A subset of monocytes (a type of immune cells) that can infiltrate the central nervous system and drive nerve cell damage in multiple sclerosis (MS) may be a better target for preventing disease progression than the cells of the immune system that are currently targeted with MS therapies, a study in mice suggests.
Current MS treatments designed to dampen immune reactions against myelin — the protective coating of nerve cells that is lost in MS — are known to put patients at higher risk of infections. But researchers found that depleting this newly identified monocyte subset can reduce clinical signs of MS without affecting immune cells that fight off infections.
The study, “Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation,” was published in the journal Nature Immunology.
The immune system plays a critical role in MS onset and progression. In patients, immune cells travel from the blood into the brain, where they wrongly attack the myelin sheath that covers neurons, and initiate a set of inflammatory reactions that eventually cause nerve cells to die.
Immune B-cells and T-cells are seen as the major drivers of this inflammation, and most MS therapies are meant to target and eliminate these immune cells. But such approaches are not without side effects, as they also deplete patients from memory immune cells needed to fight foreign threats.
“Up until now, MS drugs have essentially targeted these T and B cells, both of which are part of the acquired immune system,” Alexander Mildner, the study’s co-senior author, said in a press release. Mildner is a scientist at the Max Delbrück Center for Molecular Medicine, Germany.
“But by attacking the acquired immune system, the MS drugs adversely affect the body’s immune memory, thus making patients more susceptible to infections in the long run,” Mildner said.
Knowing this, Mildner has been focusing on another subset of immune cells that is believed to also play a major part in MS progression: a subset of monocytes that produce the CCR2 protein.
“In an earlier study with a mouse model of MS, we were able to show that disease symptoms in the mice declined significantly within a few days after their monocytes were selectively destroyed by antibodies [against CCR2],” said Mildner. “Apparently, it is not only T and B cells that are involved in causing tissue damage in MS.”
Monocytes are immune cells that travel in the blood before migrating into tissues, where they can fight threats by engulfing them.
In MS, these cells also can participate in the process of inflammation by “eating” pieces of the central nervous system (CNS). But exactly what subsets of monocytes are entering the CNS and causing disease is largely unknown.
Mildner’s team set out to explore the different subsets of monocytes that are found in the CNS of mice with experimental autoimmune encephalomyelitis (EAE), an established animal model of MS.
Results revealed several molecularly distinct populations of monocytes or closely related cells, of which two monocyte subpopulations — called Saa3+ and Cxcl10+ monocytes — exhibited a strong pro-inflammatory and disease-causing genetic signature (genes that are switched “on” or “off,” and to what extent).
Other subpopulations appeared to be more involved in wound healing, tissue remodeling, regulation of blood vessels, and engulfing processes — all natural functions of monocytes.
The composition of monocytes and related cells in the CNS varied during disease progression. Particularly, Cxcl10+ monocytes increased from 8.8% in the acute phase of disease to 21.2% in the chronic stage.
The team then examined exactly which subsets were depleted when mice were treated with a CCR2 antibody, which induced a notable clinical improvement after six days. They found that mice receiving this antibody lacked Saa3+ and Cxcl10+ monocytes in their spinal cords, but other subsets were essentially intact.
Other cells of the immune system, including B-cells, T-cells, and natural killer cells, also were not affected by the antibody treatment. Only a slight increase in the amount of regulatory T-cells (immunosuppressive cells) was noted in treated animals.
Overall, the findings revealed the presence of a previously unknown monocyte subset, called Cxcl10+ monocytes, with a unique behavior in the spinal cord of EAE mice. “It seems that these cells exhibit direct pathogenic function with minimal influences on other immune cells,” the researchers wrote.
The research team believes that Cxcl10+ monocytes may have an even bigger role than anticipated, being the immune cells that open up the blood-brain-barrier to help other immune cells enter the CNS, and then recruiting and activating other immune players in the disease.
“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,” said Mildner. “This would protect the body’s immune memory and prevent many side effects of current MS therapies.”
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