Gut Cells Linked To Positive Immune Response In MS

By Randy Dotinga

Neuroinflammation appears to trigger gut cells to enhance levels of the antibody IgA and send it to the rescue via human spinal fluid, a new study finds. Researchers believe this insight could lead to advances in the diagnosis and treatment of multiple sclerosis (MS).

Dr. Egle Cekanaviciute (left) and Dr. Sergio Baranzin.
Photo by Steve Babuljak
“The increase in IgA production can be used as a biomarker of inflammation and help diagnose MS, a state of enhanced inflammation, or an attack,” study corresponding author Sergio E. Baranzini, PhD, of the University of California, San Francisco, said in an interview. “If we identify what these cells are recognizing, and that has a direct relationship to a particular group of bacteria, we might be able to intervene and reduce the bad players or enhance the good players.”

The study, written by an international team of researchers, appears in Science Immunology.

As the researchers noted, IgA is the most common antibody isotype in people and helps to keep intestinal bacteria in balance. “Gut germs are not simple bystanders in our bodies,” Dr. Baranzini said. “We use bacteria to perform certain metabolic functions that humans cannot perform. Sometimes the balance of different bacterial species gets disrupted, and this promotes different types of immune responses in the host that ultimately lead to chronic conditions.”

Researchers have been able to trigger a disease similar to MS in mice by transferring bacteria from the guts of people with the disorder, he said. And the disease in mice is more aggressive than in the mice that received bacteria from patients without MS.

Exploring the gut-brain connection

Dr. Baranzini took part in a 2019 University of Toronto study published in Cell that provided more insight into the connections between gut bacteria and MS. In mice who developed a disease similar to MS, he said, “a cell population that is responsible for producing IgA in the gut enters the circulation and goes into the brain. This was completely unexpected. The hypothesis is that these cells enter the brain in order to help with the inflammatory process.”

For the new study, Dr. Baranzini and colleagues sought to determine if IgA-producing cells play a similar role in humans with MS. They measured taxa-specific IgA coating in fecal specimens from patients with MS – 25 in remission and 11 in relapse. The patients hadn’t received treatment for MS or had not received it for at least 6 months. Researchers also examined specimens from 31 healthy controls.

“The proportion of differential IgA-bound operational taxonomic units was significantly higher in patients with MS, compared with controls,” the resarchers reported.

An analysis of cerebrospinal fluid (CSF) in a similar population found elevated levels of IgA levels during relapsed MS. “Further,” the authors wrote, “we found CSF IgA levels to be significantly higher in active MS in comparison with neurodegenerative and healthy controls, which was also the case in active neurosarcoidosis, another autoimmune neuroinflammatory disease, compared with the respective inactive disease state and controls.”

The researchers add that “these findings suggest that IgA-producing B cells either traffic to the CNS or preferentially augment local IgA production during active neuroinflammation.”

Top image credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Image credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health

A compensatory mechanism

Dr. Baranzini highlighted a recent study published in Nature that found that another link between gut, IgA-secreting cells, and the brain: It found that “perisinus IgA plasma cells increased with age and following a breach of the intestinal barrier,” and it reported that “meningeal IgA is essential for defending the central nervous system” at a vulnerable spot.

The influx of IgA is positive, Dr. Baranzini said. “These cells appear to have a neuroregulatory function and are recruited into the central nervous system to help control the inflammatory process through the secretion of an anti-inflammatory molecule. This is what you want. What we’re describing is potentially a compensatory mechanism: It’s not part of the problem. It’s part of the solution.”

Dr. Sergio Baranzini speaks with postdoctoral scholar Dr. Egle Cekanaviciute in his lab at UCSF Mission Bay.
Credit: Photo by Steve Babuljak
Questions remain to be resolved, he said. “We don’t know if these are the only players that are rushing to the scene. But certainly these were not expected players. They’re completely surprising players of the immune system since they have to travel a lot from the gut to the brain to do their thing. There are many other cells in the circulation that could go and help. Why are these cells being called upon? We still don’t know.”

The study was funded by numerous grants from various sources. Dr. Baranzini reported no disclosures.