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The determination of human MHC class II antigenic peptide motifs, with preference to those significantly associated with major autoimmune disorders

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The class II molecules of the major histocompatibility complex (MHC) determine the immune response to all infectious agents and environmental insults. In man the MHC is composed of at least three gene loci, DP, DQ and DR. In recent years it has become evident that the MHC class II loci in mouse and man are the chief determinants of autoimmunity and immune responsiveness. The function of class II MHC molecules appears to be the formation of a complex with fragmented peptide antigens and their subsequent presentation to CD4+ T cells. Research conducted in several laboratories including the ones in this application, has shown that MHC class II molecules bind to peptides only if the latter fulfill certain patterns or motifs, each characteristic for a particular allele. Furthermore, the stability of these complexes is also dependent on the peptides bound and variants of a given peptide that bind the MHC class II molecule can modulate the response of the cognate T cell. We propose to combine our expertise and resources in an effort aimed at investigating the rules governing the selection and the binding of antigenic peptides to human MHC class II molecules, as well as the stability of the formed complex and interactions with other determinants of the immune system. We will include MHC molecules already known to be crucial in autoimmune reactions (e.g. DR4, DQ7). To this end we intend to use the tried and tested state of the art methods of: sequencing of eluted peptides from various human DQ and DR molecules, the binding of phage display and synthetic peptide libraries to isolated molecules, the electrophoretic stability of antigen-MHC II complexes, and the structural modelling of the binding based on the recently published structure of DR1. The motifs obtained by these approaches will then be tested in binding of peptides fulfilling the established motif to isolated MHC molecules as well as MHC molecules in whole cells. The results generated thus will advance our understanding of peptide antigenicity, immune reactivity and autoimmunity, leading to the synthesis of specific peptide mimetics that can be tested for their capacity to compete with autoantigenic peptides preventing the manifestation of autoimmune disease.

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CSC - Cost-sharing contracts

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Eberhard-Karls-Universität Tübingen
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15,Auf den Morgenstelle
72076 Tübingen
Deutschland

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Letzte Aktualisierung: 22 Oktober 1998

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Permalink: https://cordis.europa.eu/project/id/BIO4950263/de

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