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Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgarisand Pemphigus foliaceous

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9 pages
A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens. Methods Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences. Results Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous . The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK–RE sequence as a common motif with 75% residue identity. Conclusion This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.
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Journal of Translational Medicine
BioMedCentral
Open Access Research Proteomic definition of a desmoglein linear determinant common toPemphigus vulgarisandPemphigus foliaceous 1 2 3 Alberta Lucchese , Abraham Mittelman , Luciana Tessitore , 4 5 6 Rosario Serpico , Animesh A Sinha and Darja Kanduc*
1 2 3 Address: Dept. of Odontostomatology, University of Bari, Italy, Dept. of Medicine, New York Medical College, Valhalla, NY, USA, DISCAFF, 4 5 University A. Avogadro, Novara, Italy, Institute of Clinical Odontostomatology, 2nd University of Naples, Italy, Division of Dermatology and 6 Cutaneous Sciences, Center for Investigative Dermatology, Michigan State University, East Lansing, MI, USA and Dept. of Biochemistry and Molecular Biology, University of Bari, Italy Email: Alberta Lucchese  alucchese@hotmail.com; Abraham Mittelman  ABRAHAM_MITTELMAN@NYMC.EDU; Luciana Tessitore  Luciana.Tessitore@pharm.unipmn.it; Rosario Serpico  rosario.serpico@unina2.it; Animesh A Sinha  asinha@msu.edu; Darja Kanduc*  d.kanduc@biologia.uniba.it * Corresponding author
Published: 22 August 2006 Received: 28 June 2006 Accepted: 22 August 2006 Journal of Translational Medicine2006,4:37 doi:10.1186/1479-5876-4-37 This article is available from: http://www.translational-medicine.com/content/4/1/37 © 2006 Lucchese et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background:A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens. Methods:Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences. Results:Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera fromPemphigus vulgarisas well asPemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK–RE sequence as a common motif with 75% residue identity. Conclusion:This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.
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