Gut immune cells protect against multiple sclerosis

Gut immune cells protect against multiple sclerosis


Researchers have discovered that the intestine is the source of immune cells that reduce brain inflammation in people with multiple sclerosis (MS), and that increasing the number of these cells blocks inflammation entirely in a preclinical model of the disease.

The cells in question are plasma cells -- white blood cells that originate as B cells in the bone marrow but change their behavior when triggered by microbes in the gut. Studying mice and samples from human MS patients, the researchers found that plasma cells that reside in the gut and produce Immunoglobulin A (IgA) antibodies appear to migrate to the central nervous system and produce an anti-inflammatory effect during MS flare-ups.

MS is an autoimmune disease, driven by other types of immune cells (including B and T cells) that attack myelin, the protective coating that surrounds nerve fibers. Recent clinical studies have shown drugs that target B cells mitigate MS, while those that target plasma cells make the disease worse. The current study published in Cell offers an explanation for these divergent results.

"We already knew what was and was not working in the clinic," says the senior author on the study. "But here we've uncovered the molecular and cellular mechanism at play. It's a kind of reverse translation approach, which highlights the importance of the gut-brain axis in MS and other autoimmune conditions."

"IgAs comprise 80 per cent of all antibodies in the body, yet their exact function is still not fully understood," says a co-author on the paper. "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."


Authors show that IgA + PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse suggesting that the inflammation-suppressing cells had been recruited to help fight the patients' disease.

Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA + PC. Furthermore, mice with an over-abundance of IgA + PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. A therapeutic approach might aim to expand the number of these cells in the gut, enabling a plentiful supply that could move to the brain and dampen inflammation.

A key next step for the researchers is to figure out what microbes in the gut promote the generation of immunosuppressive IgA plasma cells. "If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut commensals," says the senior author, referring to the bacteria that live in the healthy gut. "That might be easier than getting drugs into the brain, which is a strategy that hasn't always worked in MS."

The study also raises questions about the microbiome and lifestyle choices. Do certain lifestyles nudge some people toward a gut microbiome that allows immunosuppressive plasma cells to flourish? Are specific foods conducive to creating that environment and if so, might a drug or supplement mimic the effect? Genetics are just one factor that affect susceptibility to MS; the current study highlights how non-genetic factors may confer disease resistance.

https://www.cell.com/cell/fulltext/S0092-8674(18)31560-5?_

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