Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. The chain of events that results in demyelinating lesions is not known. Most theories assume a primary immune attack on myelin, although it has been clear since long that details of MS pathology are not in line with this.New research findings, including work by Van der Knaap, Min, and colleagues, point in a different direction.
They argue that the immune attack in MS does not primarily target myelin, but rather astrocytes – a subtype of glial cells in the brain that are crucial to maintain the homeostasis of the CNS. Astrocytes contain a complex of proteins (including GlialCAM, MLC1, the water channel Aquaporin-4 and the potassium channel KIR4.1), which cluster in the endfeet with which astrocytes enwrap the brain vasculature. This complex is essential for water homeostasis in the brain. Disruption of this complex, as occurs in MLC, leads to vacuolization and damage of myelin.
Studies aiming to identify proteins targeted by the immune system in MS and the related inflammatory demyelinating disease neuromyelitis optica repeatedly point towards involvement of these endfoot proteins. Therefore, Van der Knaap and Min suggest that demyelination in MS is not the result of a direct attack on myelin but a secondary effect of an immune attack on astrocytes. This paradigm shifts the perspective on MS and opens new avenues for developing more targeted disease models and therapies.
Read the article in Nature Reviews Neurology: Multiple sclerosis: an immune attack on astrocyte-mediated ion and water homeostasis