Aims and significance: The aims of this program are (1) To obtain new understanding of how environmental and life style factors interact with genes to induce immune reactions able to cause the different forms of arthritis that are defined as RA; (2) To use this understanding to develop prevention and targeted therapy for different forms of RA, and to enable efficient and eventually curative therapy. Background: We build on new understanding or RA etiology that has followed from studies on interactions between genes, environment and immunity in different subsets of RA. This has been provided for new detailed studies on specific and eventually disease-inducing autoimmunity in RA. Research program: We will use our infrastructure (longitudinal large cohorts, biobanks genetic information and our molecular immunology laboratory) to investigate (1) how genes and environment interact in causing different forms of RA; (2) how specific immune reactions against post-translationally modified (mainly citrullinated) autoantigens are triggered by environmental agents in specific genetic contexts in different individuals; (3) How these immune reactions target different organs (joints, lungs etc) and eventually cause arthritis in model systems; (4) how the combination of genes, environment and immunity may determine disease course and response to various therapies. Novelty and opportunities to take knowledge of autoimmune disease and RA to a new level: The recent advances in understanding interactions between genes, environment and immunity in RA, provides a striking new opportunity to understand basic features of autoimmunity and autoimmune disease, as well as potentials to prevent and treat RA very early. I believe that the presented program is well positioned to use this opportunity and contribute to a new paradigm for understanding and preventing RA.