Figure 1. (a) Neurodegenerative and immunological events leading to schizophrenia. (a) According to the neurodevelopmental hypothesis of schizophrenia, an injury of unspecified origin in the hippocampus or adjacent areas of the prenatal brain contributes to behavioral and cognitive abnormalities expressed later in life 12, 13 and 14. The prenatal brain injury induces release of self-proteins from the CNS to the periphery, where these proteins enter the thymus of the fetus or neonate and are presented by thymic epithelial cells to developing T cells. This causes deletion of or tolerance to T-cell clones reactive to these brain proteins. (b) Under normal conditions, brain tissue in need of protection or maintenance receives assistance from the immune system. Stress signals (transmitted, for example, by dopamine) that originate from the stressed or damaged brain can relieve the suppression exerted by regulatory T cells (Treg) on autoimmune effector T cells (Teff), thus enabling the latter to be efficiently activated to express protection, maintenance and repair. According to this theory, patients with schizophrenia lack the neuroprotective autoimmune T cells, because of either prenatal deletion of these cells or acquisition of immune tolerance to them. Failure to obtain assistance leads to further production of the stress signal (e.g. dopamine), and this in turn completely eliminates the activity of Treg. Malfunctioning of the regulatory network due to overproduction of dopamine leads to over-activation of various T-cell clones and to positive symptoms of schizophrenia. It is assumed that the boosting of T cells that cross-react with brain antigens arrest self-perpetuating processes of damage in the brain, and that this in turn reduces the amount of the stress signal (dopamine) produced.