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Rheumatoid Arthritis (RA) is a severe chronic inflammatory disease that is characterized by an early breach in immune tolerance and persisting autoimmunity. The autoimmune response triggers the onset of a chronic arthritis affecting peripheral joints, which typically show synovial inflammation and destruction of articular cartilage and bone. Research in the field of RA has been traditionally focused on the understanding of the mechanisms underlying synovitis and joint destruction. These efforts resulted in the successful development of targeted immune modulatory drugs for the treatment of this disease. However, key questions about factors responsible for the breach in immune tolerance and the initial onset of disease remain unanswered. As a consequence, current therapies primarily aim to suppress the inflammatory response, rather than targeting autoimmunity, inducing tolerance or offering preventive strategies. Although usually effective in controlling disease activity to some extent, the established treatments do not tackle the underlying problem of autoimmunity and thus require a life-long treatment. Curative therapeutic concepts for RA patients are still out of reach. Within the Research Unit named PANDORA (Pathways triggering autoimmunity and defining onset of early rheumatoid arthritis), we bundle the expertise of internationally-renowned scientists and seek to unravel the mechanisms responsible for the early immune-pathogenesis of RA. By focusing on two key checkpoints - the loss of immune tolerance and the transition from autoimmunity to inflammation - we want to identify new concepts underlying the pathogenesis of early RA and thereby develop strategies for preventive and curative treatment approaches. Embedding this Research Unit into the research environment and infrastructure of the Friedrich Alexander University Erlangen-Nürnberg (FAU) and the University Hospital of Erlangen (UKER) offers the unique possibility of combining cutting edge techniques in immunology and molecular biology with preclinical disease models, modern imaging and well-characterized RA patient cohorts. Together with one ongoing and one additionally planned innovative clinical trial that seem to re-induce tolerance in RA, this concept provides the ground for a high level translational research program.