What happens in the body

The brain and spinal cord are normally sheltered from most of the immune system by the blood-brain barrier, a tight lining of the small blood vessels that supply them. In MS, immune cells that have been activated elsewhere in the body cross this barrier and set up inflammation inside the nervous system. Their main target is myelin and the cells that make it, called oligodendrocytes.[1]

For many years MS was thought to be driven mainly by T cells, partly because the animal model used to study it is a T-cell disease. In 2008 a trial of rituximab, a medicine that removes B cells, showed a large and rapid fall in new inflammation, and B cells have been at the centre of MS research ever since.[2][3]

Why the immune system makes this mistake is not fully known. One explanation under study is molecular mimicry: in some people with MS, antibodies against a protein of the Epstein-Barr virus also bind GlialCAM, a protein found in the brain.[4]

Where inflammation strikes, it leaves a lesion, an area where myelin has been stripped away and the tissue scarred. Lesions are easiest to see on MRI in the white matter, the bundles of nerve fibres deep in the brain and in the spinal cord. They also form in the grey matter of the cortex, often from the earliest stages of the disease, although standard MRI shows these poorly.[5]

Losing myelin slows or blocks the signals that a nerve fibre carries. The fibres themselves are also cut in active lesions, and studies of brain tissue have found large numbers of severed fibres in lesions at every stage of the disease. A nerve fibre that is lost is not replaced, and this loss is thought to explain much of the disability that builds up over time.[6][7][8]

The brain can make new myelin. Precursor cells move into a lesion, mature into oligodendrocytes and wrap the bare fibres again, a process called remyelination. In some people this repair is extensive, while in others most lesions stay bare.[9][10]

Repair often stalls at a late step. In long-standing lesions, researchers have found immature oligodendrocytes lying next to bare fibres, apparently unable to finish the job. The capacity for repair also declines with age, which experiments in animals link to the ageing of the precursor cells themselves.[11][12]

Not all of the inflammation in MS comes from cells arriving from the blood. Some lesions stay active at their edges for years, with microglia, the brain's own immune cells, slowly extending the damage. Clusters of B cells can also form in the membranes that cover the brain, close to areas of damaged cortex.[13][14]

This inflammation sits behind the blood-brain barrier, where many medicines that act on immune cells in the blood reach poorly. It is one of the leading explanations for why disability can keep worsening after relapses have been brought under control.[8]

The brain can compensate for damage by rerouting signals and recruiting other areas. This reserve helps explain why the lesions on a scan and a person's symptoms often do not match, and why disability can appear quite suddenly once the reserve has been used up. Reserve falls with age.[15]