Posts Tagged ‘immune system’

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By Moises Velasquez-Manoff

The man was 23 when the delusions came on. He became convinced that his thoughts were leaking out of his head and that other people could hear them. When he watched television, he thought the actors were signaling him, trying to communicate. He became irritable and anxious and couldn’t sleep.

Dr. Tsuyoshi Miyaoka, a psychiatrist treating him at the Shimane University School of Medicine in Japan, eventually diagnosed paranoid schizophrenia. He then prescribed a series of antipsychotic drugs. None helped. The man’s symptoms were, in medical parlance, “treatment resistant.”

A year later, the man’s condition worsened. He developed fatigue, fever and shortness of breath, and it turned out he had a cancer of the blood called acute myeloid leukemia. He’d need a bone-marrow transplant to survive. After the procedure came the miracle. The man’s delusions and paranoia almost completely disappeared. His schizophrenia seemingly vanished.

Years later, “he is completely off all medication and shows no psychiatric symptoms,” Dr. Miyaoka told me in an email. Somehow the transplant cured the man’s schizophrenia.

A bone-marrow transplant essentially reboots the immune system. Chemotherapy kills off your old white blood cells, and new ones sprout from the donor’s transplanted blood stem cells. It’s unwise to extrapolate too much from a single case study, and it’s possible it was the drugs the man took as part of the transplant procedure that helped him. But his recovery suggests that his immune system was somehow driving his psychiatric symptoms.

At first glance, the idea seems bizarre — what does the immune system have to do with the brain? — but it jibes with a growing body of literature suggesting that the immune system is involved in psychiatric disorders from depression to bipolar disorder.

The theory has a long, if somewhat overlooked, history. In the late 19th century, physicians noticed that when infections tore through psychiatric wards, the resulting fevers seemed to cause an improvement in some mentally ill and even catatonic patients.

Inspired by these observations, the Austrian physician Julius Wagner-Jauregg developed a method of deliberate infection of psychiatric patients with malaria to induce fever. Some of his patients died from the treatment, but many others recovered. He won a Nobel Prize in 1927.

One much more recent case study relates how a woman’s psychotic symptoms — she had schizoaffective disorder, which combines symptoms of schizophrenia and a mood disorder such as depression — were gone after a severe infection with high fever.

Modern doctors have also observed that people who suffer from certain autoimmune diseases, like lupus, can develop what looks like psychiatric illness. These symptoms probably result from the immune system attacking the central nervous system or from a more generalized inflammation that affects how the brain works.

Indeed, in the past 15 years or so, a new field has emerged called autoimmune neurology. Some two dozen autoimmune diseases of the brain and nervous system have been described. The best known is probably anti-NMDA-receptor encephalitis, made famous by Susannah Cahalan’s memoir “Brain on Fire.” These disorders can resemble bipolar disorder, epilepsy, even dementia — and that’s often how they’re diagnosed initially. But when promptly treated with powerful immune-suppressing therapies, what looks like dementia often reverses. Psychosis evaporates. Epilepsy stops. Patients who just a decade ago might have been institutionalized, or even died, get better and go home.

Admittedly, these diseases are exceedingly rare, but their existence suggests there could be other immune disorders of the brain and nervous system we don’t know about yet.

Dr. Robert Yolken, a professor of developmental neurovirology at Johns Hopkins, estimates that about a third of schizophrenia patients show some evidence of immune disturbance. “The role of immune activation in serious psychiatric disorders is probably the most interesting new thing to know about these disorders,” he told me.

Studies on the role of genes in schizophrenia also suggest immune involvement, a finding that, for Dr. Yolken, helps to resolve an old puzzle. People with schizophrenia tend not to have many children. So how have the genes that increase the risk of schizophrenia, assuming they exist, persisted in populations over time? One possibility is that we retain genes that might increase the risk of schizophrenia because those genes helped humans fight off pathogens in the past. Some psychiatric illness may be an inadvertent consequence, in part, of having an aggressive immune system.

Which brings us back to Dr. Miyaoka’s patient. There are other possible explanations for his recovery. Dr. Andrew McKeon, a neurologist at the Mayo Clinic in Rochester, Minn., a center of autoimmune neurology, points out that he could have suffered from a condition called paraneoplastic syndrome. That’s when a cancer patient’s immune system attacks a tumor — in this case, the leukemia — but because some molecule in the central nervous system happens to resemble one on the tumor, the immune system also attacks the brain, causing psychiatric or neurological problems. This condition was important historically because it pushed researchers to consider the immune system as a cause of neurological and psychiatric symptoms. Eventually they discovered that the immune system alone, unprompted by malignancy, could cause psychiatric symptoms.

Another case study from the Netherlands highlights this still-mysterious relationship. In this study, on which Dr. Yolken is a co-author, a man with leukemia received a bone-marrow transplant from a schizophrenic brother. He beat the cancer but developed schizophrenia. Once he had the same immune system, he developed similar psychiatric symptoms.

The bigger question is this: If so many syndromes can produce schizophrenia-like symptoms, should we examine more closely the entity we call schizophrenia?

Some psychiatrists long ago posited that many “schizophrenias” existed — different paths that led to what looked like one disorder. Perhaps one of those paths is autoinflammatory or autoimmune.

If this idea pans out, what can we do about it? Bone marrow transplant is an extreme and risky intervention, and even if the theoretical basis were completely sound — which it’s not yet — it’s unlikely to become a widespread treatment for psychiatric disorders. Dr. Yolken says that for now, doctors treating leukemia patients who also have psychiatric illnesses should monitor their psychiatric progress after transplantation, so that we can learn more.

And there may be other, softer interventions. A decade ago, Dr. Miyaoka accidentally discovered one. He treated two schizophrenia patients who were both institutionalized, and practically catatonic, with minocycline, an old antibiotic usually used for acne. Both completely normalized on the antibiotic. When Dr. Miyaoka stopped it, their psychosis returned. So he prescribed the patients a low dose on a continuing basis and discharged them.

Minocycline has since been studied by others. Larger trials suggest that it’s an effective add-on treatment for schizophrenia. Some have argued that it works because it tamps down inflammation in the brain. But it’s also possible that it affects the microbiome — the community of microbes in the human body — and thus changes how the immune system works.

Dr. Yolken and colleagues recently explored this idea with a different tool: probiotics, microbes thought to improve immune function. He focused on patients with mania, which has a relatively clear immunological signal. During manic episodes, many patients have elevated levels of cytokines, molecules secreted by immune cells. He had 33 mania patients who’d previously been hospitalized take a probiotic prophylactically. Over 24 weeks, patients who took the probiotic (along with their usual medications) were 75 percent less likely to be admitted to the hospital for manic attacks compared with patients who didn’t.

The study is preliminary, but it suggests that targeting immune function may improve mental health outcomes and that tinkering with the microbiome might be a practical, cost-effective way to do this.

Watershed moments occasionally come along in medical history when previously intractable or even deadly conditions suddenly become treatable or preventable. They are sometimes accompanied by a shift in how scientists understand the disorders in question.

We now seem to have reached such a threshold with certain rare autoimmune diseases of the brain. Not long ago, they could be a death sentence or warrant institutionalization. Now, with aggressive treatment directed at the immune system, patients can recover. Does this group encompass a larger chunk of psychiatric disorders? No one knows the answer yet, but it’s an exciting time to watch the question play out.

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Researchers have identified a brand new ‘micro-organ’ inside the immune system of mice and humans – the first discovery of its kind for decades – and it could put scientists on the path to developing more effective vaccines in the future.

Vaccines are based on centuries of research showing that once the body has encountered a specific type of infection, it’s better able to defend against it next time. And this new research suggests this new micro-organ could be key to how our body ‘remembers’ immunity.

The researchers from the Garvan Institute of Medical Research in Australia spotted thin, flat structures on top of the immune system’s lymph nodes in mice, which they’ve dubbed “subcapsular proliferative foci” (or SPFs for short).

These SPFs appear to work like biological headquarters for planning a counter-attack to infection.

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Immune cells gathering at the SPF, with the purple band showing the SPF surface.

These SPFs only appear when the mice immune systems are fighting off infections that have been encountered before.

What’s more, the researchers detected SPFs in human lymph nodes too, suggesting our bodies react in the same way.

“When you’re fighting bacteria that can double in number every 20 to 30 minutes, every moment matters,” says senior researcher Tri Phan. “To put it bluntly, if your immune system takes too long to assemble the tools to fight the infection, you die.”

“This is why vaccines are so important. Vaccination trains the immune system, so that it can make antibodies very rapidly when an infection reappears. Until now we didn’t know how and where this happened.”

Traditional microscopy approaches analyse thin 2D slices of tissue, and the researchers think that’s why SPFs haven’t been spotted before – they themselves are very thin, and they only appear temporarily.

In this case the team made the equivalent of a 3D movie of the immune system in action, which revealed the collection of many different types of immune cell in these SPFs. The researchers describe them as a “one-stop shop” for fighting off remembered infections, and fighting them quickly.

Crucially, the collection of immune cells spotted by the researchers included Memory B type cells – cells which tell the immune system how to fight off a particular infection. Memory B cells then turn into plasma cells to produce antibodies and do the actual work of tackling the threat.

“It was exciting to see the memory B cells being activated and clustering in this new structure that had never been seen before,” says one of the team, Imogen Moran.

“We could see them moving around, interacting with all these other immune cells and turning into plasma cells before our eyes.”

According to the researchers, the positioning of the SPF structures on top of lymph nodes makes them perfectly positioned for fighting off infections – and fast.

They’re strategically placed at points where bacteria would invade, and contain all the ingredients required to keep the infection at bay.

Now we know how the body does it, we might be able to improve vaccine techniques – vaccines currently focus on making memory B cells, but this study suggests the process could be made more efficient by also looking at how they transform into plasma cells through the inner workings of an SPF.

“So this is a structure that’s been there all along, but no one’s actually seen it yet, because they haven’t had the right tools,” says Phan.

“It’s a remarkable reminder that there are still mysteries hidden within the body – even though we scientists have been looking at the body’s tissues through the microscope for over 300 years.”

The research has been published in Nature Communications.

https://www.sciencealert.com/researchers-identify-new-lymph-node-structures-powering-immunity

Crohn’s disease is a long-term condition that causes inflammation of the lining of the digestive system, and results in diarrhoea, abdominal pain, extreme tiredness and other symptoms that significantly affect quality of life.

Current treatments include drugs to reduce inflammation but these have varying results, and surgery is often needed to remove the affected part of the bowel. In extreme cases, after multiple operations over the years, patients may require a final operation to divert the bowel from the anus to an opening in the stomach, called a stoma, where stools are collected in a pouch.

Chief investigator Professor James Lindsay from Queen Mary’s Blizard Institute and a consultant at Barts Health NHS Trust said: “Despite the introduction of new drugs, there are still many patients who don’t respond, or gradually lose response, to all available treatments. Although surgery with the formation of a stoma may be an option that allows patients to return to normal daily activities, it is not suitable in some and others may not want to consider this approach.

“We’re hoping that by completely resetting the patient’s immune system through a stem cell transplant, we might be able to radically alter the course of the disease. While it may not be a cure, it may allow some patients to finally respond to drugs which previously did not work.”

Helen Bartlett, a Crohn’s disease patient who had stem cell therapy at John Radcliffe Hospital, Oxford, said: “Living with Crohn’s is a daily struggle. You go to the toilet so often, you bleed a lot and it’s incredibly tiring. You also always need to be careful about where you go. I’ve had to get off trains before because there’s been no toilet, and I needed to go there and then.

“I’ve been in and out of hospital for the last twenty years, operation after operation, drug after drug, to try to beat this disease. It’s frustrating, it’s depressing and you just feel so low.

“When offered the stem cell transplant, it was a complete no brainer as I didn’t want to go through yet more failed operations. I cannot describe how much better I feel since the treatment. I still have problems and I’m always going to have problems, but I’m not in that constant pain.”

The use of stem cell transplants to wipe out and replace patients’ immune systems has recently been found to be successful in treating multiple sclerosis. This new trial will investigate whether a similar treatment could reduce gut inflammation and offer hope to people with Crohn’s disease.

In the trial, patients undergo chemotherapy and hormone treatment to mobilise their stem cells, which are then harvested from their blood. Further chemotherapy is then used to wipe out their faulty immune system. When the stem cells are re-introduced back into the body, they develop into new immune cells which give the patient a fresh immune system.

In theory, the new immune system will then no longer react adversely to the patient’s own gut to cause inflammation, and it will also not act on drug compounds to remove them from their gut before they have had a chance to work.

Professor Tom Walley, Director of the NIHR Evaluation, Trials and Studies programmes, which funded the trial, said: “Stem cell therapies are an important, active and growing area of research with great potential. There are early findings showing a role for stem cells in replacing damaged tissue. In Crohn’s disease this approach could offer real benefits for the clinical care and long term health of patients.”

The current clinical trial, called ‘ASTIClite’, is a follow up to the team’s 2015 ‘ASTIC’ trial, which investigated a similar stem cell therapy. Although the therapy in the original trial did not cure the disease, the team found that many patients did see benefit from the treatment, justifying a further clinical trial. There were also some serious side effects from the doses of drugs used, so this follow-up trial will be using a lower dose of the treatment to minimise risks due to toxicity.

Patients will be recruited to the trial through Barts Health NHS Trust, Cambridge University Hospitals NHS Foundation Trust, Guy’s & St Thomas’ NHS Foundation Trust, NHS Lothian, Nottingham University Hospitals NHS Trust, Oxford University Hospitals NHS Foundation Trust, Royal Liverpool and Broadgreen University Hospital NHS Trust and Sheffield Teaching Hospitals NHS Foundation Trust.

The trial will involve academics from the University of Manchester, University of Nottingham, University of Sheffield, Nottingham Trent University, University of Edinburgh, University of Oxford, King’s College London, as well as Queen Mary University of London.

The study was funded by a Medical Research Council and NIHR partnership created to support the evaluation of interventions with potential to make a step-change in the promotion of health, treatment of disease and improvement of rehabilitation or long-term care.

https://www.qmul.ac.uk/media/news/2018/smd/stem-cell-transplants-to-be-used-in-treating-crohns-disease.html