scholarly journals HLA-B*35-Restricted CD8+-T-Cell Epitope in Mycobacterium tuberculosis Rv2903c

2002 ◽  
Vol 70 (2) ◽  
pp. 981-984 ◽  
Author(s):  
Michèl R. Klein ◽  
Abdulrahman S. Hammond ◽  
Steve M. Smith ◽  
Assan Jaye ◽  
Pauline T. Lukey ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Mycobacterial Antigens ◽  
Necrosis Factor

ABSTRACT Few human CD8+ T-cell epitopes in mycobacterial antigens have been described to date. Here we have identified a novel HLA-B*35-restricted CD8+ T-cell epitope in Mycobacterium tuberculosis Rv2903c based on a reverse immunogenetics approach. Peptide-specific CD8 T cells were able to kill M. tuberculosis-infected macrophages and produce gamma interferon and tumor necrosis factor alpha.

scholarly journals Identification of a Promiscuous T-Cell Epitope in Mycobacterium tuberculosis Mce Proteins

2002 ◽  
Vol 70 (1) ◽  
pp. 79-85 ◽  
Author(s):  
Maddalena Panigada ◽  
Tiziana Sturniolo ◽  
Giorgio Besozzi ◽  
Maria Giovanna Boccieri ◽  
Francesco Sinigaglia ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Hla Dr

ABSTRACT The characterization of Mycobacterium tuberculosis antigens inducing CD4+ T-cell responses could critically contribute to the development of subunit vaccines for M. tuberculosis. Here we performed computational analysis by using T-cell epitope prediction software (known as TEPITOPE) to predict promiscuous HLA-DR ligands in the products of the mce genes of M. tuberculosis. The analysis of the proliferative responses of CD4+ T cells from patients with pulmonary tuberculosis to selected peptides displaying promiscuous binding to HLA-DR in vitro led us to the identification of a peptide that induced proliferation of CD4+ cells from 50% of the tested subjects. This study demonstrates that a systematic computational approach can be used to identify T-cell epitopes in proteins expressed by an intracellular pathogen.

scholarly journals Immune Complex Formation Is Associated With Loss of Tolerance and an Antibody Response to Both Drug and Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark A. Kroenke ◽  
Troy E. Barger ◽  
Jenny Hu ◽  
Mieke Jill Miller ◽  
Kevin Kalenian ◽  
...  
Keyword(s):  
T Cell ◽  
Antibody Response ◽  
Immune Complexes ◽  
T Cell Epitopes ◽  
Necrosis Factor Alpha ◽  
Cell Assays ◽  
Factor Alpha ◽  
Loss Of Tolerance ◽  
Necrosis Factor

AMG 966 is a bi-specific, heteroimmunoglobulin molecule that binds both tumor necrosis factor alpha (TNFα) and TNF-like ligand 1A (TL1A). In a first-in-human clinical study in healthy volunteers, AMG 966 elicited anti-drug antibodies (ADA) in 53 of 54 subjects (98.1%), despite a paucity of T cell epitopes observed in T cell assays. ADA were neutralizing and bound to all domains of AMG 966. Development of ADA correlated with loss of exposure. In vitro studies demonstrated that at certain drug-to-target ratios, AMG 966 forms large immune complexes with TNFα and TL1A, partially restoring the ability of the aglycosylated Fc domain to bind FcγRIa and FcγRIIa, leading to the formation of ADA. In addition to ADA against AMG 966, antibodies to endogenous TNFα were also detected in the sera of subjects dosed with AMG 966. This suggests that the formation of immune complexes between a therapeutic and target can cause loss of tolerance and elicit an antibody response against the target.

scholarly journals Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253918
Author(s):  
Jelena Repac ◽  
Marija Mandić ◽  
Tanja Lunić ◽  
Bojan Božić ◽  
Biljana Božić Nedeljković
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
De Novo ◽  
Molecular Mimicry ◽  
Sequence Similarity ◽  
Cell Epitope ◽  
Homology Search ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Painful Condition

Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.

scholarly journals Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor- alpha secretion

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2622-2631 ◽  
Author(s):  
N Oyaizu ◽  
TW McCloskey ◽  
S Than ◽  
R Hu ◽  
VS Kalyanaraman ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Apoptosis ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Cross Linking ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
T Cell Apoptosis ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract We have recently shown that, in unfractioned peripheral blood mononuclear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is sufficient to induce T-cell apoptosis. However, the underlying mechanism for the CD4XL-mediated T-cell apoptosis is largely unknown. Several recent studies have shown that Fas antigen (Ag), a cell-surface molecule, mediates apoptosis-triggering signals. We show here that cross-linking of CD4 molecules, induced either by anti-CD4 monoclonal antibody (MoAb) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal lymphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effects. The upregulation of Fas Ag closely correlated with apoptotic cell death, as determined by flow cytometry. In addition, CD4XL resulted in the induction of interferon-gamma (IFN- gamma) and tumor necrosis factor-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribute to Fas Ag upregulation and both anti- IFN-gamma and anti-TNF-alpha antibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apoptosis. These findings strongly suggest that aberrant cytokine secretion induced by CD4XL and consequent upregulation of Fas Ag expression might play a critical role in triggering peripheral T-cell apoptosis and thereby contribute to HIV disease pathogenesis.

scholarly journals Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines

mBio ◽  
2016 ◽  
Vol 7 (3) ◽  
Author(s):  
Aaron Olsen ◽  
Yong Chen ◽  
Qingzhou Ji ◽  
Guofeng Zhu ◽  
Aruna Dharshan De Silva ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Necrosis Factor ◽  
Host Cell ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Cell Responses ◽  
Cell Immunity ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis , in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4 + T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8 + T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized that M. tuberculosis mutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37Rv M. tuberculosis cosmid library constructed in M. smegmatis . The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancing M. tuberculosis mutants elicits CD4 + and CD8 + T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulating M. tuberculosis genes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines. IMPORTANCE One way to control tuberculosis (TB), which remains a major global public health burden, is by immunization with an effective vaccine. The efficacy of Mycobacterium bovis BCG, the only currently approved TB vaccine, is inconsistent. Tumor necrosis factor alpha (TNF) is a cytokine that plays an important role in controlling TB. M. tuberculosis , the causative agent of TB, can counter this TNF-based defense by decreasing host cell TNF production. This study identified M. tuberculosis genes that can mediate inhibition of TNF production by macrophage (an immune cell critical to the control of TB). We have knocked out a number of these genes to generate M. tuberculosis mutants that can enhance macrophage TNF production. Immunization with these mutants in mice triggered a T cell response stronger than that elicited by the parental bacillus. Since T cell immunity is pivotal in controlling M. tuberculosis , the TNF-enhancing mutants can be used to develop novel TB vaccines.

scholarly journals In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin

2018 ◽  
Vol 49 (4) ◽  
pp. 1600-1614 ◽  
Author(s):  
Shudong He ◽  
Jinlong Zhao ◽  
Walid Elfalleh ◽  
Mohamed Jemaà ◽  
Hanju  Sun ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cell ◽  
Phaseolus Vulgaris ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Phaseolus Vulgaris L ◽  
B Cell Epitopes ◽  
B Cell Epitope

Background/Aims: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. Methods: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. Results: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. Conclusion: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.

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