Targeting Gut Immune Cells May Alleviate Brain Inflammation in MS, Study Suggests

These findings were reported in the study, “Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10,” published in the journal Cell.

In MS, immune cells in the central nervous system attack myelin — the protective sheath around nerve fibers that is critical to an efficient conduction of electrical impulses between the brain and other parts of the body.

Recent clinical trials targeting different immune cell types in MS patients have shown contrasting results. When immune cells called B-cells are targeted, MS is alleviated; however, when different immune cells called plasma cells (white blood cells from the bone marrow that also originate as B-cells, but change their behavior upon contact with microbes in the gut) are targeted, the symptoms increase. This suggests that plasma cells may be playing a suppressive role against autoimmunity in MS.

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However, it is unclear how plasma cells can suppress inflammation.

For these reasons, researchers at the University of Toronto (U of T) and University of California, San Francisco (UCSF) analyzed samples from MS patients and a mouse model of the disorder (called an experimental autoimmune encephalomyelitis mouse model, or EAE) to identify the origin and role of these plasma cells.

Jennifer Gommerman and Olga Rojas, University of Toronto. Credit: Jim Oldfield

The team found that plasma cells present in the intestine (gut) can travel to the central nervous system (brain) and produce an anti-inflammatory effect through the production of an antibody called immunoglobulin A (IgA).

“We’ve uncovered the molecular and cellular mechanism at play,” Jennifer Gommerman, PhD, senior author of the study and professor of immunology at U of T, said in a U of T news release written by Jim Oldfield and Nicholas Weiler.

According to Gommerman, the result “highlights the importance of the gut-brain axis in multiple sclerosis and other autoimmune conditions.”

“IgAs comprise 80 per cent of all antibodies in the body, yet their exact function is still not fully understood. Showing that IgA-producing B-cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases, and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders,” said Sergio Baranzini, PhD, one of the study’s co-authors and a professor of neurology at UCSF.

The team confirmed their finding in fecal samples from MS patients with active brain inflammation. They found that, in these patients, IgA levels were decreased compared with samples from patients without active neuroinflammation, suggesting that inflammation-suppressing cells had migrated from the gut to help fight the disease in the brain.

Then, the researchers tested whether changing IgA levels in EAE mice with active brain inflammation influenced the autoimmune response. They found that increasing the number of IgA-producing plasma cells that are able to travel from the gut to the central nervous system in mice eliminated brain inflammation and the autoimmune response.

According to the team, these results pave the way for a therapeutic approach that increases the levels of plasma cells able to travel to the central nervous system to block inflammation.

“As a clinician-scientist, it is exciting that our experiments linking preclinical animal models to the biology we see in real multiple sclerosis patients may have uncovered a general mechanism for how the immune system counteracts inflammation,” said Anne-Katrin Pröbstel, PhD, a study co-author, from UCSF.

“Until now, no one has really studied these IgA-producing plasma cells in the context of disease, but we are now examining them in detail in patients with MS to begin to understand how we might manipulate them to help treat neuroinflammatory disease,” Pröbstel added.

One of the next steps for the team is to determine which microbes in the gut trigger the generation of IgA-producing plasma cells.

“If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut [bacteria],” Gommerman said. “There is something very critical about how the gut and brain are connected, and we’re starting to unravel the molecular threads behind that clinical observation.”