Our project aims to analyze the molecular mechanisms of presentation of cryptic epitopes and their participation in the development of autoimmune diseases. Seven European laboratories from five different countries, specialized in biochemical, cell biological, immunological and clinical aspects of antigen presentation and autoimmuniy, will concert their efforts aiming at:
l) analyzing the molecular basis for crypticity. We will determine why certain peptides are not normally presented to T.
2) defining the molecular and cellular mechanisms whereby cryptic epitopes are efficiently processed and presented to T cells under particular conditions or by certain antigen presenting cells
3) analyzing antigen presentation in autoimmunity and defining the role of cryptic epitopes in autoimmune pathogenesis.
Autoimmune diseases represent one of the most common chronic diseases in European countries. Despite their frequency, and despite an enormous amount of work in many different human pathologies and murine models, the fundamental immunological basis for the onset and the development of autoimmune diseases remain unclear. It is clear, however, that most chronic autoimmune diseases involve pathologic self reactive T lymphocytes. The central question is then why autoreactive T cells, which are norrmally tolerized in the thymus, escape negative selection and then initiate an autoimmune disease.
A simple unifying hypothesis has recently been proposed: the epitopes involved in autoimmune pathogenesis are "cryptic" self epitopes (i.e. epitopes corresponding to peptides which do not induce a T cell response after immunization with intact antigens, but which do trigger normal responses after direct immunization with the peptide) (Lanzavecchia, 1995; Sercarz et al., 1993). These self epitopes do not induce central T cell tolerance because they are not efficiently presented in the thymus. T cells specific for these epitopes are therefore not tolerized and may become pathogenic if the crypitic epitopes are presented in the periphery. Autoimmunity then results from the pathogenic presentation in peripherical tissues of normally hidden, cryptic epitopes. This, of course, does not exclude the possibility that autoimmunity can also result from breakdown of tolerance against dominant self-epitopes.
In view of the fact that increasing evidence implicates the presentation of cryptic epitopes in autoimmunity, these studies have as ultimate goal to provide a better understanding of the pathogenesis of autoimmune diseases. This project will potentially lead to the identification of pharmaceutical targets and the development of new therapeutic strategies based on the manipulation of antigen processing and presentation in autoimmune diseases.
Autoimmunity, cryptic epitopes, antigen presentation, immunology, antigen receptors, T lymphocytes. MHC molecules.
Funding SchemeCSC - Cost-sharing contracts
W6 8LW Hammersmith
DD1 4HN Dundee