It has recently been proposed that experimental autoimmune encephalomyelitis, once considered the classical Th1 disease, is predominantly Th17 driven. In this study we show that myelin-reactive Th1 preparations devoid of contaminating IL-17+ cells are highly pathogenic. In contrast, Th17 preparations lacking IFN-γ+ cells do not cause disease. Our key observation is that only Th1 cells can access the noninflamed CNS. Once Th1 cells establish the experimental autoimmune encephalomyelitis lesion, Th17 cells appear in the CNS. These data shed important new light on the ability of Th1 vs Th17 cells to access inflamed vs normal tissue. Because the IL-17-triggered release of chemokines by stromal cells could attract many other immune cells, allowing Th17 cells to access the tissues only under conditions of inflammation may be a key process limiting (auto)immune pathology. This has major implications for the design of therapeutic interventions, many of which are now aiming at Th17 rather than Th1 cells.

No abstract

Under normal physiological conditions there is minimal entry of immune cells into the central nervous system (CNS) for the purpose of immune surveillance. During inflammation, however, extensive infiltration of immune cells can lead to the induction of CNS autoimmune disease, for example multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The barriers that regulate cellular entry are the blood-brain barrier (BBB) within the CNS parenchyma, and the blood-cerebrospinal fluid (blood-CSF) barrier within the choroid plexus. Understanding how these barriers function to allow the passage of leukocytes from the periphery into the CNS for normal immune surveillance, and under inflammatory conditions, is vital for the development of novel therapeutics targeting immune cell migration in CNS diseases. Contributions from selectins, chemokines, integrins and matrix metalloproteinases allow the migration of leukocytes across the BBB and into the CNS parenchyma. In EAE and MS, the strict maintenance of this process is lost and a large influx of cells is seen. This review focuses on the role of these homing molecules, chemokines and enzymes in the entry of leukocytes into the CNS during inflammatory conditions. It concludes with a model of immune cell entry of the CNS, summarising the current knowledge in this area. Targeting specific molecules to prevent infiltration of inflammatory cells into the CNS could allow disease inhibition without compromising beneficial immune surveillance.