on March 23, 2009
IRB Researchers identify a novel mechanism leading to brain inflammation in model of multiple sclerosis
Andrea Reboldi and Federica Sallusto
Researchers at the IRB, in collaboration with colleagues from the Theodore Kocher institute in Bern and the Neuroimmunology Unit at the University of Genoa, Italy have identified a key mechanism implicated in the initiation of experimental autoimmune encephalomyelitis (EAE).
EAE is used as an experimental model for Multiple Sclerosis (MS), a devastating disease that results in the loss of neurons and permanent disability by damaging myelin, the protective sheath of nerves (Box1). The ability to block EAE may have therapeutic implications for MS.
EAE and MS are autoimmune diseases. In MS, the T cells of the immune system that normally defend our body against pathogens, attack the central nervous system (CNS) leading to the destruction of myelin and neurons. In order to cause this damage, T cells have to enter the CNS by crossing the blood brain barrier (BBB) that normally shields the CNS from the peripheral blood (Box2).
The new study led by Federica Sallusto (IRB, Bellinzona) and published in Nature Immunology (Andrea Reboldi et al. Nature Immunology online XXX. CCR6-regulated entry of Th17 cells into the CNS through the choroid plexus is required for the initiation of EAE), identifies a molecule, namely CCR6, expressed by disease-inducing T cells that is required for the initiation of brain inflammation.
Federica Sallusto explains that CCR6 acts as a key for T cells to open the lock on epithelial cells of the choroid plexus (a specialized structure where cerebrospinal fluid is formed) allowing their entry into the cerebrospinal fluid. From there the T cells can disseminate to the brain cortex and open the BBB. “Once in the CNS, these “pioneer” T cells open the way to other inflammatory cells that sustain the disease. Importantly, in the absence of these pioneers disease does not develop”.
Britta Engelhardt from the Theodor Kocher Institute in Bern says that it was not clear that CNS inflammation can in fact be initiated via the choroid plexus. “The new pathway of T cell entry into the CNS is consistent with the distribution of the early lesions in EAE and MS”.
Antonio Uccelli from the University of Genoa, underlines that CCR6 expressing T cells can be detected in the brain of subjects with MS, suggesting that the identified mechanism of T cell migration in the CNS is relevant in humans.
This study was funded by the Swiss National Science Foundation, the European Commission Sixth Framework Programme, the National MS Society (USA), the Swiss MS Society and the Italian MS Foundation. According to Antonio Lanzavecchia (a co-author and director of the IRB) CCR6 is a target molecule that could be exploited for developing new MS therapies.
Multiple sclerosis affects about one in 1,000 people and is one of the most common causes of neurological disability. It usually appears between the ages of 20 and 40.
In healthy individuals, conduction of neural signals along nerves inside the central nervous system requires an intact protective layer known as the myelin sheath. In multiple sclerosis the T cells that react against myelin are activated in the peripheral blood by yet unknown environmental triggers and cross the blood brain barrier (Box 2). The T cells then cause inflammation and damage to the myelin sheath resulting in chronic damage of neurons and, after time, irreversible disability.
Multiple sclerosis is an autoimmune disease (a condition in which an individual’s immune system starts reacting against his or her own tissues) and cannot be spread from person to person.
Blood Brain Barrier: Crossing the Gap
The central nervous system includes the brain and spinal cord. It contains the nerves that control everything your body does, such as thinking, feeling, seeing, smelling, tasting, and moving. The central nervous system is separated from the peripheral blood by a barrier, the BBB, protecting the brain. In diseases such as multiple sclerosis the blood brain barrier is disrupted and inflammatory cells can enter the central nervous system.
