Collagen induced arthritis (CIA) is an inflammatory autoimmune disease that sufficiently resembles human rheumatoid arthritis to be considered an experimental model. This autoimmune model is induced by the immunization of animals with type II collagen and is characterized by both an antigen specific T cell and antibody response. One of the most interesting aspects of both rheumatoid arthritis and collagen induced arthritis is that susceptibility is linked to the expression of certain major histocompatibility complex class II molecules. In the murine model, susceptibility to CIA is linked to the expression of the class II molecules I-Aq and I-Ar. However, strains expressing other class II molecules also mount an immune response to type II collagen without developing disease. Although the antibody response to type II collagen has been well studied in the experimental model, little is known about the antigenic determinants that stimulate the T cells that regulate the production of the autoantibodies in CIA. The goal of this proposal is to determine what molecular aspect of both the antigen (type II collagen) and the class II molecule controls the susceptibility to CIA. Our hypothesis is that the class II molecules expressed by the susceptible strains selectively bind arthritogenic peptides derived from type II collagen, and only these peptides in the context of I-Aq or I-Ar are capable of stimulating the T cells that can promote the production of collagen specific, arthritogenic antibodies. Our specific objectives are to identify collagen derived- peptides that are specifically presented by I-Aq, a class II molecule expressed by a susceptible strain, and to determine the molecular interactions involved in the induction of CIA by these antigenic determinants. These goals will be accomplished by: 1) identifying the antigenic peptides derived from type II collagen that specifically stimulate, I-Aq-restricted T cells; 2) determining if susceptibility to CIA is mediated by the capacity of I-Aq molecules to selectively bind type II collagen-derived peptides; 3) identifying T cell lines that participate in the induction of CIA; and 4) determining the contribution of individual T cell determinants to the production of antibodies to type II collagen and subsequently the induction of CIA. Through these experiments, we will develop a well defined autoimmune model in which the contribution of individual T-cell determinants to the production of autoantibodies can be thoroughly studied. These data will provide us with a solid understanding of the molecular events involved in the initiation of a class II linked autoimmune disease and, in conjunction with studies proposed in Project 2, supply us with a framework for addressing our long term goal, the development of experimental immunotherapeutic strategies.
Showing the most recent 10 out of 122 publications
