New therapeutic approach for multiple sclerosis
Previous approaches to treating multiple sclerosis have focused on T and B cells. However, it may be more effective to fight another form of immune cells - namely, certain monocytes.
Both the symptoms and the course of multiple sclerosis (MS) differ greatly from patient to patient. However, one thing is the same for all sick people: cells of their own immune system migrate into the brain and destroy the myelin sheaths, the protective outer layer of the nerve fibers. As a result, electrical "short circuits" occur in the brain and nerve signals can no longer be passed on properly.
Researchers do not yet know in detail which immune cells are involved in breaking down the myelin sheaths. Autoreactive T and B cells, which, due to an error, recognize the myelin sheaths in the brain as foreign, migrate into the brain and initiate the disease. "This is why the MS drugs available to date are mainly directed against these T and B cells, both of which belong to the adaptive immune system," said the head of research, Dr. Alexander Mildner from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC).
"By attacking the acquired immune system, however, the MS drugs impair the body's immune memory, which can make it more susceptible to infections in the long term," said the scientist.
Mildner had therefore been pursuing a different strategy for a few years. He wanted to find out what role immune cells play in the development of MS, which are part of the innate body defense - and whether they too could be a suitable target structure for the treatment of the disease. "In an earlier study with a mouse model for multiple sclerosis, we were able to show that the disease symptoms in the animals were greatly reduced within just a few days when antibodies specifically destroyed their monocytes," reported the researcher. That surprised him and many of his colleagues at the time.
"Apparently, it is not only T and B cells that are involved in tissue damage in MS," said Mildner. The monocytes he examined are a special form of white blood cells that circulate in the blood for a while before they migrate into the tissue. There they transform into phagocytes that destroy tissue foreign to the body - or what they mistakenly believe to be, as is the case with MS. This leads to inflammation in the brain, said Mildner.
"We know that there are several forms of these immune cells that have different tasks," said the scientist: "In our mouse model of MS, we wanted to examine the cells more closely using single-cell sequencing and find out which monocytes are present in the brain in MS . "
He and his colleagues came across six different monocyte subtypes, four of which were previously unknown. As in his earlier study, Mildner injected the mice with antibodies against a specific surface protein of the monocytes. As expected, the cells then died and the MS symptoms in the animals diminished within a very short time. "What was surprising for us, however, was the observation that the antibodies did not destroy all of the monocytes in the brain that had this surface protein," explained Mildner.
"Only a very specific form of monocytes, the Cxcl10 + cells, perished as a result of the antibody treatment," said Mildner: "Apparently, they are the cells that primarily cause the tissue damage typical of MS in the brain."
As he and his team also found out with single-cell sequencing, this cell type differs from the other monocytes in two essential ways. On the one hand, Cxcl10 + cells have a particularly large number of receptors for a signal substance released by T cells, which causes tissue-damaging properties in monocytes. On the other hand, these cells produce a particularly large amount of interleukin-1-beta, a substance that opens the blood-brain barrier so that the cells can more easily get from the blood to the brain.
"Our research suggests that T cells, as disease initiators, migrate to the central nervous system (CNS) in order to attract monocytes there, which are responsible for the primary tissue damage," said Mildner, explaining the theory.
The other monocytes may even be involved in repair processes in which the body tries to rebuild the damaged myelin, speculated Mildner. Based on the results of his study, he also considers it conceivable that the T and B cells are not directly involved in the breakdown of the myelin sheaths, but only indirectly: by causing the Cxcl10 + monocytes to attack the protective covering of the nerve fibers.
"If that were the case, it would be sufficient to treat the vast majority of forms of MS in the future to specifically switch off the Cxcl10 + monocytes instead of taking action against the T or B cells of the immune system," continued Mildner: "This would be the immune memory of the Protect your body and avoid many of the side effects of current MS therapies."
In a next step, the researcher and his team would like to find out whether the Cxcl10 + monocytes can also be found outside the CNS. "If, for example, they already exist in the body's periphery, for example in the lymph nodes," he concluded, "they would be much easier to attack there for therapeutic purposes than in the brain."