We still don't know exactly what causes multiple sclerosis (MS), or many other disorders that involve inflammation in the brain, but researchers have now identified a type of immune cells that could be involved. They are a subset of immune cells called group 3 innate lymphoid cells (ILC3s), and they normally help the body tolerate microbes that reside in the gut microbiome by suppressing inflammatory responses there and in other regions. But some ILC3s seem to infiltrate the bloodstream, and once in circulation, they can penetrate the brain. But they don't tamp down inflammation there, they appear to to promote it. These findings have been reported in Nature.
In this work, the researchers were analyzing a mouse model of MS, and identified these inflammatory ILC3s there. In the mice, the ILC3s activated T cells to attack the myelin sheath surrounding nerves. Myelin acts as a crucial insulator that helps keep signals flowing in the nervous system. MS is known to involve the degradation of myelin, and when the myelin was disrupted in the mice, MS symptoms appeared. The researchers also found inflammatory ILC3s in samples of blood and cerebrospinal fluid from MS patients.
“This work has the potential to inform our understanding of, and potential treatments for, a broad variety of conditions involving T cell infiltration of the brain,” said senior study author Dr. Gregory Sonnenberg, an associate professor of microbiology and immunology in medicine at Weill Cornell Medicine.
Neuroinflammation has been implicated in a variety of disorders aside from MS, including Parkinson's and Alzheimer's.
The ILC3s were found to cause myelin destruction by functioning as antigen-presenting cells, but in this case, the antigens were coming from myelin, causing T cells to attack it. Antigen presenting cells are a normal part of the immune system, but they should direct the immune system to attack invaders, not parts of the self. The researchers also found that in the mouse brains, ILC3 and T cells were closely associated in areas where inflammation and damage occurred.
These immune cells are a crucial to the pathogenesis of neuroinflammation, said first study author and Sonnenberg lab graduate student John Benji Grigg.
The scientists were also able to prevent MS symptoms in the mouse model by eliminating a molecule called MHCII from the ILC3 cells. MHCII is a critical part of antigen presentation, so once the ILC3 cells couldn't present 'myelin antigens' to T cells, the disease symptoms were relieved.
Additional work by this research team in a mouse model has suggested that other ILC3s in the body could counteract the harmful effect of those that cause brain inflammation; when intestinal ILC3 were exposed to myelin, neuroinflammation caused by T cells was prevented.
This work has to be confirmed in people, but it could lead to a major breakthrough in therapeutics for MS.
Sources: Weill Cornell Medicine, Nature
