Monocytes may play key role in myelin damage

April 24, 2020
According to findings in a recent study, it is possible that the T and B cells are only indirectly involved in stripping away the myelin sheath in that they prompt a type of monocyte cell to attack myelin. If true, in the future most forms of MS could be treated by specifically deactivating monocytes, protecting the body's immune memory and prevent many side effects of current MS therapies.

Scientists don't yet know exactly which immune cells are involved in stripping away the myelin sheath. Autoreactive T and B cells, which wrongly identify the myelin sheath as a foreign body, travel to the brain and initiate the disease. 

Researchers at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, in Berlin, wanted to know what role immune cells – particularly those that are part of innate immunity – play in the development of MS and whether they represent a promising target structure for therapy of MS patients. In an earlier mouse model study, research showed disease symptoms in the mice declined significantly within a few days after their monocytes were selectively destroyed by antibodies. This result surprised the researchers. Apparently, it is not only T and B cells that are involved in causing tissue damage in MS.

The monocytes they studied are a special type of white blood cells that shortly circulate in the blood before migrating into tissue. Once there, they transform themselves into effector cells (phagocytes) and destroy foreign tissue in the central nervous system – or which, during MS, they wrongly identify as such.

In the current study, which was conducted in collaboration with an Israeli team at the Department of Immunology at the Weizmann Institute of Science, in Rehovot, Israel, the research team also focused on monocytes. They identified six different monocyte subtypes, four of which were previously unknown. As in his earlier study, researchers injected the mice with antibodies against a specific monocyte surface protein. As expected, the cells died and the MS symptoms in the mice decreased within a short period of time. 

Only a certain type of monocyte, the Cxcl10+ cells, was destroyed by the antibody treatment. These are apparently the cells that are primarily responsible for causing MS tissue damage in the brain. With the help of single-cell sequencing, the team discovered this cell type differs from other monocytes in two essential ways. First, Cxcl10+ cells have a particularly large number of receptors for a signal protein secreted by T cells that induces tissue damaging properties in monocytes. Second, these cells produce large amounts of interleukin-1-beta, a substance that opens the blood-brain barrier, enabling immune cells to more easily pass from the blood to the brain and exacerbate the symptoms. The findings suggest T cells, as disease initiators, travel to the central nervous system in order to lure there the monocytes that are responsible for the primary tissue damage.

The other monocyte subsets that were identified are perhaps even involved in repair processes in which the body tries to rebuild the damaged myelin. In light of the study's findings, the researchers think it is also possible that the T and B cells are not even directly involved in stripping away the myelin sheath, but only indirectly in that they prompt the Cxcl10+ monocytes to attack the protective layer of the axons. If that is the case, in the future most forms of MS could be treated by specifically deactivating the Cxcl10+ monocytes instead of targeting the T or B cells of the immune system. This would protect the body's immune memory and prevent many side effects of current MS therapies. The research team plan to investigate whether the Cxcl10+ monocytes are also present outside the CNS. If they exist in the body's periphery, for example, in the lymph nodes. There they would be easier to target with therapeutics than in the brain.

The study was published in Nature Immunology.

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