A new study identifies how cytokines are metabolically regulated in B cells. It identifies adenosine triphosphate and its metabolites as a “fourth signal” that shapes B cell responses. These findings suggest oxidative phosphorylation may be a potential target for the treatment of multiple sclerosis.

B cells can control responses of myeloid cells through the release of particular small proteins that control the growth and activity of cells in the immune system, cytokines, and challenging the prevailing view that T cells are the principal orchestrators of immune responses. In individuals with MS, abnormally active respiration in B cells drives pro-inflammatory responses of myeloid cells and T cells, leading them to attack the protective sheath, myelin, that covers nerve fibers, and leading to nerve damage that causes symptoms of MS. An emerging class of drugs, called Bruton’s tyrosine kinase inhibitors may alter this abnormal B cell respiration and stop the signaling that leads to MS flare-ups.

According to researchers at the Perelman School of Medicine at the University of Pennsylvania, experts previously thought T cells were the main orchestrators of responses by other immune cell types, and MS was principally caused by overly activated T cells. The current research highlights 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 was thought.

A healthy immune system is always responding to stimuli by activating or suppressing immune responses, in part through release of different cytokines that tell other cell types how to respond. Normally, every immune response generates a counter response, and this constant “push-me-pull-you” helps maintain the proper balance between immune responses. This way, an individual's immune system can, on one hand, respond to an infection but also ensure the response does not become overactive and cause damage to the body, as might occur in an autoimmune disease such as MS.

In this study, researchers used both human samples and mouse models of MS to show not only does the cytokine signaling between B cells and T cells go awry in MS, but also that B cells of MS patients produce an abnormal cytokine profile that drives myeloid cells to generate an inflammatory response.

They found these actions can all be traced back to metabolic dysregulation in a process within the B cells called oxidative phosphorylation, a type of mitochondrial respiration. Researchers found that normal B cells can break down oxygen and release chemical energy signals that illicit a further response in the B cells themselves, and subsequently also in myeloid cells, telling them to produce an anti- or proinflammatory response. However, when this B cell metabolism is over-active, as it is in MS, the signaling results in abnormal myeloid as well as T cell responses that have been implicated in MS symptom flare-ups.

The authors further showed an emerging class of drugs, called BTK inhibitors, slow overactive B cell respiration and “calm down” B cells of MS patients, so they don’t release the same abnormal cytokine profile that drives abnormal proinflammatory myeloid cell and T cell responses.

Existing MS therapies, such as anti-CD20 treatments, deplete B cells. However, because B cells are eliminated, the individual’s immune system may be compromised, struggling to mount certain immune responses – for example antibody responses to infections or vaccinations. In contrast, BTK inhibitors do not deplete B cells, but correct the metabolic abnormality, making the B cells less prone to drive pro-inflammatory responses of other cells.

The findings were published in Science Immunology.