The balancing act of autoimmunity: central and peripheral tolerance versus infection control

Genetic associations with autoimmune disease are enriched in immune response regulators. The immune system in individuals at genetic risk of autoimmunity must balance pressures on the innate and adaptive immune system, most notably infection control, with those of maintaining self-tolerance or controlling autoimmune inflammation. In spite of multiple tolerance mechanisms, inflammation becomes chronic in autoimmune disease, and complete resolution is difficult. This article proposes a perspective on the pathogenesis of autoimmunity-focusing on rheumatoid arthritis and type 1 diabetes-integrating clinical advances and animal models with the role that colonizing micro-organisms play in the balance between tolerance and autoimmunity.