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Theses

LE ROLE DE L'AUTOANTIGENE DANS LES MALADIES AUTO-IMMUNES : ETUDE DE LA DESMOGLEINE 1 AU COURS DES PEMPHIGUS

Abstract : Pemphigus are specific-autoimmune diseases affecting skin and mucous membranes. They are mediated by pathogenic autoantibodies directed cell-cell adhesion molecules expressed in desmosome particularly, desmogleins. Desmoglein 1 (Dsg1) is targeted by the autoimmune response in pemphigus foliaceous (PF). The production of anti-Dsg1 antibodies is dependent on Dsg1-specific T-helper lymphocytes which are detected in PF patients. The tolerance breakdown against Dsg1 is not restricted to PF, since anti-Dsg1 antibodies can also be found in other forms of pemphigus, including pemphigus vulgaris and paraneoplastic pemphigus. Self-antigens play a major role in the occurrence of autoimmune diseases since they participate in both the initiation and maintenance of the autoimmune response and the development of lesional immune effectors. Based on this concept, we studied the role of Dsg1 in pemphigus pathogenesis. First, we describe an alternative transcript of DSG1 which contains a 101 bp insertion corresponding to the 3´ end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence. This alternative transcript leads to the synthesis of a truncated isoform of Dsg1 expressed in normal human epidermis. This isoform bears a specific peptide sequence which binds to PF-associated HLA class II DRβ1*0102 molecule as shown in an HLA-DR peptide binding assay, and induces PF T-cell proliferation. These data provide an illustration of an autoantigen encoded by alternative spliced transcript which may participate in the pathogenesis of the disease by bearing PF-associated HLA class II restricted epitope. Second, immunoproteomic analysis of human epidermal extract allowed to characterize the diversity of the anti-desmosome antibody response induced in normal mice immunized with Dsg1. In particular, this analysis enables us to characterize the binding properties of anti-desmosome monoclonal antibodies derived from these mice and to show that the autoantibody response induced upon immunization with a single autoantigen targets different epidermal autoantigens with a pattern similar to that observed in certain variety of human pemphigus, i.e., paraneoplastic pemphigus. Finally, we demonstrated that mRNA of the DSG1 gene is present in human normal thymus and show by quantitative real-time PCR analysis that the expression of DSG1 transcript increases with age.
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https://tel.archives-ouvertes.fr/tel-00130209
Contributor : Hugo Mouquet <>
Submitted on : Friday, February 9, 2007 - 5:45:14 PM
Last modification on : Friday, October 23, 2020 - 4:35:16 PM
Long-term archiving on: : Tuesday, April 6, 2010 - 8:57:54 PM

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  • HAL Id : tel-00130209, version 1

Citation

Hugo Mouquet. LE ROLE DE L'AUTOANTIGENE DANS LES MALADIES AUTO-IMMUNES : ETUDE DE LA DESMOGLEINE 1 AU COURS DES PEMPHIGUS. Immunologie. Université de Rouen, 2006. Français. ⟨tel-00130209⟩

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