Autoimmunity. Physiological control mechanisms and pathways to autoimmune disease

Immunological tolerance towards self antigens is ensured by at least two different mechanisms, i.e. the deletion of potentially autoreactive T-lymphocytes in the thymus ("negative selection") and the active suppression of unwanted (auto) immune responses in the periphery through regulatory T-cells (Treg). With few exceptions, autoimmune diseases result from a multifactorial disturbance of the physiological immune homeostasis. Underlying mechanisms include a genetic predisposition and an aberrant activation of the immune system due to exogenous stimuli such as infectious microorganisms or endogenous stimuli such as disturbed epithelial barrier function. Microbe-derived Toll-like receptor ligands interfere with the control of immune cell activation at several levels including stimulation of autoreactive B-lymphocytes, promotion of autoantigen presentation to T-lymphocytes, and modulation of the suppressive capacity of Treg. In addition, recent evidence indicates that the newly discovered interleukin-17 producing Th-17 T-cells play an important role in promoting inflammatory reactions and tissue destruction in autoimmune diseases.