Abstract Pemphigoid (Pg) is an autoimmune subepidermal blistering disease that affects the elderly population. The phenotype can be Bullous Pemphigoid (BP), which primarily involves the skin, or ...Mucous Membrane Pemphigoid (MMP), which primarily involves mucus membranes. Ocular Cicatricial Pemphigoid (OCP) and Oral Pemphigoid (OP) are subsets of MMP. The known antigens in BP are Bullous Pemphigoid Antigen 1 (BPAG1, also known as BP230), Bullous Pemphigoid Antigen 2 (BPAG2, also known as BP180), and subunits of human integrins α6 and β4. The Human Leukocyte Antigen (HLA) allele HLA-DQβ1*0301 has been reported to be associated with enhanced susceptibility to all of these subsets. Sera of patients with the four subsets are characterized by the presence of anti-Basement Membrane Zone (anti-BMZ) antibodies. In this manuscript, we present a model in which relevant portions of the four different antigens involved in pemphigoid have potential sites that could be presented by an antigen presenting cell (APC) in conjunction with DQβ1*0301 to a T cell receptor to initiate the process that results in anti-BMZ antibody production. Thus, this model provides a hypothetical computer-based mechanism to explain how a single HLA allele can be associated with the production of antibodies to four different antigens that result in four different subsets of a disease with four different clinical profiles and prognoses.
The sequence of a novel hemopoietic cytokine was discovered in a computational screen of genomic databases, and its homology to mouse thymic stromal lymphopoietin (TSLP) suggests that it is the human ...orthologue. Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5. Human TSLPR and IL-7Ralpha are principally coexpressed on monocytes and dendritic cell populations and to a much lesser extent on various lymphoid cells. In accord, we find that human TSLP functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells, as evidenced by the strong induction of the costimulatory molecules CD40 and CD80 and the enhanced capacity to elicit proliferation of naive T cells.
Major histocompatibility complex class I (MHCI) and class II (MHCII) molecules display peptides on antigen-presenting cell surfaces for subsequent T-cell recognition. Within the human population, ...allelic variation among the classical MHCI and II gene products is the basis for differential peptide binding, thymic repertoire bias and allograft rejection. While available 3D structural analysis suggests that polymorphisms are found primarily within the peptide-binding site, a broader informatic approach pinpointing functional polymorphisms relevant for immune recognition is currently lacking. To this end, we have now analyzed known human class I (774) and class II (485) alleles at each amino acid position using a variability metric (
V). Polymorphisms (
V>1) have been identified in residues that contact the peptide and/or T-cell receptor (TCR). Using sequence logos to investigate TCR contact sites on HLA molecules, we have identified conserved MHCI residues distinct from those of conserved MHCII residues. In addition, specific class II (HLA-DP, -DQ, -DR) and class I (HLA-A, -B, -C) contacts for TCR binding are revealed. We discuss these findings in the context of TCR restriction and alloreactivity.
We have developed PVS (Protein Variability Server), a web-based tool that uses several variability metrics to compute the absolute site variability in multiple protein-sequence alignments (MSAs). The ...variability is then assigned to a user-selected reference sequence consisting of either the first sequence in the alignment or a consensus sequence. Subsequently, PVS performs tasks that are relevant for structure-function studies, such as plotting and visualizing the variability in a relevant 3D-structure. Neatly, PVS also implements some other tasks that are thought to facilitate the design of epitope discovery-driven vaccines against pathogens where sequence variability largely contributes to immune evasion. Thus, PVS can return the conserved fragments in the MSA--as defined by a user-provided variability threshold--and locate them in a relevant 3D-structure. Furthermore, PVS can return a variability-masked sequence, which can be directly submitted to the RANKPEP server for the prediction of conserved T-cell epitopes. PVS is freely available at: http://imed.med.ucm.es/PVS/.
Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T(H)2)-type allergic inflammation is not known. We show here that human thymic stromal lymphopoietin ...(TSLP) potently activated CD11c(+) dendritic cells (DCs) and induced production of the T(H)2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22). TSLP-activated DCs primed naïve T(H) cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-alpha, while down-regulating IL-10 and interferon-gamma. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis. TSLP expression was associated with Langerhans cell migration and activation in situ. These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation.
With sufficient territory and abundant biomass resources Spain appears to have suitable conditions to develop biomass utilization technologies. As an important decentralized power technology, biomass ...gasification and power generation has a potential market in making use of biomass wastes. This paper addresses biomass fuelled generation of electricity in the specific aspect of finding the best location and the supply area of the electric generation plant for three alternative technologies (gas motor, gas turbine and fuel cell-microturbine hybrid power cycle), taking into account the variables involved in the problem, such as the local distribution of biomass resources, transportation costs, distance to existing electric lines, etc. For each technology, not only optimal location and supply area of the biomass plant, but also net present value and generated electric power are determined by an own binary variant of Particle Swarm Optimization (PSO). According to the values derived from the optimization algorithm, the most profitable technology can be chosen. Computer simulations show the good performance of the proposed binary PSO algorithm to optimize biomass fuelled systems for distributed power generation.
Peptides that bind to a given major histocompatibility complex (MHC) molecule share sequence similarity. Therefore, a position specific scoring matrix (PSSM) or profile derived from a set of peptides ...known to bind to a specific MHC molecule would be a suitable predictor of whether other peptides might bind, thus anticipating possible T-cell epitopes within a protein. In this approach, the binding potential of any peptide sequence (query) to a given MHC molecule is linked to its similarity to a group of aligned peptides known to bind to that MHC, and can be obtained by comparing the query to the PSSM. This article describes the derivation of alignments and profiles from a collection of peptides known to bind a specific MHC, compatible with the structural and molecular basis of the peptide-MHC class I (MHCI) interaction. Moreover, in order to apply these profiles to the prediction of peptide-MHCI binding, we have developed a new search algorithm (RANKPEP) that ranks all possible peptides from an input protein using the PSSM coefficients. The predictive power of the method was evaluated by running RANKPEP on proteins known to bear MHCI K
b- and D
b-restricted T-cell epitopes. Analysis of the results indicates that > 80% of these epitopes are among the top 2% of scoring peptides. Prediction of peptide-MHC binding using a variety of MHCI-specific PSSMs is available on line at our RANKPEP web server (www.mifoundation.org/Tools/rankpep.html). In addition, the RANKPEP server also allows the user to enter additional profiles, making the server a powerful and versatile computational biology benchmark for the prediction of peptide-MHC binding.
This paper deals with the application and comparison of several metaheuristic techniques to optimize the placement and supply area of biomass-fueled power plants. Both, trajectory and ...population-based methods are applied for our goal. In particular, two well-known trajectory method, such as Simulated Annealing (SA) and Tabu Search (TS), and two commonly used population-based methods, such as Genetic Algorithms (GA) and Particle Swarm Optimization (PSO) are hereby considered. In addition, a new binary PSO algorithm has been proposed, which incorporates an inertia weight factor, like the classical continuous approach. The fitness function for the metaheuristics is the profitability index, defined as the ratio between the net present value and the initial investment. In this work, forest residues are considered as biomass source, and the problem constraints are: the generation system must be located inside the supply area, and its maximum electric power is 5
MW. The comparative results obtained by all considered metaheuristics are discussed. Random walk has also been assessed for the problem we deal with.
The mesoporous silicon microparticles (MSMPs) are excellent vehicles for releasing molecules inside the cell. The aim of this work was to use MSMPs to deliver viral specific MHC class I restricted ...epitopes into human antigen presenting cells (monocyte derived dendritic cells, MDDCs) to facilitate their capture, processing, and presentation to CD8+ (cytotoxic) T lymphocytes. We show for the first time that MSMPs vehiculation of antigenic peptides enhances their MHC class I presentation by human MDDCs to CD8 T lymphocytes.
Prediction of peptide binding to major histocompatibility complex (MHC) molecules is a basis for anticipating T-cell epitopes, as well as epitope discovery-driven vaccine development. In the human, ...MHC molecules are known as human leukocyte antigens (HLAs) and are extremely polymorphic. HLA polymorphism is the basis of differential peptide binding, until now limiting the practical use of current epitope-prediction tools for vaccine development. Here, we describe a web server, PEPVAC (Promiscuous EPitope-based VACcine), optimized for the formulation of multi-epitope vaccines with broad population coverage. This optimization is accomplished through the prediction of peptides that bind to several HLA molecules with similar peptide-binding specificity (supertypes). Specifically, we offer the possibility of identifying promiscuous peptide binders to five distinct HLA class I supertypes (A2, A3, B7, A24 and B15). We estimated the phenotypic population frequency of these supertypes to be 95%, regardless of ethnicity. Targeting these supertypes for promiscuous peptide-binding predictions results in a limited number of potential epitopes without compromising the population coverage required for practical vaccine design considerations. PEPVAC can also identify conserved MHC ligands, as well as those with a C-terminus resulting from proteasomal cleavage. The combination of these features with the prediction of promiscuous HLA class I ligands further limits the number of potential epitopes. The PEPVAC server is hosted by the Dana-Farber Cancer Institute at the site http://immunax.dfci.harvard.edu/PEPVAC/.
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