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Antigen Recognition (antigen + recognition)
Selected AbstractsEnhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class,I invariant regionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007Linda Wooldridge Abstract CD8+ cytotoxic T,lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class,I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the ,2,domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by,,50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 ,,chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens. [source] Decreased specific CD8+ T,cell cross-reactivity of antigen recognition following vaccination with Melan-A peptideEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2006Victor Appay Abstract The aim of T,cell vaccines is the expansion of antigen-specific T,cells able to confer immune protection against pathogens or tumors. Although increase in absolute cell numbers, effector functions and TCR repertoire of vaccine-induced T,cells are often evaluated, their reactivity for the cognate antigen versus their cross-reactive potential is rarely considered. In fact, little information is available regarding the influence of vaccines on T,cell fine specificity of antigen recognition despite the impact that this feature may have in protective immunity. To shed light on the cross-reactive potential of vaccine-induced cells, we analyzed the reactivity of CD8+ T,cells following vaccination of HLA-A2+ melanoma patients with Melan-A peptide, incomplete Freund's adjuvant and CpG-oligodeoxynucleotide adjuvant, which was shown to induce strong expansion of Melan-A-reactive CD8+ T,cells in vivo. A collection of predicted Melan-A cross-reactive peptides, identified from a combinatorial peptide library, was used to probe functional antigen recognition of PBMC ex vivo and Melan-A-reactive CD8+ T,cell clones. While Melan-A-reactive CD8+ T,cells prior to vaccination are usually constituted of widely cross-reactive naive cells, we show that peptide vaccination resulted in expansion of memory T,cells displaying a reactivity predominantly restricted to the antigen of interest. Importantly, these cells are tumor-reactive. [source] On the molecular basis of the recognition of angiotensin II (AII)FEBS JOURNAL, Issue 5 2003NMR structure of AII in solution compared with the X-ray structure of AII bound to the mAb Fab13 The high-resolution 3D structure of the octapeptide hormone angiotensin II (AII) in aqueous solution has been obtained by simulated annealing calculations, using high-resolution NMR-derived restraints. After final refinement in explicit water, a family of 13 structures was obtained with a backbone RMSD of 0.73 ± 0.23 Å. AII adopts a fairly compact folded structure, with its C-terminus and N-terminus approaching to within ,,7.2 Å of each other. The side chains of Arg2, Tyr4, Ile5 and His6 are oriented on one side of a plane defined by the peptide backbone, and the Val3 and Pro7 are pointing in opposite directions. The stabilization of the folded conformation can be explained by the stacking of the Val3 side chain with the Pro7 ring and by a hydrophobic cluster formed by the Tyr4, Ile5 and His6 side chains. Comparison between the NMR-derived structure of AII in aqueous solution and the refined crystal structure of the complex of AII with a high-affinity mAb (Fab131) [Garcia, K.C., Ronco, P.M., Verroust, P.J., Brunger, A.T., Amzel, L.M. (1992) Science257, 502,507] provides important quantitative information on two common structural features: (a) a U-shaped structure of the Tyr4-Ile5-His6-Pro7 sequence, which is the most immunogenic epitope of the peptide, with the Asp1 side chain oriented towards the interior of the turn approaching the C-terminus; (b) an Asx-turn-like motif with the side chain aspartate carboxyl group hydrogen-bonded to the main chain NH group of Arg2. It can be concluded that small rearrangements of the epitope 4,7 in the solution structure of AII are required by a mean value of 0.76 ± 0.03 Å for structure alignment and ,,1.27 ± 0.02 Å for sequence alignment with the X-ray structure of AII bound to the mAb Fab131. These data are interpreted in terms of a biological ,nucleus' conformation of the hormone in solution, which requires a limited number of structural rearrangements for receptor,antigen recognition and binding. [source] Normal and abnormal secretion by haemopoietic cellsIMMUNOLOGY, Issue 1 2001Jane C. Stinchcombe Summary The secretory lysosomes found in haemopoietic cells provide a very efficient mechanism for delivering the effector proteins of many immune cells in response to antigen recognition. Although secretion shows some similarities to the secretion of specialized granules in other secretory cell types, some aspects of secretory lysosome release appear to be unique to melanocytes and cells of the haemopoietic lineage. Mast cells and platelets have provided excellent models for studying secretion, but recent advances in characterizing the immunological synapse allow a very fine dissection of the secretory process in T lymphocytes. These studies show that secretory lysosomes are secreted from the centre of the talin ring at the synapse. Proper secretion requires a series of Rab and cytoskeletal elements which play critical roles in the specialized secretion of lysosomes in haemopoietic cells. [source] Determinants of skin sensitisation potentialJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2008David W. Roberts Abstract Skin sensitisation is an important toxicological endpoint. The possibility that chemicals used in the workplace and in consumer products might cause skin sensitisation is a major concern for individuals, for employers and for marketing. In European REACH (Registration, Evaluation, and Authorisation of Chemicals) legislation, the sensitising potential should therefore be assessed for chemicals below the 10 ton threshold. Development of methods for prediction of skin sensitisation potential without animal testing has been an active research area for some time, but has received further impetus with the advent of REACH and the EU Cosmetics Directive (EU 2003). This paper addresses the issue of non-animal based prediction of sensitisation by a mechanistic approach. It is known that the sequence of molecular, biomolecular and cellular events between exposure to a skin sensitiser and development of the sensitised state involves several stages, in particular penetration through the stratum corneum, covalent binding to carrier protein, migration of Langerhans cells, presentation of the antigen to naïve T-cells. In this paper each of these stages is considered with respect to the extent to which it is dependent on the chemical properties of the sensitiser. The evidence suggests that, although penetration of the stratum corneum, stimulation of migration and maturation of Langerhans cells, and antigen recognition are important events in the induction of sensitisation, except in certain specific circumstances they can be taken for granted. They are not important factors in determining whether a compound will be a sensitiser or not, nor are they important factors in determining how potent one sensitiser will be relative to another. The ability to bind covalently to carrier protein is the major structure-dependent determinant of skin sensitisation potential. A chemistry-based prediction strategy is proposed involving reaction mechanistic domain assignment, reactivity and hydrophobicity determination, and application of quantitative mechanistic modelling (QMM) or read-across. Copyright © 2007 John Wiley & Sons, Ltd. [source] Comparison of three different serological techniques for primary diagnosis and monitoring of nasopharyngeal carcinoma in two age groups from TunisiaJOURNAL OF MEDICAL VIROLOGY, Issue 4 2005H. Karray Abstract Nasopharyngeal carcinoma (NPC) in Tunisia is characterized by its bimodal age distribution involving juvenile patients of 10,24 years and adult patients of 40,60 years. Three serological techniques were compared for primary diagnosis (N,=,117) and post-treatment monitoring (N,=,21) of NPC patients separated in two age groups. Immunofluorescence assay (IFA) was used as the "gold standard" for detection of IgG and IgA antibodies reactive with Epstein-Barr virus (EBV) early (EA) and viral capsid (VCA) antigens. Results were compared with ELISA measuring IgG and IgA antibody reactivity to defined EBNA1, EA, and VCA antigens. Immunoblot was used to reveal the molecular diversity underlying the anti-EBV IgG and IgA antibody responses. The results indicate that young NPC patients have significantly more restricted anti-EBV IgG and IgA antibody responses with aberrant IgG VCA/EA levels in 78% compared to 91.7% in elder patients. IgA VCA/EA was detected in 50% of young patients versus 89.4% for the elder group (P,<,0.001). Immunoblot revealed a reduced overall diversity of EBV antigen recognition for both IgG and IgA in young patients. A good concordance was observed between ELISA and IFA for primary NPC diagnosis with 81,91% overall agreement. Even better agreement (95,100%) was found for antibody changes during follow-up monitoring, showing declining reactivity in patients in remission and increasing reactivity in patients with persistent disease or relapse. ELISA for IgA anti-VCA-p18 and immunoblot proved most sensitive for predicting tumor relapse. VCA-p18 IgA ELISA seems suitable for routine diagnosis and early detection of NPC complication. J. Med. Virol. 75:593,602, 2005. © 2005 Wiley-Liss, Inc. [source] Spatial pattern of MHC class II variation in the great snipe (Gallinago media)MOLECULAR ECOLOGY, Issue 7 2007ROBERT EKBLOM Abstract The genes of the major histocompatibility complex (MHC) code for proteins involved in antigen recognition and triggering of the adaptive immune response, and are therefore likely to be under selection from parasites. These selection regimes may vary in space and time. Here we report a strong geographical structure in MHC class II B genes of a migrating bird, the great snipe (Gallinago media). Genetic differentiation in the MHC between two ecologically distinct distributional regions (Scandinavian mountain populations vs. East European lowland populations) was still present after statistically controlling for the effect of selectively neutral variation (microsatellites) using partial Mantel tests. This suggests a role for selection in generating this spatial structure and that it represents local adaptation to different environments. Differentiation between populations within the two regions was negligible. Overall, we found a high number of MHC alleles (50, from 175 individuals). This, together with a tendency for a higher rate of nonsynonymous than synonymous substitutions in the peptide binding sites, and high Tajima's D in certain regions of the gene, suggests a history of balancing selection. MHC variation is often thought to be maintained by some form of balancing selection, but the nature of this selection remains unclear. Our results support the hypothesis that spatial variation in selection regimes contributes to the high polymorphism. [source] Quantitative nuclear proteomics reveals new phenotypes altered in lymphoblastoid cellsPROTEOMICS - CLINICAL APPLICATIONS, Issue 3 2009Paul Brennan Dr. Abstract B-lymphocytes are essential for the production of antibodies to fight pathogens and are the cells of origin in 95% of human lymphomas. During their activation, and immortalisation by Epstein,Barr virus (EBV) which contributes to human cancers, B-lymphocytes undergo dramatic changes in cell size and protein content. This study was initiated to compare the proteome of two B-cell lines, from the same individual, that reflect different patterns of activation, one is EBV negative and the other is EBV positive. Using isobaric tags, LC-MALDI TOF-TOF and subcellular fractionation, we quantified 499 proteins from B-cells. From a detergent lysed protein extract, we identified 34 proteins that were differentially expressed in EBV-immortalised B-cells. By analysing a nuclear extract, we identified a further 29 differentially expressed proteins with only four proteins shared between the two extracts, illustrating the benefit of subcellular fractionation. This analysis has identified proteins involved in the cytoskeletal phenotype of activated B-cells and the increased antigen recognition in EBV-immortalised cells. Importantly, we have also identified new regulators of transcription and changes in ribonuclear proteins that may contribute to the increased cell size and immortalisation of lymphoblastoid cells. [source] Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients: Possible involvement of c-myc suppression by interferon-,in situCANCER SCIENCE, Issue 1 2006Kazuyuki Matsushita Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients, although the precise mechanism is controversial. From an immunological point of view, HLA-DR antigen, induced by interferon (IFN)-,, is required for tumor-associated antigen recognition by CD4+ T cells. For instance, as reported previously, the expression of HLA-DR antigen in normal colorectal epithelium immediately adjacent to cancer coincided significantly with the existence of IFN-, mRNA in the tissue. From another aspect, IFN-, has been revealed to suppress c-myc expression in vivo through a stat1-dependent mechanism, which is important for cell growth, cell cycle and chromosome instability. In the present study, strong HLA-DR-positive expression on cancer cells was significantly related to better prognosis for colorectal cancer patients. High IFN-, mRNA expression in situ indicated significantly less activation of c-myc mRNA expression. Further, HLA-DR antigen expression in cancer cells, as well as Dukes stages, was an independent factor for better long-term survival by multivariate analysis. Taken together, IFN-,, which induces HLA-DR antigens on the cell surface, also suppresses c-myc expression in situ, and is a possible non-immunological mechanism involved in the better long-term survival of colorectal cancer patients. (Cancer Sci 2006; 97: 57, 63) [source] Innate immunity and biodefence vaccinesCELLULAR MICROBIOLOGY, Issue 11 2003Nicholas M. Valiante Summary Host defence in vertebrates is achieved by the integration of two distinct arms of the immune system: the innate and adaptive responses. The innate response acts early after infection (within minutes), detecting and responding to broad cues from invading pathogens. The adaptive response takes time (days to weeks) to become effective, but provides the fine antigenic specificity required for complete elimination of the pathogen and the generation of immunologic memory. Antigen-independent recognition of pathogens by the innate immune system leads to the rapid mobilization of immune effector and regulatory mechanisms that provide the host with three critical advantages: (i) initiating the immune response (both innate and adaptive) and providing the inflammatory and co-stimulatory context for antigen recognition; (ii) mounting a first line of defence, thereby holding the pathogen in check during the maturation of the adaptive response; and (iii) steering the adaptive immune system towards the cellular or humoral responses most effective against the particular infectious agent. The quest for safer and more effective vaccines and immune-based therapies has taken on a sudden urgency with the increased threat of bioterrorism. Only a handful of vaccines covering a small proportion of potential biowarfare agents are available for human use (e.g. anthrax and small pox) and these suffer from poor safety profiles. Therefore, next generation biodefence-related vaccines and therapies with improved safety and the capacity to induce more rapid, more potent and broader protection are needed. To this end, strategies to target both the innate and adaptive immune systems will be required. [source] | ||||||||||||||||