The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Gregory A. Dasch - One of the best experts on this subject based on the ideXlab platform.
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complexity of type specific 56 kda antigen cd4 t cell epitopes of orientia tsutsugamushi strains causing scrub typhus in india
PLOS ONE, 2018Co-Authors: Arunachalam Ramaiah, Munegowda C. Koralur, Gregory A. DaschAbstract:Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI-III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14–36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only <50% of CD4 TCEs in variable domains exhibited such HBA. The phylogenetically and immunologically important amino acids in the conserved spacer domains were identified. Our results suggest that the conserved spacer domains are predicted to be functionally more important than previously appreciated in immune responses to Ots infections. Changes occurring at the TCE level of TSA may contribute to the wide range of pathogenicity of Ots in humans and mouse models. CD4 T-cell functional experiments are needed to assess the immunological significance of these HBA spacer domains and their role in clearance of Ots from Indian patients.
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Complexity of type-specific 56 kDa antigen CD4 T-cell epitopes of Orientia tsutsugamushi strains causing scrub typhus in India
2018Co-Authors: Arunachalam Ramaiah, Munegowda C. Koralur, Gregory A. DaschAbstract:Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI-III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14–36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only
Arunachalam Ramaiah - One of the best experts on this subject based on the ideXlab platform.
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complexity of type specific 56 kda antigen cd4 t cell epitopes of orientia tsutsugamushi strains causing scrub typhus in india
PLOS ONE, 2018Co-Authors: Arunachalam Ramaiah, Munegowda C. Koralur, Gregory A. DaschAbstract:Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI-III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14–36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only <50% of CD4 TCEs in variable domains exhibited such HBA. The phylogenetically and immunologically important amino acids in the conserved spacer domains were identified. Our results suggest that the conserved spacer domains are predicted to be functionally more important than previously appreciated in immune responses to Ots infections. Changes occurring at the TCE level of TSA may contribute to the wide range of pathogenicity of Ots in humans and mouse models. CD4 T-cell functional experiments are needed to assess the immunological significance of these HBA spacer domains and their role in clearance of Ots from Indian patients.
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Complexity of type-specific 56 kDa antigen CD4 T-cell epitopes of Orientia tsutsugamushi strains causing scrub typhus in India
2018Co-Authors: Arunachalam Ramaiah, Munegowda C. Koralur, Gregory A. DaschAbstract:Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI-III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14–36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only
Rossjohn Jamie - One of the best experts on this subject based on the ideXlab platform.
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Discriminative T-cell receptor recognition of highly homologous HLA-DQ2–bound gluten epitopes
'American Society for Biochemistry & Molecular Biology (ASBMB)', 2019Co-Authors: Dahal-koirala Shiva, Ciacchi Laura, Petersen Jan, Risnes, Louise Fremgaard, Neumann, Ralf Stefan, Christophersen Asbjørn, Reid, Hugh H., Lundin, Knut E. A., Qiao Shuo-wang, Rossjohn JamieAbstract:Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restricted gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-α1a and HLA-DQ2.5–DQ2.5-glia-ω1 tetramers and single-cell αβ T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-α1a– and DQ2.5-glia-ω1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-α1a (2.0 Å) and DQ2.5-glia-ω1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting
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Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes
2018Co-Authors: Dahal-koirala Shiva, Ciacchi Laura, Petersen Jan, Risnes, Louise Fremgaard, Neumann, Ralf Stefan, Christophersen Asbjørn, Lundin, Knut Erik Aslaksen, Reid, Hugh H., Qiao, Shuo Wang, Rossjohn JamieAbstract:Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restricted gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-α1a and HLA-DQ2.5–DQ2.5-glia-ω1 tetramers and single-cell αβ T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-α1a– and DQ2.5-glia-ω1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-α1a (2.0 Å) and DQ2.5-glia-ω1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting
Andrew J. Sinclair - One of the best experts on this subject based on the ideXlab platform.
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Effects of conjugated linolenic acid and conjugated linoleic acid on lipid metabolism in mice.
European Journal of Lipid Science and Technology, 2009Co-Authors: Gaofeng Yuan, Haiyan Sun, Andrew J. SinclairAbstract:The effects of two isomers of conjugated linolenic acid (CLnA), α-eleostearic acid (α-ESA) and punicic acid (PA), on body fat and lipid metabolism were investigated, compared with a conjugated linoleic acid (CLA) mixture (primarily cis9,trans11- and trans10,cis12-18:2) and α-linolenic acid (ALA), a non-conjugated octadecatrienoic acid, in the present study. ICR mice were fed either a control diet or one of four experimental diets supplemented with 1 % α-ESA, 1 % PA, 1 % CLA mixture and 1 % ALA in the form of triacylglycerols (TAG) for 6 weeks. The weights of perirenal and epididymal adipose tissues were significantly decreased while the liver weight was significantly increased in mice fed CLA, compared with the control. In contrast to CLA, the tissue weights in α―ESA-, PA- and ALA-fed mice were not affected. No significant differences were observed in TAG, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol levels among the five groups. The liver TAG level was significantly decreased in mice fed α-ESA and PA while it was significantly increased in mice fed the CLA mixture. These results indicate that CLnA and CLA have differential effects on body fat mass and liver TAG levels in mice.
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failure of conjugated linoleic acid supplementation to enhance biosynthesis of docosahexaenoic acid from α linolenic acid in healthy human volunteers
Prostaglandins Leukotrienes and Essential Fatty Acids, 2007Co-Authors: Nadia M Attarbashi, R S Weisinger, Denovan P Begg, Andrew J. SinclairAbstract:A rate-limiting step in docosahexaenoic acid (DHA) formation from α-linolenic acid (ALA) involves peroxisomal oxidation of 24:6n-3 to DHA. The aim of the study was to determine whether conjugated linoleic acid (CLA) would enhance conversion of ALA to DHA in humans on an ALA-supplemented diet. The subjects ( n =8 per group) received daily supplementation of ALA (11g) and either CLA (3.2g) or placebo for 8 weeks. At baseline, 4 and 8 weeks, blood was collected for plasma fatty acid analysis and a number of physiological measures were examined. The ALA-supplemented diet increased plasma levels of ALA and eicosapentaenoic acid (EPA). The addition of CLA to the ALA diet resulted in increased plasma levels of CLA, as well as ALA and EPA. Plasma level of DHA was not increased with either the ALA alone or ALA plus CLA supplementation. The results demonstrated that CLA was not effective in enhancing DHA levels in plasma in healthy volunteers.
Masafumi Takiguchi - One of the best experts on this subject based on the ideXlab platform.
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Binding of nonamer peptides to three HLA-B51 molecules which differ by a single amino acid substitution in the A-pocket
Immunogenetics, 1996Co-Authors: Akiko Kikuchi, Kiyoshi Miwa, Yuji Takamiya, Yutaro Kaneko, Hansgeorg Rammensee, Takashi Sakaguchi, Masafumi TakiguchiAbstract:The interaction between 9-mer peptides and HLA-B51 molecules was investigated by quantitative peptide binding assay using RMA-S cell expressing human β2-microglobulin and HLA-B51 molecules. Of 147 chemically synthesized 9-mer peptides possessing two anchor residues corresponding to the motif of HLA-B^*5101 binding self-peptides, 27 paptides bound to HLA-B^*5101 molecules. Pro and Ala at position 2 as well as Ile at position 9 were confirmed to be main anchor residues, while Gly at position 2 as well as Val, Leu, and Met at position 9 were weak anchor residues for HLA-B^*5101. The A-pocket is suspected to have a critical role in peptide binding to MHC class I molecules because this pocket corresponds to the N-terminus of peptides and has a strong hydrogen bond formed by conserved Tyr residues. Further analysis of peptide binding to HLA-B^*5102 and B^*5103 molecules showed that a single amino acid substitution of Tyor for His at residue 171(B^*5102) and that of Gly for Trp at residue 167 (B^*5103) has a minimum effect in HLA-B51-peptide binding. Since previous studies showed that some HLA-B51 alloreactive CTL clones failed to kill the cells expressing HLA-B^*5102 or HLA-B^*5103, these results imply that the structural change of the A-pocket among HLA-B51 subtypes causes a critical conformational change of the epitope for TCR recognition rather than influences the interaction between peptides and MHC class I molecules.