Etiopathogenesis of autoimmune diseases. Outline showing the plausible stages for a multifactorial etiology to develop over time. Each stage shows the known phenomena that cumulatively will be the causative scenario for the onset of disease(s). First, heritable factors (that is, genetics, including ancestry, and epigenetics) impact over the life of the individuals. They converge and interact to create and increase or decrease the liability an individual would have to develop the phenotype depending on risk and protective effects. Women are more affected than men. Second, the autoimmune ecology is characterized by the interactions between an individual and its environment, which acting stochastically will also influence the risk and course of disease. The additive effects of heritable and environmental risk factors favor the loss of autoimmune tolerance. Then, a preclinical stage characterized by B and T cell dysregulation arises. This third phase may take years before the phenotype becomes clinically evident. Adapted from Anaya  (with permission from Elsevier). This model may apply to all complex diseases. TCR, T cell receptor.