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Autoimmune Disease, Immunology, Public Health, Research, Sleep, Stanford News

Cause of 2009 swine-flu-vaccine association with narcolepsy revealed?

Cause of 2009 swine-flu-vaccine association with narcolepsy revealed?

syringesBack in 2001, in the wacko cinematic tour de farce “Rat Race,” British actor Rowan Atkinson – a.k.a. the iconic “Mr. Bean” – put a humorous face on narcolepsy, a rare, chronic, incurable and lifelong sleep disorder that can strike at any time, even in the heat of a foot race.

In 2009, narcolepsy suddenly became, for a time, not quite so rare.

The swine flu pandemic sweeping the world that year was no joke. In the United States alone, the H1N1 strain of influenza virus responsible for that pandemic resulted in 274,304 hospitalizations and 12,469 deaths, as mentioned in our news release on a just-published study in Science Translational Medicine.

There probably would have been far more hospitalizations and deaths had not several vaccines tailored to that particular influenza strain been rushed to the market. Two vaccines in particular — Focetria, manufactured by Novartis, and Pandemrix, made by GlaxoSmithKline — are credited with saving a lot of lives in Europe. But there was a dark side. As our news release notes:

Populations that had been immunized with GlaxoSmithKline’s Pandemrix vaccine showed an increase in narcolepsy, but those immunized with Novartis’ Focetria did not.

That’s not news; it’s been known for some time. But the findings in the new study, whose senior author is Stanford neuroimmunologist Larry Steinman, MD, may explain why.

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Autoimmune Disease, Bioengineering, Immunology, Research, Stanford News

Adult humans harbor lots of risky autoreactive immune cells, study finds

Adult humans harbor lots of risky autoreactive immune cells, study finds

dangerIf a new study published in Immunity is on the mark, the question immunologists may start asking themselves will be not “Why do some people get autoimmune disease?” but “Why doesn’t everybody get it?”

The study, by pioneering Stanford immunologist Mark Davis, PhD, and colleagues, found that vast numbers of self-reactive immune cells remain in circulation well into adulthood, upending a long-established consensus among immunologist that these self-reactive immune cells are weeded out early in life in an organ called the thymus.

A particular type of immune cell, called “killer T cells,” is particularly adept at attacking cells showing signs of harboring viruses or of becoming cancerous. As I wrote in my news release about Davis’s study:

[The human immune system generates] a formidable repertoire of such cells, collectively capable of recognizing and distinguishing between a vast array of different antigens – the biochemical bits that mark pathogens or cancerous cells (as well as healthy cells) for immune detection. For this reason, pathogenic invaders and cancerous cells seldom get away with their nefarious plans.

Trouble is, I wrote:

[This repertoire includes] not only immune cells that can become appropriately aroused by any of the billions of different antigens characteristic of pathogens or tumors, but also immune cells whose activation could be triggered by myriad antigens in the body’s healthy tissues. This does happen on occasion, giving rise to autoimmune disease. But it happens among few enough people and, mostly, late enough in life that it seems obvious that something is keeping it from happening to the rest of us from day one.

It’s been previously thought that the human body solves this problem by eliminating all the self-reactive T cells during our early years via a mysterious select-and-delete operation performed in a mysterious gland called the thymus that’s nestled between your heart and your breastbone. Sometime in or near your early teens, the thymus mysteriously begins to shrink, eventually withering and largely turning to useless fat. (Is that mysterious enough for you? It sure creeps me out.)

But Davis and his team used some sophisticated technology – some of it originally invented by Davis, some of it by Stanford bioengineering professor and fellow study co-author Stephen Quake, PhD – to show that, contrary to prevailing dogma, tons of self-reactive killer T-cells remain in circulation well into adulthood. Then the scientists proceeded to explore possible reasons why the immune system keeps these risky cells around (it boils down to: just in case a pathogen from Mars comes along and we need to throw the kitchen sink at it) and why (at least most of the time) they leave our healthy tissues alone: A still-to-be-fully-elucidated set of molecular mechanisms keeps these self-reactive cells locked in the biochemical equivalent of parking gear, shifting out of which requires unambiguous signs of an actual pathogen’s presence: bits of debris from a bacterial cell wall, or stretches of characteristically viral DNA.

That’s our immune system, folks. Complicated, mysterious, and yet somehow incredibly efficient. You really don’t want to leave home – or even the womb – without it.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, In men, a high testosterone count can mean a low immune response and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Frederic Bisson

Autoimmune Disease, Cancer, Infectious Disease, Microbiology, Nutrition, Stanford News

Getting to the good gut: how to go about it

Getting to the good gut: how to go about it

In a blog post a few years ago I wrote, The Good Gutwith misplaced parenthetical self-assuredness:

Anybody who’s ever picked up an M&M off the sidewalk and popped it into his or her mouth (and, really, who among us hasn’t?) will be gratified to learn that the more germs you’re exposed to, the less likely you are to get asthma … hay fever and eczema.

I soon learned to my surprise, if not necessarily to my embarrassment, that virtually nobody – at least nobody over 6 – cops to having stooped-and-scooped as I routinely did as a kid on what I called my “lucky-sidewalk” days.

But those M&Ms may have been the best pills I ever took.

Stanford microbiologists Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, (they’re married) have written a new book, The Good Gut, about the importance of restocking our germ-depleted lower intestines.

Massive improvements in public sanitation and personal hygiene, the discovery of antibiotics and the advent of sedentary lifestyles have taken a toll on the number and diversity of microbes that wind up inhabiting our gut. According to The Good Gut, we need more, and more varieties, of them. And we need to treat them better. The dearth of friendly microorganisms in the contemporary colon is due not just to a lack of bug intake but to a lack of fiber in the modern Western diet. Indigestible to us, roughage is the food microbes feast on.

The Good Gut packages that message for non-scientists. “We wanted to convey the exciting findings in our field to the general public,” Justin Sonnenberg recently told me. “We’d noticed we were living our life differently due to our new understanding. We were eating differently and had modified both our own lifestyle and the way we were raising our children.”

In simple language, the Sonnenburgs explain how the pieces of our intestinal ecosystem fit together, what can go wrong (obesity, cancer, autoimmunity, allergy, depression and more), and how we may be able to improve our health by modifying our inner microbial profiles. Their book includes everything from theories to recipes, along with some frank discussion of digestive processes and a slew of anecdotes capturing their family’s knowledge-altered lifestyle.

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Autoimmune Disease, Chronic Disease, Health and Fitness, Nutrition, Obesity, Research

Study clarifies link between dieting, exercise and reduced inflammation

Study clarifies link between dieting, exercise and reduced inflammation

4503404991_13da58b6e6_bIf you’ve ever wondered how dieting and exercise reduce inflammation, read on. According to new research, a compound that our bodies crank out when energy supplies are low could be the link between diet and exercise, and reduced swelling in the body.

When diet, fasting and exercise starve the body for calories, the body increases production of a compound called beta hydroxybutyrate (BHB). This compound has long been known as an alternate source of energy; the new research suggests that BHB can also block the inflammatory response.

In their study, published this week in Nature Medicine online (subscription required), a team of scientists co-led by Yun-Hee Youm and Kim Yen Nguyen at the Yale School of Medicine, discovered that the compound BHB reduces swelling in the body by inactivating a group of proteins, called the inflammasome, that drive the inflammatory response.

The research team used human immune cells and mice to explore the effects of BHB in the body. They found that mice given BHB directly, and mice fed a low-carbohydrate diet (that prompted their bodies to synthesize their own BHB), both benefited from reduced inflammation.

These results are noteworthy because a better understanding of the mechanism that links diet, exercise and inflammation could help scientists develop more effective treatments for inflammatory disorders such as Type 2 diabetes, atherosclerosis and Alzheimer’s disease.

Previously: Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroesImproving your health using herbs and spices, Exercise may alleviate symptoms of arthritis regardless of weight loss, Study points to inflammation as cause of plaque buildup in heart vessels and Examining the role of exercise in managing and preventing diabetes
Via ScienceDaily
Photo by Dave Nakayama

Autoimmune Disease, Chronic Disease, Immunology, Stanford News, Videos

Chronic fatigue syndrome gets more respect (and a new name)

Chronic fatigue syndrome gets more respect (and a new name)

As has been widely reported, an Institute of Medicine (IOM) report released yesterday acknowledged that chronic fatigue syndrome is a real and serious disease and renamed the disorder “systemic exertion intolerance disease” to better reflect its key symptoms.

Stanford professor José Montoya, MD, who served as a reviewer on the IOM report, is featured in the video above, which accompanied Washington Post coverage of the development. The Post article goes on to say:

“We just needed to put to rest, once and for all, the idea that this is just psychosomatic or that people were making this up, or that they were just lazy,” said Ellen Wright Clayton, a professor of pediatrics and law at Vanderbilt University, who chaired the committee of the Institute of Medicine, the health arm of the National Academy of Sciences.

Although the cause of the disorder is still unknown, the panel established three critical symptoms for the condition (also known as myalgic encephalomyelitis):

  • A sharp reduction in the ability to engage in pre-illness activity levels that lasts for more than six months and is accompanied by deep fatigue that only recently developed.
  • Worsening of symptoms after any type of exertion, including “physical, cognitive or emotional stress.”
  • Sleep that doesn’t refresh the sufferer.

The panel also requires that a patient have one of two other disease manifestations, either cognitive impairment or orthostatic intolerance. Orthostatic intolerance is an autonomic nervous system disorder that is caused by an abnormal increase in heart rate and low blood pressure, believed to be triggered by the disease.

Susan Kruetzer, an SEID patient interviewed by Erin Allday in this San Francisico Chronicle article, expressed guarded optimism about the report’s ability to generate more research funding and patient support, saying “What I want to see is someone in Congress get pretty riled up by this report — have them see how many people are affected, how these people are really ill, how they’ve been mistreated,” Kreutzer said. “I’d just like to light a fire. I don’t know if this report will do that, but I suppose it gives us some ammunition.”

Previously: Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed, Unbroken: A chronic fatigue syndrome patient’s long road to recovery and Deciphering the puzzle of chronic fatigue syndrome

Autoimmune Disease, Behavioral Science, Immunology, Pediatrics, Research

What happens when the immune system attacks the brain? Stanford doctors investigate

What happens when the immune system attacks the brain? Stanford doctors investigate

SM PANS image - smallerThe first time he flew into a psychotic rage, Paul Michael Nelson was only 7 years old. He stabbed at a door in his family’s home with a knife, tore at blankets with his teeth, spoke in gibberish. His very worried parents, Paul and Mary Nelson, rushed him to their local emergency room, where the medical staff thought that perhaps the little boy had simply had a bad temper tantrum.

But his rages got worse. Over the weeks and months that followed the first March 2009 emergency room visit, as Paul Michael cycled in and out of psychiatric hospitals, his parents and doctors struggled to understand what was wrong. Finally, they came to a surprising conclusion: Paul Michael had an autoimmune disease. His immune system appeared to be attacking his brain.

As strange as the case seems, the Nelsons are far from alone. As I describe in a recent story for Stanford Medicine magazine, Paul Michael was the first of more than 70 children who have been evaluated at a new clinic at Lucile Packard Children’s Hospital Stanford for pediatric acute-onset neuropsychiatric syndrome, a disease (or, more likely, a group of diseases) that doctors are still working to define. The suddenness and severity of the syndrome are frightening. Healthy children abruptly begin to show psychiatric symptoms that can include severe obsessive-compulsive behavior; anorexia; intense separation anxiety at the thought of being away from a parent; deterioration in their school work, and many other problems. From my story:

“In some ways, it’s like having your kid suddenly become an Alzheimer’s patient, or like having your child revert back to being a toddler,” says Jennifer Frankovich, MD, clinical assistant professor of pediatric rheumatology at the School of Medicine and one of the clinic’s founders.

“We can’t say how many kids with psychiatric symptoms have an underlying immune or inflammatory component to their disorder, but given the burgeoning research indicating that inflammation drives mood disorders and other psychiatric problems, it’s likely to be a large subset of children and even adults diagnosed with psychiatric illnesses,” says Kiki Chang, MD, professor of psychiatry and behavioral sciences.

To shed light on the disease, Frankovich and Chang are working with scientists from around the world on defining the parameters of the illness and launching urgently-needed research. In a special issue of the Journal of Child and Adolescent Psychopharmacology that published online this month, the researchers lay out several aspects of the problem. The Stanford experts are co-authors of a scientific article describing how doctors should evaluate children with the disease, known by its acronym, PANS. Other researchers have written about disordered eating in PANS and given a detailed description of the disease phenotype.

Recognition and treatment of the disease are still an uphill battle, but the growth of research efforts is a hopeful step. As Frankovich says at the conclusion of the Stanford Medicine story, “We cannot give up on this. There are so many of these cases out there.”

Previously: Stanford Medicine magazine traverses the immune system and My descent into madness – a conversation with author Susannah Cahalan
Illustration by Jeffrey Decoster

Autoimmune Disease, Chronic Disease, Immunology, Stanford News, Videos

Unbroken: A chronic fatigue syndrome patient’s long road to recovery

Unbroken: A chronic fatigue syndrome patient’s long road to recovery

“Fatigue is what we experience, but it is what a match is to an atomic bomb,” said Laura Hillenbrand, the author of Unbroken, about how it feels to live with chronic fatigue syndrome.

I recently finished a Stanford Medicine story and video (above) about another CFS patient, “Erin,” who asked that her real name not be used. After an acute illness in rural Mexico, Erin went from being an elite soccer player to one of the 17 million people worldwide who suffer from the condition.

Most people who acquire hit-and-run infections go back to their normal lives after a few days. But these patients don’t. They become virtual shut-ins, prisoners of a never-ending cycle of flu-like symptoms, many of them bedridden for years. CFS, also called myalgic encephalomyelitis or ME/CFS, has no known cause or cure, frustrating both patients and physicians.

What makes Erin’s CFS story somewhat rare is its happy ending. With the help of Stanford infectious disease expert José Montoya, MD, and cardiac electrophysiologist Karen Friday, MD, Erin is back to working fulltime and playing soccer.

“Dr. Montoya and doctors like him are heroes for taking up an unpopular disease and patients that most doctors shun,” said Lori Chapo-Kroger, a registered nurse and CEO of the patient charity, PANDORA Org. “He combines his medical expertise and a creative approach with a truly caring heart for suffering patients.”

Dr. Montoya is also collaborating with immunologist Mark Davis, PhD, on the Stanford Initiative on Infection-Associated Chronic Diseases, a research project using cutting-edge technologies to identify the biomarkers and root causes of ME/CFS. Working at the Human Immune Monitoring Center, team members are searching 600 blood samples for infectious microbes, inflammation-related molecules and genetic flaws. In addition, they’re conducting brain scans and physical exams to look for physical abnormalities among these patients.

Early results are promising — the team has discovered a number of measurable biological markers that indicate that ME/CFS patients may be suffering from out-of-control inflammation.

The team’s goal: To find out what is wrong with the immune systems of patients with infection-triggered diseases such ME/CFS and Lyme disease, then figure out how to help them get better.

Previously: Deciphering the puzzle of chronic fatigue syndrome

The HIMC is partially funded by Spectrum, Stanford’s NIH Clinical and Translational Science Award.

Autoimmune Disease, Genetics, NIH, Research, Science

Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease

Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease

I don’t know about you, but I’m fascinated with the idea of the “microbiome.” If you’re unfamiliar with the term, it describes the millions upon millions of tiny, non-human hitchhikers that live on and in you (think bacteria, viruses, fungi and other microscopic life). Although the exact composition of these molecular roommates can vary from person to person, they aren’t freeloaders. Many are vitally important to your metabolism and health.

We’ve reported here on the Human Microbiome Project, launched in 2007 and supported by the National Institutes of Health’s Common Fund. Phase 2 of the project started last fall, with grants to three groups around the country to study how the composition of a person’s microbiome might affect the onset of diseases such as type 2 diabetes and inflammatory bowel disease, as well as its role in pregnancy and preterm birth. Now the researchers, which include Stanford geneticist Michael Snyder, PhD, have published an article in Cell Host & Microbe detailing what data will be gathered and how it will be shared.

As explained in a release by the National Human Genome Research Institute:

“We’re producing an incredibly rich array of data for the community from the microbiomes and hosts in these cohorts, so that scientists can evaluate for themselves with these freely available data which properties are the most relevant for understanding the role of the microbiome in the human host,” said Lita M. Proctor, Ph.D., program director of the Human Microbiome Project at NIH’s National Human Genome Research Institute (NHGRI).

“The members of the Consortium can take advantage of each other’s expertise in dealing with some very complex science in these projects,” she said. “We’re generating these data as a community resource and we want to describe this resource in enough detail so people can anticipate the data that will be produced, where they can find it and the analyses that will come out of the Consortium’s efforts.”

As I’ve recently blogged, data-sharing among researchers and groups is particularly important for research efficiency and reproducibility. And I’m excited to hear what the project will discover. More from the release:

For years the number of microbial cells on or in each human was thought to outnumber human cells by 10 to 1. This now seems a huge understatement. Dr. Proctor noted that the 10-to-1 estimate was based only on bacterial cells, but the microbiome also includes viruses, protozoa, fungi and other forms of microscopic life. “So if you really look at the entire microbial community, you’re probably looking at more like a 100-to-1 ratio,” she said.

Although thousands of bacterial species may make their homes with human beings, each individual person is host to only about 1,000 species at a time, according to the findings of the Human Microbiome Project’s first phase in 2012.

In addition, judging from the array of common functions of bacterial genes, if the bacteria are healthy, each individual’s particular suite of species appear to come together to perform roughly the same biological functions as another healthy individual. In fact, researchers found that certain bacterial metabolic pathways were always present in healthy people, and that many of those pathways were often lost or altered in people who were ill.

Stanford’s Snyder will join forces with researchers in the laboratory of George Weinstock, PhD, of the Jackson Laboratory for Genomic Medicine in Connecticut to investigate the effect of the microbiome on  the onset of Type 2 diabetes. Snyder may be uniquely positioned to investigate the causes of the condition. In 2012, he made headlines when he performed the first ever ‘omics’ profile of himself (an analysis that involves whole genome DNA sequencing with repeated measurements of the levels of RNA, proteins and metabolites in a person’s blood over time). During the process, he learned that he was on the cusp of developing type 2 diabetes. He was able to halt the progression of the disease with changes in exercise and diet.

Previously: Stanford team awarded NIH Human Microbiome Project grantElite rugby players may have more diverse gut microbiota, study shows and Could gut bacteria play a role in mental health?

Autoimmune Disease, Chronic Disease, Health and Fitness, Research, Technology

Video game accessory may help multiple sclerosis patients reduce falls, boost brain connections

Wii_balance_boardNintendo’s Wii Balance Board has helped get people off the couch and moving as they play aerobic video games like Super Hula Hoop or Dance Dance Revolution. Now a study published this week in Radiology shows that the video game console’s balance board may help reduce multiple sclerosis (MS) patients’ risk of falls by rewiring their brains.

In a small study, researchers used an MRI technique called diffusion tensor imaging to analyze changes in the brain of MS patients that used the Wii Balance Board while playing video games for 30-40 minutes a day five days a week.

According to a recent Forbes post:

MRI scans in the MS patients in the study demonstrated significant growth of nerve tracts which are integral in movement as well as balance. It turns out that the changes seen on MRI correlated with improvements in balance as measured by an assessment technique called posturography.

These brain changes in MS patients are likely a manifestation of neural plasticity, or the ability of the brain to adapt and form new connections throughout life, said lead author Luca Prosperini, M.D., Ph.D., from Sapienza University in Rome, Italy.

”The most important finding in this study is that a task-oriented and repetitive training aimed at managing a specific symptom is highly effective and induces brain plasticity.”

“More specifically, the improvements promoted by the Wii balance board can reduce the risk of accidental falls in patients with MS, thereby reducing the risk of fall-related comorbidities like trauma and fractures,”

 added Prosperini.

Researchers cautioned that the improvements in balance did not persist after patients stopped playing the video games, suggesting that patients will need to continue their training in order benefit from the intervention.

Previously: Study analyzes video game-related injuries and Comparing the Wii Fit board to a clinical force platform
Photo by Joachim S. Müller

Aging, Autoimmune Disease, Immunology, Infectious Disease, Research, Stanford News

Our aging immune systems are still in business, but increasingly thrown out of balance

Our aging immune systems are still in business, but increasingly thrown out of balance

business as usual

Stanford immunologist Jorg Goronzy, MD, told me a few years ago that a person’s immune response declines slowly but surely starting at around age 40. “While 90 percent of young adults respond to most vaccines, after age 60 that response rate is down to around 40-45 percent,” he said. “With some vaccines, it’s as low as 20 percent.”

A shaky vaccine response isn’t the only immune-system slip-up. With advancing age, we grow increasingly vulnerable to infection (whether or not we’ve been vaccinated), autoimmune disease (an immune attack on our own tissues) and cancer (when a once well-behaved cell metamorphoses into a ceaselessly dividing one).

A new study led by Goronzy and published in Proceedings of the National Academy of Sciences, suggests why that may come about. The culprit he and his colleagues have fingered turns out not to be the most likely suspect: the thymus.

This all-important organ’s job is to nurture an army of specialized  immune cells called T cells. (The “T” is for “Thymus.”) T cells are capable of recognizing and mounting an immune response to an unbelievably large number of different molecular shapes, including ones found only on invading pathogens or on our own cells when they morph into incipient tumor cells.

Exactly which feature a given T cell recognizes depends on the structure of a receptor molecule carried in abundance on that T cell’s surface.  Although each T cell sports just one receptor type, in the aggregate the number of different shapes T-cells recognize is gigantic, due to a high rate of reshuffling and mutation in the genes dictating their receptors’ makeup. (Stanford immunologist Mark Davis, PhD, perhaps more than any other single individual,  figured out in the early 1980s how this all works.)

T cells don’t live forever, and their generation from scratch completely depends on the thymus. Yet by our early teens the organ,  situated  in front of the lungs at the midpoint of our chest, starts shriveling up and replaced by (sigh – you knew this was coming)  fat tissue.

After the thymus melts away,  new T-cells come into being only when already-existing ones undergo cell division, for example to compensate for the attrition of their neighbors in one or another immune-system dormitory (such as bone marrow, spleen or a lymph node).

It’s been thought that the immune-system’s capacity to recognize and mount a response to pathogens (or incipient tumors) fades away because with age-related T-cell loss comes a corresponding erosion of diversity:  We just run out of T-cells with the appropriate receptors.

The new study found otherwise.  “Our study shows that the diversity of the human T-cell receptor repertoire is much higher than previously assumed, somewhere in the range of one billion different receptor types,” Goronzy says. “Any age-associated loss in diversity is trivial.” But the study also showed an increasing imbalance, with some subgroups of T cells (characterized by genetically identical  receptors)  hogging the show and other subgroups becoming vanishingly scarce.

The good news is that the players in an immune response are all still there, even in old age. How to restore that lost balance is the question.

Previously: How to amp up an aging immune response, Age-related drop in immune responsiveness may be reversible and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Lars Plougmann

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