Altered immune B-cell metabolism drives inflammation in MS: Study

An abnormally active metabolism in immune B-cells can trigger the release of pro-inflammatory signaling molecules that drive further inflammation in multiple sclerosis (MS), a study found.

Selectively blocking certain metabolic processes with a Bruton’s tyrosine kinase (BTK) inhibitor normalized B-cell metabolism and shifted their signaling to an anti-inflammatory state. In an MS mouse model, the treatment also reduced disease severity.

“An exciting approach for new MS treatments, then, might be to partially mute [metabolism] in B cells, which could then stop the cascade of interactions between immune cells that drives inflammation and MS activity,” study lead Amit Bar-Or, MD, professor of neurology at the University of Pennsylvania and director of Penn’s Center for Neuroinflammation and Neurotherapeutics, said in a university press release.

The study, “Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis,” was published in Science Immunology.

MS is caused by inflammation that damages parts of the brain and spinal cord, together known as the central nervous system. A number of immune cells are known to be involved in that immune-mediated damage, but T-cells were thought to be the main drivers of inflammation.

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T-cells had been thought ‘main orchestrators’ of inflammation in MS

“Experts previously thought that T cells were the main orchestrators of responses by other immune cell types, and that MS was principally caused by overly activated T cells,” Bar-Or said.

B-cells are immune cells best known for producing antibodies, but they can also secrete immune signaling molecules called cytokines that activate or suppress local immune responses.

In MS, an imbalance between the pro- and anti-inflammatory cytokines made by B-cells has been shown to activate pro-inflammatory T-cells and another class of immune cells called myeloid cells. However, little is known about the mechanisms regulating the balance between these cytokines, particularly those that affect local myeloid cell responses.

A team of researchers led by Bar-Or showed that human B-cells secreting a pro-inflammatory cytokine called CM-CSF, which activates myeloid cells, had considerably higher metabolic activity compared with B-cells that release interleukin-10 (IL-10), an anti-inflammatory cytokine that suppresses myeloid cells. B-cells that secreted GM-CSF also had more mitochondria, the structures in cells that produce energy.

This higher metabolic activity in B-cells releasing GM-CSF was due to an increase in oxidative phosphorylation (OXPHOS), a metabolic pathway that uses nutrients to produce energy in the form of adenosine triphosphate (ATP). Partially blocking OXPHOS during B-cell activation led to an anti-inflammatory state.

Researchers carried out a series of experiments using a molecule that selectively blocks BTK, an enzyme essential for B-cell survival and activation. Several molecules that inhibit BTK, including tolebrutinib and fenebrutinib, are being developed for MS.

Tests showed that the BTK inhibitor decreased the elevated OXPHOS in activated B-cells while reducing the production of GM-CSF, resulting in a significantly decreased ratio of GM-CSF over IL-10.

Elevated OXPHOS was also detected in B-cells isolated from untreated MS patients compared with age- and sex-balanced healthy controls, and BTK inhibition reversed and normalized these metabolic abnormalities.

In a mouse model of MS, lowering B-cell OXPHOS also decreased clinical severity and tissue damage. At the same time, the levels of GM-CSF-producing B-cells were reduced, while B-cells that produced IL-10 were increased.

Looking more closely, the team found that ATP and its metabolites bound to receptors on the surface of B-cells and modulated the balance between pro- and anti-inflammatory cytokine production. This finding represented a new type of signaling, in addition to three well-established B-cell signaling pathways, the researchers noted.

“Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a ‘fourth signal’ that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases,” the researchers wrote.

The research “highlights that it is actually how multiple cell types interact that matters, and that B cells modulating myeloid cells play a much more active role in the immune system than we thought,” Bar-Or said.