Autoimmunity has been a topic of intensive research for several decades, yet amazingly, no uniform hypothesis exists to explain the basis for the spectrum of autoantibody specificities seen in autoimmune diseases. It therefore seems appropriate to consider whether our current framework for understanding tolerance, and thus the mechanisms controlling the initiation and perpetuation of autoimmunity, may be faulty. Adapting the paradigm of Matzinger-the 'danger model', a case can be made for a perspective that appreciates the fundamental role of the tissues in controlling immune response, favouring a shift of focus in studies on the initiation of autoimmunity. Applying the elements of this model, I set forth a number of scenarios for how autoreactivity could emerge, with emphasis on the likely sources of the involved autoantigens and the functional basis of their appearance. The emerging picture is one in which disruption of tissue homeostasis takes centre stage, with the antigen-presenting cells as the key players.
