b cells

Posted on May 17, 2024May 17, 2024 Multiple Sclerosis

Wow! B cells drive responses of other immune cells and can be modified to prevent Multiple Sclerosis symptoms.

Immune cell interactions driving MS attacks. CREDIT Penn Medicine

B cells can control the responses of myeloid cells through the release of particular cytokines (small proteins that control the growth and activity of cells in the immune system), challenging the prevailing view that T cells are the principal orchestrators of immune responses. In individuals with Multiple Sclerosis (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 fibres and leading to nerve damage that causes symptoms of MS.

An emerging class of drugs, Bruton’s tyrosine kinase (BTK) inhibitors, may alter this abnormal B cell respiration and stop the signalling leading to MS flare-ups.

“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,” said Amit Bar-Or, MD, a professor of Neurology and director of Penn’s Center for Neuroinflammation and Neurotherapeutics. “This 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.”

A healthy immune system always responds to stimuli by activating or suppressing immune responses, partly through the release of different cytokines which 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 that the response does not become overactive and cause damage to the body, as might occur in an autoimmune disease like MS.

In this study, researchers used both human samples and mouse models of MS to show that not only does the cytokine signalling 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 that 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 in myeloid cells, telling them to produce a pro- or anti-inflammatory response. However, when this B cell metabolism is over-active, as in MS, the signalling results in abnormal myeloid and T cell responses, which have been implicated in MS symptom flare-ups.

“An exciting approach for new MS treatments, then, might be to partially mute respiration in B cells, which could then stop the cascade of interactions between immune cells that drives inflammation and MS activity,” said Bar-Or.

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

Existing MS therapies, like anti-CD20 treatments, deplete B cells. However, since 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.

Posted on October 12, 2019October 12, 2019 Multiple Sclerosis

NEW RESEARCH COULD STOP MULTIPLE SCLEROSIS IN ITS TRACKS

Ms and guts

When a person has multiple sclerosis (MS), their immune system causes inflammation that affects parts of the central nervous system, including the brain. This can result in a variety of symptoms, ranging from fatigue and pain to loss of cognition and even paralysis.

We can’t currently cure MS, just slow it down — but a specific type of cell originating from the gut could change that.

Going Up

Based on previous studies, researchers already knew that certain plasma cells, also known as B cells, that produce the antibody Immunoglobulin A (IgA) can reduce inflammation in the brains of MS sufferers during flare-ups.

B cells among factors leading to brain lesions in multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. The body’s own immune cells attack and damage the layer that surrounds nerve cells in the brain and spinal cord, which affects their ability to communicate with each other. The disease, which affects around 2.5 million people worldwide, is a common cause of disability in young adults and affects women particularly often. MS can lead to severe neurological disabilities such as sensory problems, pain and signs of paralysis.

B cells activate T cells

A team led by neurologist Roland Martin and immunologist Mireia Sospedra at the University of Zurich (UZH), the University Hospital Zurich (USZ) and researchers at the Karolinska Institute in Sweden has now discovered a key aspect in the pathogenesis of MS. “We were able to show for the first time that certain B cells – the cells of the immune system that produce antibodies – activate the specific T cells that cause inflammation in the brain and nerve cell lesions,” says Roland Martin, Director of the Clinical Research Priority Program Multiple Sclerosis at UZH.

Novel MS drugs attack B cells

Until recently, MS research had mainly focused on T cells, or T helper cells. They are the immune system’s “guardians”, which for example sound the alarm if the organism is infected with a virus or bacteria. In about one in a 1,000 people, the cells’ ability to distinguish between the body’s own and foreign structures becomes disturbed. The effect of this is that the misguided T cells start to attack the body’s own nerve tissue – the onset of MS. However, the T cells aren’t the sole cause of this. “A class of MS drugs called Rituximab and Ocrelizumab led us to believe that B cells also played an important part in the pathogenesis of the disease,” explains Roland Martin. These drugs eliminate B cells, which very effectively inhibits inflammation of the brain and flare-ups in patients.

B cells’ “complicity” revealed

The researchers established the role of B cells by using an experimental in-vitro system that allowed blood samples to be analyzed. The blood of people with MS revealed increased levels of activation and cellular division among those T cells attacking the body’s myelin sheaths that surround nerve cells. This was caused by B cells interacting with the T cells. When the B cells were eliminated, the researchers found that it very effectively inhibited the proliferation of T cells. “This means that we can now explain the previously unclear mechanism of these MS drugs,” says Roland Martin.

Activated T cells migrate to the brain

Moreover, the team also discovered that the activated T cells in the blood notably included those that also occur in the brain in MS patients during flare-ups of the disease. It is suspected that they cause the inflammation. Further studies showed that these T cells recognize the structures of a protein that is produced by the B cells as well as nerve cells in the brain. After being activated in the peripheral blood, the T cells migrate to the brain, where they destroy nerve tissue. “Our findings not only explain how new MS drugs take effect, but also pave the way for novel approaches in basic research and therapy for MS,” concludes Roland Martin.

Posted on December 18, 2018December 18, 2018 Multiple Sclerosis

Researchers study the mechanisms that prevent autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis after an infection

Andre Ballesteros-Tato. UAB

The key weapon against viruses and bacteria that invade the body is production of antibodies, which act like guided missiles to attack and neutralize pathogens.

But as the body throws its effort into making ever-better antibodies during an infection, the random mutations that create those ever-stronger antibodies may also produce antibody-producing B cells that attack one’s own body, mistakenly triggering autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis.

André Ballesteros-Tato, Ph.D., assistant professor, University of Alabama at Birmingham Department of Medicine, likens those mistaken autoimmune attacks to the collateral damage that can happen in a wartime battle.

In research published in Nature Immunology, Ballesteros-Tato and colleagues used mice to study regulatory mechanisms in the immune system that prevent autoimmune disease. Using an influenza infection model in mice, they have found that a particular population of immune cells developed during the later stages of the immune response to the influenza infection. These cells, called T follicular regulatory cells, or TFR cells, subsequently prevented the generation of self-reactive antibody responses. At the same time, they did not affect the influenza-specific immune reaction.

“This research gives us clues of what to look for when we look at how autoimmune disease develops,” Ballesteros-Tato said.

Study details

TFR cells are poorly understood compared with the more common T regulatory, or Treg, cells, which act to shut down or suppress immunity at the end of an immune reaction. The UAB team found that the two types behaved differently during influenza infections of mice.

As is well-known, the signaling molecule interleukin 2, or IL-2, has elevated levels as the immune response begins, and IL-2 stimulates the development of the conventional Treg cells. In the mice, these cells reached their peak one week after infection. In contrast, the UAB researchers found that IL-2 signaling inhibited, rather than promoted, the development of TFR cells during the peak of the immune response in mice. This inhibition used a mechanism that depended on the Blimp1 transcriptional repressor. Blimp1 prevented expression of the Bcl-6 master transcription factor, precluding TFR cell development.

When the influenza virus was eliminated and IL-2 levels were falling, some Treg cells downregulated the expression of CD25, which is part of the IL-2 receptor on the surface of Treg cells. Those cells upregulated the Bcl-6 master transcription factor and differentiated into TFR cells, reaching their peak numbers 30 days after infection. The TFR cells migrated to follicles of the lymph nodes, where antibody-producing B cells are known to proliferate and mutate their antibody genes to create ever-stronger antibodies.

In the follicles, the TFR cells prevented the accumulation of B cell variants that had mistakenly mutated to make antibodies that could attack the body’s own cells. The TFR cells did not reduce the immune response against the influenza virus. Experimental methods that removed the TFR cells or prevented their development allowed expansion of B cells that made anti-self antibodies, as measured by anti-nuclear antibodies.

“In summary,” Ballesteros-Tato and colleagues wrote in the paper, “our data demonstrate that IL-2 signaling temporarily inhibits TFR cell responses during influenza infection. However, once the immune response is resolved, TFR cells differentiate and migrate to B cell follicles, where they are required for maintaining B cell tolerance after infection. Thus, the same mechanism that promotes conventional Treg cell responses, namely IL-2 signaling, also prevents TFR cell formation.

Posted on November 10, 2018November 10, 2018 Multiple Sclerosis

Multiple sclerosis: Accumulation of B cells triggers nervous system damage

Stem cells and multiple sclerosis

B cells are important in helping the immune system fight pathogens. However, in the case of the neurological autoimmune disease Multiple Sclerosis (MS) they can damage nerve tissue. When particular control cells are missing, too many B cells accumulate in the meninges, resulting in inflammation of the central nervous system. A team from the Technical University of Munich (TUM) demonstrated the process using animal and patient samples.

The fight against illnesses and pathogens requires activation or deactivation of a large number of different cell types in our immune system at the right place and the right time. In recent years certain immune cells, the myeloid-derived suppressor cells (MDSCs), have been receiving increasing attention in this context. They function as an important control mechanism in the immune system and make sure that immunoreactions do not become too strong.

Impacts of the loss of control

In the case of MS these controls in the nervous system appear to fail in part. Together with his team, Thomas Korn, Professor for Experimental Neuroimmunology at the TUM Neurology Clinic, succeeded in demonstrating this in a study published in the journal Nature Immunology. During MS the body attacks its own nerve tissue, resulting in damage and inflammations. This can in turn lead to paralysis as well as vision and movement disorders.

“We were primarily interested in the control effect of the MDSCs on the B cells. Their function in the occurrence of MS is not yet clear. But they appear to play an important role, something we wanted to take a closer look at,” says Korn, explaining the study’s objective. B cells can develop into cells which produce antibodies, but they can also activate other immune cells by secreting immune messengers. Korn and his team used a mouse model in which the inflammatory disease can be triggered and develops much the same way as in the human body.

MDSCs influence the B cell count

The team removed the MDSCs from the meningeal tissue and then observed an increase in the accumulation of B cells there. At the same time inflammations and damage occurred, triggered by the high number of B cells in the nerve tissue. This phenomenon did not occur when enough MDSCs were present, controlling the number of B cells.

In the future Korn and his team want to explain how the B cells destroy the nervous system. According to the researcher there are two possibilities: In the meninges B cells emit substances which attract immune cells that then incorrectly destroy the body’s own tissues; or, B cells activate immune cells in the blood and lymph systems which then move to the meninges, where they cause damage.

Patient tests confirm results

Based on 25 tests of the cerebrospinal fluid (CSF) of subjects with MS, the lack of MDSCs could also have a negative effect on the course of the illness in patients. When the researchers found large numbers of MDSCs in CSF, the patients usually also experienced milder symptoms with fewer episodes of inflammation. In contrast, patients with lower MDSC counts experienced stronger symptoms. “There are already approved therapies in which B cells are regulated and suppressed on a medicinal basis. Now we’ve provided an explanation of why this could be an effective treatment, at least in cases where the course of the disease is poor,” says Korn. Since the number of subjects tested in this case was small, he and his team are planning larger patient studies for the future.

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