from 26 survivors responded to at least one EBOV antigen. A minority, 10 of 26 responders (38%), made CD8+T cell responses to the viral GP or sGP. In contrast, 25 of the 26 responders (96%) made response to viral NP, 77% to VP24 (20 of 26), 69% to VP40 (18 of 26), 42% (11 of 26) to VP35, with no response to VP30. Individuals making CD8+T cells to EBOV VP24, VP35, and VP40 also made CD8+T cells to NP, but rarely to GP. We identified 34 CD8+T cell epitopes for Ebola. Our data indicate the immunodominance of the EBOV NP-specific T cell response and suggest that its inclusion in a vaccine along with the EBOV GP would best mimic survivor responses and help boost cell-mediated immunity during vaccination.

scholarly journals Rational design of chimeric Multiepitope Based Vaccine (MEBV) against human T-cell lymphotropic virus type 1: An integrated vaccine informatics and molecular docking based approach

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258443
Author(s):  
Muhammad Hamza Tariq ◽  
Rashid Bhatti ◽  
Nida Fatima Ali ◽  
Usman Ali Ashfaq ◽  
Farah Shahid ◽  
...  
Keyword(s):  
Molecular Docking ◽  
T Cell ◽  
T Lymphocytes ◽  
Virus Type ◽  
Rational Design ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Human T Cell ◽  
Antigenic Properties

Human T-cell lymphotropic virus type 1 (HTLV-1) is an infectious virus that has been linked to adult T cell leukemia /lymphoma, aggressive CD4-T cell malignancy and many other immune-related medical illnesses. So far, no effective vaccine is known to combat HTLV-1, hence, the current research work was performed to design a potential multi-epitope-based subunit vaccine (MEBV) by adopting the latest methodology of reverse vaccinology. Briefly, three highly antigenic proteins (Glycoprotein, Accessory protein, and Tax protein) with no or minimal (<37%) similarity with human proteome were sorted out and potential B- and T-cell epitopes were forecasted from them. Highly antigenic, immunogenic, non-toxic, non-allergenic and overlapping epitopes were short-listed for vaccine development. The chosen T-cell epitopes displayed a strong binding affinity with their corresponding Human Leukocyte Antigen alleles and demonstrated 95.8% coverage of the world’s population. Finally, nine Cytotoxic T Lymphocytes, six Helper T Lymphocytes and five Linear B Lymphocytes epitopes, joint through linkers and adjuvant, were exploited to design the final MEBV construct, comprising of 382 amino acids. The developed MEBV structure showed highly antigenic properties while being non-toxic, soluble, non-allergenic, and stable in nature. Moreover, disulphide engineering further enhanced the stability of the final vaccine protein. Additionally, Molecular docking analysis and Molecular Dynamics (MD) simulations confirmed the strong association between MEBV construct and human pathogenic immune receptor TLR-3. Repeated-exposure simulations and Immune simulations ensured the rapid antigen clearance and higher levels of cell-mediated immunity, respectively. Furthermore, MEBV codon optimization and in-silico cloning was carried out to confirm its augmented expression. Results of our experiments suggested that the proposed MEBV could be a potential immunogenic against HTLV-1; nevertheless, additional wet lab experiments are needed to elucidate our conclusion.

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