When the solution to a clinical or scientific puzzle eludes us for more than a century, as with schizophrenia, we need new methods to examine the pathology. If we want to make an impact on the disease we must shift research paradigms and focus on the early detection, early intervention, and new avenues of treatment that address different symptoms of schizophrenia. Immunological and blood-brain barrier (BBB) abnormalities in patients with psychosis have been repeatedly noted. Hundreds of studies of schizophrenic illness in adults have documented immunological abnormalities in these patients, and an increasing number of studies have shown a link between S100b, a marker of BBB function, and schizophrenic illness (Table).1-3
In looking at the possible causes of schizophrenia, earlier studies focused on neurons. Increasing evidence now suggests that the glia, cerebral vasculature, and the BBB may be involved. Two postmortem studies reported activated glial cells in a subgroup of patients with schizophrenia.4,5 Using the marker PK11195 to label glial cells in patients with psychosis, Hirsch6 found activation throughout the cortex using positron emission tomographic accentuation in the frontal lobes. Here we present evidence linking inflammation, immunological abnormalities, BBB disruption, and neurological disorders.
BBB in health and disease
The BBB is a physical and metabolic barrier that regulates and protects the brain. This barrier is composed of tight junctions between endothelial cells in CNS vessels that restrict the passage of solutes. Several lines of evidence have pointed to a link between CNS problems—such as psychiatric disorders and inflammation—that occur in response to pathogens. Impairment of the BBB may be the consequence of immunopathogenic mechanisms.7
Little is known about the microvascular endothelial cells that form the BBB. Technical difficulties and lack of specific markers for BBB endothelial cells have made this research difficult. However, with recent advances in methodological techniques, it is becoming possible to identify important characteristics of BBB endothelial cells.
Integrity of the BBB reduces entry of immunocompetent cells and antibodies and is necessary for the immune system to attack infectious agents. A highly specialized tight endothelium isolates the brain from immune surveillance and allows only a few mononuclear cells, activated T cells, and macrophages to migrate into the CNS.8
During inflammation, extensive leukocyte migration occurs at the BBB.9 Both endothelial cells and astrocytes act as antigen-presenting cells to facilitate entry of T lymphocytes and antibodies. The BBB itself plays an active role in mediating the neuro-immune response.