Intestinal IgA-Producing B Cells Help Curb CNS Inflammation In MS

During a multiple sclerosis (MS) exacerbation, specific IgA-producing B cells in the intestines travel to inflamed sites in the central nervous system (CNS), exerting an anti-inflammatory effect, researchers say.

Principal author Dr. Sergio Baranzini of the University of California, San Francisco told Reuters Health that his group's previous work "described an unprecedented phenomenon in which IgA-producing cells from the gut migrated to the brain to dampen inflammation in an experimental (murine) model of MS called EAE. Here we wanted to test whether this process was also at play in humans with MS."

"We discovered that IgA-producing cells leave the gut and enter the CNS during an MS exacerbation. These cells produce IgA that can be found in the cerebrospinal fluid (CSF) and this could be a biomarker of neuroinflammation," he explained. "This IgA recognizes specific molecules present on the surface of certain gut bacteria, which reinforces the model that the gut and the brain are part of a functional continuum (gut-brain axis)."

"This is the first time that this process is being described in humans," he added. "We think a similar mechanism may operate in other neuroinflammatory diseases."

Nonetheless, he noted, "This is still basic research and immediate clinical use may be off the table."

As reported in Science Immunology, the team analyzed IgA and IgA-producing B cells in the gut, blood, CSF, and brain tissue of patients with MS and other neuroinflammatory diseases, such as neurosarcoidosis.

Among participants with clinically isolated syndrome or relapsing-remitting MS, 31 were in remission and 12, in relapse. All were treatment naive or off immunomodulatory treatment for more than six months.

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Analyses of stool samples showed that MS patients have IgA-producing B cells in their intestines that are specific for MS-associated taxa, and that these cells traffic to the inflamed CNS.

Further analyses showed that IgA-positive B cells accumulated in the cerebrospinal fluid and brain tissue of MS patients within acute sites of inflammation, releasing an anti-inflammatory substance. Notably, the CNS-infiltrating IgA-positive B cells recognized gut microbia but not brain antigens, suggesting these cells originate from the gut.

In addition, more patients had gut microbiota - reactive IgA in the CSF during relapsing MS (80%) compared with remission, as well as in patients with active neurosarcoidosis but not those with neurodegenerative disease or controls.

Summing up, the authors state, "We propose that our study establishes gut microbiota-specific IgA-producing cells as a major constituent of the active immune response in MS with broad implications for the role of antigen-specific IgA responses in (neuro)inflammatory diseases and for the development of therapeutic strategies that potentially harness this anti-inflammatory gut-brain immune axis."

Dr. Baranzini said, "Identifying exactly what these cells are doing the in the brain will be important step towards fully understanding how MS establishes and perpetuates an inflammatory state in the brain."

Dr. Benjamin Segal, Chair and Professor, Department of Neurology, Director, The Neuroscience Research Institute and Co-Director, The Neurological Institute at The Ohio State Wexner Medical Center in Columbus, commented in an email to Reuters Health, "The study breaks new ground in that compares the patterns of IgA binding to bacterial strains in fecal samples from individuals with MS and healthy controls, as well as other neuroinflammatory conditions."

Participants were treatment-naïve or off treatment for more than six months prior to sample collection, he noted, "which avoids artifacts introduced by the impact of pharmaceutical agents on immune responses and, hence, the microbiota."

"While the study is compelling, only future research will definitively determine the biological properties of CNS-infiltrating IgA-positive plasma cells and their impact on disease," he said. "Of note, IgA levels rose in the CSF during relapses, not remissions. Therefore, if CNS-infiltrating IgA-positive B cells and plasma cells are playing a beneficial role, their effect would have to be delayed."

"In general, B cell-depleting therapies reduce circulating B cells to undetectable levels, and are highly effective in suppressing clinical MS relapses and new lesion formation," he said. "It will be interesting to determine if those therapies spare IgA-positive B cells, as well as plasma cells, that have already infiltrated the CNS."

"In future research," he added, "it would also be of interest to analyze IgA-bound bacteria in the gut, and IgA-producing B cells in the cerebrospinal fluid, obtained from the same MS patients during relapses versus remissions. By providing internal controls, this approach would eliminate potentially confounding variables such as genetic and dietary differences."

—Marilynn Larkin

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