A review. During the development of T lymphocytes in the thymus, the cells with reactivity against self antigens are deleted or rendered inactive (central tolerance). Because this system in not perfect, an addnl. number of regulatory mechanisms in the periphery prevent the unwanted reactivity against self antigens. Regulatory T lymphocytes (Tregs), with the phenotype CD4+CD25+ and which express the FOXP3 transcription factor, play an important role in this regulation. Tregs produce IL-10, a cytokine which is important for maintaining a balanced cytokine production and thus a well regulated immune response in terms of direction, magnitude, and duration. Defects in these regulatory mechanisms can lead to organ specific or systemic autoimmune diseases. In these diseases abnormal cytokine-production patterns are found with increased levels of pro-inflammatory cytokines and often reduced Treg function. The primary (mol. or environmental) cause of systemic autoimmune diseases, as well as the relevant autoantigens are unknown, but an important role can be attributed to heat shock proteins (HSPs). The HSPs are found in bacteria as well as man and their sequence is strongly conserved during evolution. A T lymphocyte response against bacterial specific sequences induces arthritis, while a response of Tregs against conserved sequences protects. The general intervention in the disturbed immune regulation in autoimmune diseases by TNF blockade clin. is very effective, but does have serious side effects. Restoration of antigen specific immune regulation (e.g. against HSPs) for the future would offer an alternative therapeutic strategy.