Multiple sclerosis (MS) patients suffer from periodic attacks that can lead to vision loss, memory problems, pain, and other symptoms that can subside on their own after days or weeks. It has remained unclear what causes the switch from flare-up to remission and back again.
Now, an international research collaboration has discovered a connection between the intestinal flora and sites of inflammation in the central nervous system in MS. Further, they have shown, for the first time, that gut immune cells travel to the brain during MS flare-ups in patients. These gut cells seem to be playing a protective role, helping drive MS symptoms back into remission.
A specific class of immune cell plays a central role in this newly identified gut-brain axis. The discovery could pave the way for new treatments for MS that target the intestinal flora.
This work is published in Science Immunology in a paper titled, “Gut microbiota–specific IgA+ B cells traffic to the CNS in active multiple sclerosis.”
Changes in gut microbiota composition and a diverse role of B cells have both been recently implicated in MS.
“We knew from earlier studies that the composition of intestinal flora plays a role in MS. But how exactly intestinal bacteria and immune cells influence one another was previously unknown,” explains Anne-Katrin Pröbstel, M.D., a former UCSF postdoctoral researcher, now at the University of Basel in Switzerland and first author on the paper.
The findings suggest that an unexpected new player might help bring flare-ups under control: IgA-producing B cells. Immunoglobulin A (IgA) is a class of antibodies that specializes in immune defense of mucous membranes; the IgA B cells are key to intestinal health. In the gut, these cells serve as a critical first line of defense against foreign invaders and, scientists think, help keep the teeming bacteria of our gut microbiome from growing out of control.
Recently, scientists made the surprising discovery that, in animal models of MS, these gut immune cells leave the digestive system and travel to the brain where they appear to help cut inflammation.
“It was a very new idea,” says Sergio Baranzini, Ph.D., a professor of neurology and member of the UCSF Weill Institute for Neurosciences, lead author on the new study. “Nobody thought to look for this type of immune cell.”
By analyzing stool samples from MS patients and healthy people, the researchers discovered that MS patients have IgA B cells in their intestines that target bacteria that are more common in MS sufferers.
Next, the researchers analyzed the role of these immune cells during acute flares of the illness in a total of 56 MS patients. They found that IgA B cells accumulated in the cerebrospinal fluid and brain tissue of MS patients with acute sites of inflammation.
The team found traces of the IgA antibody in the cerebrospinal fluid of MS patients during flare-ups, but not when episodes are in remission. “Only at the time of an attack was there an increase in these cells and the antibodies they produce,” Baranzini says. “That really caught our attention.” They also found signs of IgA-producing immune cells in donated postmortem brain tissue that had been damaged during MS attacks.
“Apparently, these immune cells migrate from the intestine to the inflammation sites in the central nervous system, where they release an anti-inflammatory messenger substance,” says Pröbstel. “That could explain why the illness worsens if these immune cells are removed from the blood with medication.”
In the hopes of determining what these gut immune cells were doing in the brain, the team then looked to see what kinds of molecules the IgA antibody reacted to. Recent research has provided evidence that an unhealthy gut microbiome plays a role in MS, when certain potentially damaging species of bacteria proliferate.
The authors found that “unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue.” This suggests that, unlike other immune cells, which are known to cause damage in MS, IgA-expressing immune cells play a protective role, possibly chasing these harmful bacteria to the brain and mounting a defense against them there.
These findings, the authors wrote, “establish gut microbiota–specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.”
What exactly activates the IgA B cells as helpers against MS and triggers their migration from the intestine to the central nervous system is still being investigated. “If we find the trigger for that, we could use it to treat MS,” says Pröbstel. For example, it may be conceivable to change the composition of the intestinal flora of MS sufferers in a targeted way in order to mobilize IgA B cells as helpers against inflammation in the nervous system.
“This opens up a whole new line of research,” says Pröbstel. “I think it has huge potential for therapeutics.”