b 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.

1 Comment Posted on February 17, 2014February 16, 2017 Multiple Sclerosis, Patient Talk

“Killer T cells” – a new way to fight Multiple Sclerosis. Read our interview with Gary Allen one of the test subjects for Prof Michael Pender MS research!

Gary Allen Multiple Sclerosis

PatientTalk.Org have just completed perhaps the most important interview in the blog’s history. Today we interview Mr Gary Allen. Gary has been a participant in some of the most encouraging research into multiple sclerosis for some years.

In the interview below Gary tells us about his multiple sclerosis and his role as a “guinea pig” in the research of Prof Michael Pender of the QIMR Berghofer Medical Research Institute. He tells how being part of the research has been significant improvements on his pain levels, feelings of fatigue and general cognition.

You can check out more about the research at http://msqld.org.au/homepage/latest-news/808-prof-pender-research-update

a) Please describe the story of your initial diagnosis and symptoms of MS?

I had what we now know was my first MS episode in 1994. I had terrible motion sickness and nausea, lost control of some of my facial muscles and had some reduced power in my legs. At the time there were a number of possible diagnoses, so when I recovered I got on with my life. It wasn’t until 2000 when I had another major episode that I was clinically diagnosed with relapsing remitting ms. In 2004 my MS went progressive.

b) How did the MS progress?

During the last 10 years my symptoms have… well, progressed. I slowly went from walking with a stick, to a crutch, to furniture walking and using a wheelchair for longer distances, to pretty much being in a wheelchair all the time, and then needing a hoist for transfers. I have no real touch or temperature sensation in my legs or arms. I also have intention tremors and lack of dexterity in my hands. My legs reached a point where they have very little voluntary movement but my involuntary reflex / spasms were ‘brisk’ (a term that doesn’t do it justice). The spasms can be painful and I had just started to experience the ‘lightning strike’ pain around my head before the treatment started. I also would get long periods of painful pins and needles in my hands and face. Looking back, I was really struggling with fatigue, concentration and cognition issues, which I didn’t notice because it crept up on me. All of which was impacting on my working life (I have continued to be very busy with two plus jobs… yes I am a self-confessed workaholic), time with my family and my social life.

c) Does the Queensland climate affect your MS?

Like many people living with MS, I have a certain degree of heat intolerance – so my symptoms become more pronounced as it gets hotter. Consequently Brisbane’s 68-82 degree F average in Summer and subtropical humidity can be a real challenge. At the age of 18 I moved from the grey and wet joys of England to Queensland, so you can imagine what a effortless transition in climate it was for me. <chuckle> Fortunately we have air conditioning at home so we can keep me reasonably cool.

d) Please can you introduce our readers to Prof Michael Pender’s treatment and research?

Back in 2004 (or thereabouts) Prof Pender theorised that the Epstein Barr virus (a common cause of glandular fever) was mutating the B cells of people with MS. As a consequence the virus was remaining in their systems – building up in the brain and spine. This was also responsible for the body attacking the brain and spine column causing the implication and damage associated with the progression of MS. More recently he’s been working with an oncology researcher at QIMR Berghofer Medical Research Institute. In 2013 Michael took 400ml of my blood, prompted it to develop ‘killer T Cells’ that eradicated EBV from my B cells. Because I was the ‘first human guinea pig’, they reinfused my cells over 4 visits in a 6 week period. Because I was first, we really had no idea of what to expect, but inside the first 2 weeks the results were astonishing.

e) How did you hear about it?

I donated some blood to Prof Pender’s research back in 2000. It turns out that I was an excellent candidate for the treatment (having lots of EBV infected cells and almost no EB antibodies). So in 2012 Michael visited me a couple of times to meet with me and my wife to discuss the treatment. It was something of a jump in the dark, with there not being any previous patients with MS receiving the treatment. The science looked excellent (I read research proposals for a living) but essentially it boiled down to: we think it will put a handbrake on the progression, but it might cause you to have a massive attack. Frankly 10 years into progression and no real treatment available, I had the attitude that it was well worth a punt. Looking back I am just so grateful for having had the opportunity, delighted we made the right decision, and very conscious of my responsibility to get the message out there that there is a light at the end of the tunnel for families struggling with progressive MS. I want to do what I can to help make a clinical trial a reality. The extra lumbar punctures and MRIs I’ve had to help collect data to make the case for a trial is the smallest of asks.

f) Can you describe the procedure to us?

It took around 4 weeks to ‘grow’ the killer T cells and do the lab testing. The cells were returned into my system via four infusions over a 6 week period. It was done this way so I could be closely monitored for adverse reactions / side effects. Following the treatment I returned to the ward several times for tests and neurological assessments. Next month I am due to have my (12 months on) lumbar puncture and MRI.

g) What were the outcomes negative and positive?

In less than 2 weeks we started seeing very positive outcomes. At first I was very conscious of the potential for the placebo effect, but the positives kept building, and have been sustained for a year. I have a remarkable change to my fatigue, cognition and memory. I have a significant improvement in pain levels (which is pretty much gone) and marked improvement in the size and duration of pins-and-needle discomfort. I saw a reduction in painful legs spasms and my intention tremor has in my left hand has reduced. I work as a policy officer at Griffith University and went from struggling through the delivery of three workshops a year to delivering one or two per week. I have a very nerdy indicator of the improvements: Prior to 2007 I could score up to 97 planes landed in the iPad game Flight Control. After 2007 I gave up playing because I couldn’t land more than 14. Two weeks after starting the treatment I got 117. In May last year I landed 561! At which point my wife gently observed that it might be time for a different challenge. 🙂 Last month my wife, son and I went on our first long holiday together in more than 10 years. I have the energy and enthusiasm to play with my boy. We’ve noticed some increase in voluntary movement in my legs – not much and we’re trying to work out now how much of that is because muscle shortening and atrophy. It was exciting when the scans and tests started to echo my lived experience. My MRI, (pre, during and post) went from showing four areas of my brain under attack to 2 and those 2 areas were 40% the size of what they were. The next scan results are going to be very interesting. I am yet to experience any side effect or negative outcome.

h) What do you think the future for the technique is?

MS Queensland is trying to raise AU$400,000 to conduct a clinical trial. That will provide more data about the effectiveness and safety of the treatment and is the first step in registering the testament with the Australian TGA. Ironically one of the of the things that attracted me to the treatment – the fact it involves no drug, no stem cells, just my own cells returned to me – also now is the funding challenge, there’s no drug for a pharmaceutical company to commercialise.

i) What is the prognosis of your multiple sclerosis?

Because I am the first guinea pig we have no idea how long this will last, whether it will need to be ‘topped up’ or what it means for my long-term prognosis. What I can say is that I have been blessed with an amazing year with no progression, some tangible improvements and perhaps the greatest gift of all: Hope.

j) Have you any advice for somebody just diagnosed with multiple sclerosis?

Oooo how much space do I have? <chuckle>. Perhaps 3 things:

There really is reason to hope. An effective treatment is within reach.
Keep up with your physio, stretches and working those muscles because you don’t want to be like me now wondering whether, if I’d practised what I’m preaching now, my legs maybe could be doing more.
Always remember that accepting help, whether it’s in the form of pain management or other medication, counselling, a wheelchair or whatever isn’t giving up or admitting how bad things might go for you… it’s just help, and if it means you can cope better or can go out and about, it’s worth it!

k) What is, in your view, the future of Prof Pender’s research?

Michael believes that the theory and treatment works for early diagnosis relapsing remitting patients – i.e. at some point soon it will stop the damage before it happens. Now if that doesn’t take your breath away I don’t know what will.

To help raise money for a clinical trial my wonderful wife Renay is conducting a short story competition where the entry fee is donated to the Society. Go to http://www.renayallen.com/community-2/ to find out more and to enter the competition.