New Subset of Regulatory B-cells May Help MS, Mouse Study Shows

Treatment with a newly discovered subset of regulatory B-cells (Bregs) — a type of immune cell that dampens immune responses — significantly reduced symptoms in a mouse model of multiple sclerosis (MS), a study shows.

Similar effects were observed in a mouse model of uveitis, an inflammatory eye disease triggered by infections or autoimmune responses.

In both models, these benefits were associated with the suppression of pro-inflammatory immune cells linked with autoimmune diseases and an increase in other subsets of Bregs.

These findings suggest that this immunosuppressive Breg subset, which produces a molecule called IL-27, may be an effective therapeutic approach for MS and other autoimmune diseases, the researchers noted.

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“We are the first to describe this unique population of regulatory B cells,” called i27-Breg, Charles Egwuagu, PhD, the study’s senior author and the director of the National Eye Institute (NEI)’s Molecular Immunology Section at the National Institutes of Health, said in a press release.

“While similar in function to other Bregs, I27-Breg have a distinct gene expression profile” and origin, Egwuagu added.

The study, “IL-27–producing B-1a cells suppress neuroinflammation and CNS autoimmune diseases,” was published in the journal PNAS.

The body’s inflammatory and immune responses are kept in check by regulatory immune cells, such as Bregs, which work by suppressing the activity of other immune cells. These regulatory cells also control immune responses against the body’s own molecules, which is key in preventing autoimmune reactions.

Bregs were previously shown to exert their functions through the production of IL-10 and IL-35, two anti-inflammatory molecules. IL-35-producing Bregs (i35-Breg) were identified in 2014 by Egwuagu and his team, which also found that these cells suppressed central nervous system (CNS) autoimmune disease by promoting the expansion of IL-10-producing Bregs. (CNS comprises the brain and spinal cord.)

Now, Egwuagu’s team, along with colleagues at NEI, identified a new subset of Bregs that produce IL-27, a molecule with both pro- and anti-inflammatory effects, depending on cellular context. These cells were detected in the abdomen of mice and in human umbilical cord blood and differed from other Bregs in both their molecular signature and origin.

Particularly, while Bregs identified to date are largely antigen-specific and derive mainly from an adaptive B2-cell lineage, i27-Bregs were derived from an innate B-1a cell lineage.

Put simply, each person is born with a set of innate immune cells that comprise the first responders to any type of threat, while adaptive immunity is acquired when some immune cells are exposed to specific antigens, or molecules with the potential to trigger an immune response.

The researchers found that upon stimulation with an innate immune stimulus, i27-Bregs moved from the abdominal cavity to sites where immune cells gather to mount responses against potential threats.

The treatment was then found to be effective in suppressing autoimmunity. In mouse models of MS and autoimmune uveitis, i27-Bregs lessened disease symptoms, which was associated with a suppression of Th17/Th1 cells — pro-inflammatory immune T-cells known to contribute to MS and other CNS autoimmune diseases.

Treatment also resulted in the propagation of inhibitory signals that converted conventional B-cells, involved in mounting immune responses, to immunosuppressive Bregs that produced IL-10 and/or IL-35 in the eye, brain, and spinal cord.

Further analysis showed that i27-Breg treatment was ineffective in mice lacking the IL-27 receptor, confirming that IL-27 is the key driver of i27-Breg’s beneficial effects in these autoimmune diseases.

I27-Bregs “can proliferate [grow] after they’re injected, unlike i35-Bregs, which stop dividing when mature,” Jin Kyeong Choi, PhD, the study’s first author and a former NEI postdoctoral fellow who is now at Jeonbuk National University in South Korea.

This new Breg subset was also found to sustain the production of IL-27 in the CNS and immune cell-rich sites, an advantage over treatments directly delivering IL-10 and IL-35 that are rapidly broken down by the body, the team noted.

As such, while i35-Bregs and i27-Bregs “have similar functions, i27-Breg may have greater therapeutic potential,” Choi said.

Moreover, and consistent with their innate origin, i27-Bregs’ immunosuppressive effects were neither antigen-specific nor disease-specific, suggesting that these cells would work as an “effective immunotherapy for a wide spectrum of autoimmune diseases,” the researchers wrote.

The team is now exploring the use of exosomes as potential carriers for delivering lab-grown IL-27 into the body, since such an approach would be less technically challenging than generating i27-Bregs in the lab, they said.

Exosomes are tiny fatty vesicles released by nearly every cell type to deliver molecules that act as messengers to regulate several cellular processes, such as immune and inflammatory responses.

Importantly, these vesicles can easily enter cells by merging with their membranes and also evade natural degradation processes, making make them strong, long-lasting carriers of therapeutic molecules.