Publications (5) View all
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Article: Zinc finger domain of Ro60kD autoantigen is essential for binding of Ro52kD and autoantibodies
Arthritis Research & Therapy 04/2012; 5:1-1. · 4.45 Impact Factor -
Article: HLA-DQ7 beta(1) and beta(2) derived peptides as immunomodulators.
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ABSTRACT: Modulation of protein-protein interactions involved in the immune system by using small molecular mimics of the contact interfaces may lead to the blockage of the autoimmune response and the development of drugs for immunotherapy. The nonpolymorphic beta-regions, exposed to the microenvironment, of the modeled HLA-DQ7, which is genetically linked to autoimmune diseases, were determined. Peptides 132-141 and 58-67, located at the beta(1) and beta(2) domains of HLA-DQ7, respectively, were tested for their involvement in the interactions with CD4(+) T lymphocytes. Linear, cyclic, and dimeric analogs that mimic the exposed surfaces of HLA-DQ7 were designed and synthesized. Their immunosuppressory activities, found in the secondary, humoral immune response to sheep erythrocytes (SRBC) in mice in vitro, ranged from 11% to 53%. The significance of the total charge of the peptides, the pattern of the hydrogen bonding, and the presence of secondary structure were investigated in relation to the immunomodulatory effect of the peptides. Two dimeric analogs of the HLA-DQ7 58-67 fragment, consisting of the two monomers covalently linked by a polyethylene glycol (PEG) spacer, able to mimic the superdimers, were also synthesized and studied. As the 58-67 segment is located at the beta(1) region of HLA-DQ7, close to the major histocompatibility complex (MHC) groove, one may assume that the 58-67 peptide could accommodate the association between T-cell receptor (TCR) and human leukocyte antigen (HLA) by activating a co-stimulatory molecule of the TCR/HLA interaction. This hypothesis is supported by the confocal laser image of the fluorescein-labeled 58-67 peptide and by the fact that it is an immunostimulator at low concentration.Journal of Peptide Science 03/2009; 15(4):296-304. · 1.80 Impact Factor -
Article: T-cell epitopes of the La/SSB autoantigen: prediction based on the homology modeling of HLA-DQ2/DQ7 with the insulin-B peptide/HLA-DQ8 complex.
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ABSTRACT: T-cell epitopes are important components of the inappropriate response of the immune system to self-proteins in autoimmune diseases. In this study, the candidate T-cell epitopes of the La/SSB autoantigen, the main target of the autoimmune response in patients with Sjogren's Syndrome (SS), and Systemic Lupus Erythematosus (SLE) were predicted using as a template the HLA-DQ2 and DQ7 molecules, which are genetically linked to patients with SS and SLE. Modeling of DQ2 and DQ7 was based on the crystal structure of HLA-DQ8, an HLA molecule of high risk factor of type I diabetes, which is also an autoimmune disease. The quality and reliability of the modeled DQ2 and DQ7 was confirmed by the Ramachandran plot and the TINKER molecular modeling software. Common and/or similar candidate T-cell epitopes, obtained by comparing three different approaches the Taylor's sequence pattern, the TEPITOPE quantitative matrices, and the MULTIPRED artificial neural network, were subjected to homology modeling with the crystal structure of the insulin-B peptide complexed with HLA-DQ8, and the best superposed candidate epitopes were placed into the modeled HLA-DQ2 and DQ7 binding grooves to perform energy minimization calculations. Six T-cell epitopes were predicted for HLA-DQ7 and nine for HLA-DQ2 covering parts of the amino-terminal and the central regions of the La/SSB autoantigen. Residues corresponding to the P1, P4, and P9 pockets of the HLA-DQ2 and DQ7 binding grooves experience very low SASA because they are less exposed to the microenvironment of the groove. The proposed T-cell epitopes complexed with HLA-DQ2/DQ7 were further evaluated for their binding efficiency according to their potential interaction energy, binding affinity, and IC50 values. Our approach constitutes the ground work for a rapid and reliable experimentation concerning the T-cell epitope mapping of autoantigens, and could lead to the development of T-cell inhibitors as immunotherapeutics in autoimmune diseases.Journal of Computational Chemistry 08/2006; 27(9):1033-44. · 4.58 Impact Factor -
Article: Zinc ion dependent B-cell epitope, associated with primary Sjogren's syndrome, resides within the putative zinc finger domain of Ro60kD autoantigen: physical and immunologic properties.
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ABSTRACT: The Ro/La ribonucleoprotein (RNP) complex is composed of the proteins Ro60kD, Ro52kD, and La48kD that are in association with one small cytoplasmic RNA (YRNA). Specific protein-RNA and protein-protein interactions are thought to occur through the RNP and zinc-finger secondary structure elements of the Ro60kD protein. The aim of our study was to investigate the antigenic properties of the zinc finger domain of the Ro60KD autoantigen and its contribution to the formation of Ro/La RNP complex. It was found that the peptide VSLVCEKLCNEKLLKKARIHPFHILIA (Zif-1), which corresponds to the natural sequence of the zinc finger domain (301-327), and the peptide C(Acm)NEKLLKKARIC(Acm), analogous to the intermediate loop 310-319 (Zif-3) of the same domain of Ro60KD, are recognized by the majority of anti-Ro/SSA and anti-La/SSB positive sera (82.6% and 77.1%, respectively) in the absence of zinc ions. The same sera failed to react with Zif-1 peptide in the presence of Zn2+. In contrast, the addition of zinc ions was necessary for the binding of Zif-1 to recombinant Ro52KD as shown by direct binding experiments of the recombinant protein with synthetic peptides. Our data suggest the zinc finger domain of Ro60kD contains a B-cell epitope with high specificity for primary Sjogren's syndrome. Furthermore, depending on the presence of zinc ions, the zinc finger domain of the Ro60KD protein can exist in two different conformational states favoring either an interaction with the Ro52KD protein or binding with autoantibodies.Journal of Medicinal Chemistry 09/2004; 47(17):4327-34. · 5.25 Impact Factor -
Article: Complementary peptide epitopes and anti-idiotypic antibodies in autoimmunity.
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ABSTRACT: Application of complementary B and T cell epitopes in inducing anti-idiotypic and anti-clonotypic antibodies capable of regulating or suppressing the autoimmune responses in experimental autoimmune myasthenia gravis (EAMG), allergic neuritis (EAN) and allergic encephalomyelitis (EAE) has been the stimulus of many research efforts. Studies on the idiotypic/anti-idiotypic network of anti-La/SSB positive sera from patients with Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) and on animals immunized with the complementary epitopes are presented.Protein and Peptide Letters 09/2004; 11(4):367-75. · 1.94 Impact Factor
