Work Package 2 - Immune Responses
Coordinator Anthony Weetman, Sheffield, UK
Last updated 2006-03-28
The aim of this package is to employ a range of techniques to produce for the first time a comprehensive analysis of the autoimmune response in APS I. The development of new transgenic animal models will enable studies of the role of Aire expression in T cell development and the ensuing immune response to a defined autoantigen. B cell responses will be probed through the identification of novel antigenic targets and corresponding B cell epitopes using a combination of heterologous cDNA expression screening and proteomic approaches.
The role of Aire expression in thymic T cell development and the establishment of tolerance.
The information derived from the proposed transgenic mouse studies will provide valuable insights into the role of Aire in T cell development and how defects in the Aire gene could give rise to the characteristic autoimmune features of APS I. Attention will also be given to the selection of CD1 restricted NKT cells.
Identification and characterization of novel APS I autoantigens.
Novel antigenic targets will provide knowledge regarding the initiation of the autoimmune process in APS I and the basis of tissue specificity in the immune response. In addition to improving our understanding of the etiology of APS I, this information may provide valuable insights into the initiation and pathophysiology of other more common autoimmune diseases. The parallel development of novel diagnostic materials will offer new avenues for both the detection of APS I and the monitoring of disease progress.
T cell and B cell epitope mapping and interactions.
Knowledge of the key autoantigenic epitopes involved in the patient responses to APS I autoantigens will advance our understanding of how the autoimmune process is both initiated and progresses in the course of disease. The data obtained will also highlight possible interactions between the T cell repertoire and MHC alleles in terms of susceptibility, tissue specificity, and disease severity. Analysis of B cell and T cell epitopes will increase our understanding of the potential role of antigen processing in the development of autoimmunity, and finally, could suggest novel therapeutic strategies based on immune suppression and the manipulation of tolerance.