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Immunology, Neuroscience, Research, Stanford News

Double vision: How the brain creates a single view of the world

Double vision: How the brain creates a single view of the world

eyes close-upAbout a decade ago, Stanford Bio-X director Carla Shatz, PhD, found that some proteins from the immune system seemed to be playing a role in the brain. Not all scientists were on board with the protein’s double life. Then Ben Barres, MD, PhD, a neurobiologist at Stanford, started finding the same thing with a different set of proteins – these immune system denizens appeared to be functioning in the brain (here’s a write-up on that work by my colleague Bruce Goldman). And still, not all immunologists accepted that the brain might also be using these proteins.

Now Shatz has published a paper online March 30 in Nature that should put the disagreement to rest. She very carefully showed that a protein originally known for its role in the immune system, called MHC Class I D, or D for short, was present in the nerves of the developing brain. She told me, ”The nervous system has just as much right to these immune proteins as the immune system.”

The role D plays is in helping the brain trim back connections as it develops. I didn’t know this before working on my story, but the brain starts out with about double the number of nerve connections than it will eventually use. The ones the brain doesn’t use get trimmed back. Shatz studies this process in a part of the brain that tries to create a single view of the world out of signals coming from the two eyes. In my press release I wrote:

Shatz said the rule of which connections the brain cuts back to create that single vision follows a simple mantra: “Fire together, wire together. Out of sync, lose your link.” Or rather, if early in life the left sides of both eyes see the same duck motif wallpaper, those neurons fire together and stay linked up. When the top of one eye and bottom of the other eye form a connection, the nerves fire out of sync, and the connection weakens and is eventually pruned back. Over time, the only connections that remain are between parts of the two eyes that are seeing the same thing.

I spoke with Lawrence Steinman, MD, PhD, a neurologist at Stanford who studies multiple sclerosis, a disease of both the immune system and the nervous system. He has a foot in both worlds and has followed Shatz’ work from the beginning. He says part of the problem in gaining acceptance for Shatz’ findings was in a name. A rose by any name may smell as sweet, but a protein with a name like “major histocompatibility complex I” only sounds to a biologist like an immune protein. He says he teaches students that if Shatz had published her work first the protein would have an entirely different name and it would be the immunologists fighting to claim the protein’s role in their world.

“They clearly have major roles in both the nervous system and the immune system,” he said.

Previously: Protein known for initiating immune response may set our brains up for neurodegenerative disorders and Pioneers in science
Photo by Ali Moradmand

Global Health, Immunology, Infectious Disease, Microbiology, Research, Stanford News

Discovered: Why so many people with schistosomiasis (there’s a lot of them) are so vulnerable to bacterial co-infection

Discovered: Why so many people with schistosomiasis (there's a lot of them) are so vulnerable to bacterial co-infection

More than a billion people worldwide – almost all of them in developing countries – are infected by worm-like parasitic organisms called helminths. Organisms making up just a single genus of helminth, Schistosoma, account for one-quarter of those infections, which damage different body parts depending on what schistosomal species is doing the infecting. Some go for the lung. Others (card-carrying members of the species Schistosoma haematobium) head for the urinary tract, with one in ten infected patients suffering severe physical consequences.

People with schistosomiasis of the urinary tract are especially vulnerable to bacterial co-infections. Worse, these co-infections exacerbate an already heightened risk of bladder cancer in infected individuals, it’s believed. Unfortunately, considering the massive numbers of cases, surprisingly little is understood about the molecular aspects of the infection’s course.

A big reason for that relative ignorance has been the absence of an effective animal model enabling the detailed study of urinary-tract schistosomiasis. A couple of years ago, Stanford schistosomiasis expert Mike Hsieh, MD, PhD, developed the world’s first decent mouse model for the disease, allowing him to explore the molecular pathology that occurs early in the course of infection. Now, in a just-published study in Infection and Immunity, Hsieh has put that mouse model to work in coaxing out the cause of the curious collegiality of S. haematobium and co-infecting bacteria.

The secret, the scientists learned, is that S. haemotobium infection induces a spike in levels of a circulating immune-system signaling protein, or cytokine, called IL-4. That excess, in turn, results in a drop in the number and potency of a subset of immune cells that are important in fighting off bacterial infections. The discovery opens a pathway toward the development of new, non-antibiotic drug treatments for co-infected patients that won’t wreak havoc with their microbiomes, as antibiotics typically do.

Previously: Is the worm turning? Early stages of schistosomiasis bladder infection charted, Neglected story of schistosomiasis in Ghana, as told in a  sand animation and A good mouse model for a bad worm

Clinical Trials, Immunology, Pediatrics, Research, Stanford News

Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows

Simultaneous treatment for several food allergies passes safety hurdle, Stanford team shows

milk and eggsLiving with one food allergy is a challenge; living with more than one can make ordinary activities such as eating at a restaurant feel downright impossible.

That’s because the standard medical advice for the 4 million Americans with food allergies is to avoid all of your allergy triggers, all the time – and, by the way, make sure you always carry injectable epinephrine in case you accidentally eat something contaminated with a food that triggers anaphylactic shock.

So it will be welcome news to these food-allergy sufferers to hear that a Stanford team is making progress on a new way to help them. In research published today in the journal Allergy, Asthma & Clinical Immunology, a team led by Kari Nadeau, MD, PhD, found that an experimental treatment already being widely tested for single food allergies, called oral immunotherapy, could be modified so that patients can be desensitized to multiple food allergens at the same time. The results now being reported are the products of a pair of phase-1 safety trials.

In our press release about the findings, Nadeau explained why she wanted to develop the new therapy:

“Parents came up to me and said things like, ‘It’s great that you’re desensitizing children to their peanut or milk allergies, but my daughter is allergic to wheat, cashews, eggs and almonds. What can you do about that?’” said Kari Nadeau, MD, PhD, associate professor of pediatrics at the medical school and an immunologist at Stanford Hospital & Clinics and Lucile Packard Children’s Hospital Stanford. Nadeau is the senior author of the new study.

… [O]ral immunotherapy is still experimental and quite slow: In prior studies, patients took as long as three years to become desensitized to one food. Being desensitized to several foods, one at a time, could prospectively take decades. Yet Stanford researchers succeeded in safely desensitizing patients to several food allergens at once and were able to speed up desensitization by supplementing oral immunotherapy with injections of omalizumab (brand name Xolair).

With omalizumab, patients were desensitized to up to five of their allergens in a median of 18 weeks; without the medication, the same process took a median of 85 weeks, the research team found. The published results add weight to the anecdotal findings from three of Nadeau’s patients who participated in the trial and shared their experience in a story in the New York Times magazine last spring.

The researchers stress that the treatment is still experimental and must be performed in a hospital setting, but they are excited by the next step in the process: a phase-2 trial to evaluate the therapy more rigorously in a larger number of patients. The phase-2 trial will be conducted at Stanford, where recruitment of new patients has already begun, and at four other centers across the country, which will begin recruiting patients in the coming months. Individuals who are interested in learning more about participating in the new studies can check the federal clinical trials website for opportunities in their region.

Previously: Researchers show how DNA-based test could keep peanut allergy at bay, A mom’s perspective on a food allergy trial and Searching for a cure for pediatric food allergies
Photo by Logan Brumm Photography and Design

Genetics, Immunology, Pediatrics, Research, Stanford News

Researchers show how DNA-based test could keep peanut allergy at bay

Researchers show how DNA-based test could keep peanut allergy at bay

peanut butter cookies

Treating peanut allergy is an arduous process. The only option is a still-experimental therapy, known as oral immunotherapy, in which a patient consumes tiny, gradually increasing doses of peanut powder under a doctor’s supervision. After months or years of treatment, the patient can eat small amounts of peanuts in ordinary foods without provoking an allergic response.

People with severe peanut allergy may think the effort is worthwhile because it frees them from worry that a stray, peanut-containing cookie or stir-fry will trigger anaphylactic shock. But there’s a catch. To maintain this hard-won tolerance, patients who have completed oral immunotherapy are told they must eat peanuts every day for the rest of their lives. If they don’t, they may regain their allergy.

Now, Stanford researchers think they’ve come up with a better option: a potential blood test to see which patients can safely stop eating peanuts without losing their peanut tolerance. A new study led by Kari Nadeau, MD, PhD, found that differences in the DNA of certain white blood cells separated patients who kept their immune tolerance from those who lost it after oral immunotherapy. The study, published today in the Journal of Allergy and Clinical Immunology, followed 20 child and adult patients who completed two years of oral immunotherapy to treat their peanut allergies. They were asked to stop eating peanuts for three months. In that time, 13 regained their sensitivity to peanuts and seven stayed peanut-tolerant.

The researchers saw epigenetic differences between the groups – genetic changes that affect the structure of the chromosome but not the gene sequence itself. The differences could be detected in small blood samples with commonly-available lab equipment, pointing the way to a possible clinical test. FDA approval is needed before the test could be clinically used for this purpose.

From our press release about the study:

“It’s interesting that the change we saw is at the epigenetic level,” Nadeau said, referring to changes in gene activity and expression caused by factors other than DNA sequence. “This might help us tell people if they can safely go off of immunotherapy, or if they need to continue to eat the food every day.” The test could also help researchers determine whether some individuals would benefit from longer courses of immunotherapy, she added.

Interestingly, the new research answers some questions that physicians posed about another just-released study of oral immunotherapy for the treatment of peanut allergies.

Previously: Eating nuts during pregnancy may protect baby from nut allergies, Ask Stanford Med: pediatric immunologist answers your questions about food allergy research and A mom’s perspective on a food-allergy trial
Photo by Muy Yum

Chronic Disease, Immunology, Research, Stanford News

Another piece of the pulmonary-hypertension puzzle gets plugged into place

Another piece of the pulmonary-hypertension puzzle gets plugged into place

puzzle piecePulmonary hypertension, a dangerous increase in the pressure of blood vessels in the lung, is one nasty disease, as I wrote in a Stanford Medicine article a few years ago. As many as three times as many women – many of them quite young – as men are diagnosed with the spontaneous form of PH (which can also arise from scleroderma or bad pharmaceuticals). While an increasing number of pharmaceutical treatments and advocacy groups have made the diagnosis more palatable, there is still no outright cure. Largely, this is because the molecular mechanisms of pulmonary hypertension have remained mysterious.

But recent work has strongly implicated inflammation in pushing predisposed tissues over the edge into the diseased state. And this week, a Journal of Experimental Medicine study led by PH specialist Marlene Rabinovitch, MD, and her colleagues at Stanford’s PH-focused Vera Moulton Wall Center plunks a potentially pivotal piece of the puzzle into place. Rabinovitch and her associates showed that levels of a pro-inflammatory growth factor usually designated by the acronym GM-CSF (if you really must know, it’s “granulocyte-macrophage colony stimulating factor”) rise substantially when a cell-surface receptor with a heavyweight acronym of its own, BMPR2 (for “bone morphogenic protein receptor”) isn’t functioning properly. That can be due to mutations in the gene that codes for the receptor (as occurs in familial versions of PH), to various environmental causes, or the interaction of the two.

Elevated GM-CSF levels in pulmonary tissue work like a siren to call various hot-tempered inflammatory cells to the vasculature of the lung, resulting in thickened vessel walls and commensurately narrowed blood vessels. Conversely, by finding ways to compensate for BMPR2 under-performance, perhaps researchers will be able to develop therapeutics that keep GM-CSF levels within safe limits, modifying the course of incipient PH or even arresting it.

Several million actual and potential sufferers await that Big If with bated breath.

Previously: Researchers reverse pulmonary hypertension in rats by blocking inflammation-producing pathway, New arterial insights portend potential treatments for life-threatening diseases, and Man receives life-saving transplant thanks to health-care reform and a truck
Photo by ePublicist

Immunology, Mental Health, Microbiology, Public Health

Examining how microbes may affect mental health

Examining how microbes may affect mental health

Over on the NIH Director’s Blog today, there’s an interesting post about research efforts aimed at determining how the colonies of bacteria in our gut could play a role in mental health. As described in the piece, past research has shown there are a number of ways microbes can influence our thoughts, behavior and mood:

First of all, and perhaps most obviously, gut bacteria are engaged in a wide range of biochemical activities, producing metabolites that are absorbed into the human bloodstream. But there are other connections. One species of bacterium, for example, sends messages that are carried via the vagus nerve, which links the intestinal lining to the brain. When this species is present, the mice demonstrate fewer depressive behaviors than when it’s absent. Another bacterium plays an enormous role in shaping the immune system, which goes awry in many neurological diseases. This species of bacterium interacts directly with the immune system’s regulatory T-cells to provide resistance against a mouse version of multiple sclerosis, a progressive disease in which the immune cells damage the central nervous system by stripping away the insulating covers of nerve cells.

As Stanford microbiologist and immunologist Justin Sonnenburg, PhD, commented in a past entry on Scope, “There’s no doubt about it. These microbes are influencing every aspect of our neurobiology. There’s a direct connection between the microbes inside our gut and the central nervous system. They’re influencing our behavior, our moods, even our decisions.”

Previously: Could gut bacteria play a role in mental health?Study shows probiotic foods may alter metabolism, but can they boost your health? and Study shows intestinal microbes may fall into three distinct categories

Evolution, Immunology, Infectious Disease, Men's Health, Research, Stanford News

In men, a high testosterone count can mean a low immune response

In men, a high testosterone count can mean a low immune response

alpha maleMen have deeper voices and tons more facial and body hair than women. They are (usually) bigger, stronger, and much more likely to risk their lives on a whim. I, for example, have been known to bite a full-sized salami in half with a single snap of my jaws when hungry, angry or threatened. Or just for the hell of it.

But when it comes to immune response, men are wimps. It’s well documented that, for reasons that aren’t clear, men are more susceptible to bacterial, viral, fungal and parasitic infection than women are and that men’s immune systems don’t respond as strongly as women’s to vaccinations against influenza, yellow fever, measles, hepatitis and many other infectious diseases.

A new study just published in the Proceedings of the National Academy of Sciences by immunologist Mark Davis, PhD, who directs Stanford’s Institute for Immunity, Transplantation and Infection, and his colleagues may explain why. The same steroid hormone that makes a man’s beard, bones and muscles grow operates – albeit it in a slightly indirect way – to shrink immune responsiveness. Yep, we’re talking about (sigh…) that much-maligned male molecule, testosterone. In a nutshell, high circulating testosterone levels boost the activity of a clutch of genes that, among other things, dial down the aggressiveness with which our immune systems fight back against invading pathogens.

Now why, we ask ourselves, would evolution be so perverse as to have designed a hormone that on the one hand enhances classic male secondary sexual characteristics such as muscle strength, beard growth (or antler size, as the case may be) and risk-taking propensity – the very hallmarks of the alpha male – but on the other hand wussifies men’s immune systems?

Here’s what I got from talking at length (and, I admit, in an uncharacteristically high-pitched voice) to Davis in preparation for the news release I wrote about the study:

The evolutionary selection pressure for male characteristics ranging from peacocks’ plumage to deer’s antlers to fighter pilots’ heroism is pretty obvious: Females, especially at mating-cycle peaks, prefer males with prodigious testosterone-driven traits. Davis speculates that high testosterone may provide another, less obvious evolutionary advantage… Men are prone to suffer wounds from their competitive encounters, not to mention from their traditional roles in hunting, defending kin and hauling things around, increasing their infection risk. While it’s good to have a decent immune response to pathogens, an overreaction to them — as occurs in highly virulent influenza strains, SARS, dengue and many other diseases — can be more damaging than the pathogen itself. Women, with their robust immune responses, are twice as susceptible as men to death from the systemic inflammatory overdrive called sepsis. So perhaps, Davis suggests, having a somewhat weakened (but not too weak) immune system can prove more lifesaving than life-threatening for a dominant male in the prime of life.

Previously: Best thing since sliced bread? A (potential) new diagnostic for celiac disease, Deja Vu: Adults’ immune systems “remember” microscopic monsters they’ve seen before, Immunology escapes from the mouse trap and Immunology meets infotech
Photo by Craig Sunter *Click-64*

Immunology, Nutrition, Pediatrics, Pregnancy

Eating nuts during pregnancy may protect baby from nut allergies

Eating nuts during pregnancy may protect baby from nut allergies

peanutbutterjelly.jpgThank goodness I ate so much peanut butter while I was pregnant.

That was my first reaction to new research, published today in JAMA Pediatrics, that found an association between higher nut consumption during pregnancy and lower rates of nut allergies in the baby. The researchers, at the Dana-Farber Children’s Cancer Center, Boston, asked women to record information about their diets during or soon after pregnancy, and came back later to find out whether their babies developed nut allergies. Among moms who were not themselves allergic to nuts, regular consumption of peanuts and tree nuts (almonds, walnuts and so on) was linked to reduced nut allergies in the babies. Women with the highest nut consumption, who ate nuts five times or more per week, had babies with the lowest allergy risk.

The finding helps clarify a debate about whether expectant women can do anything to reduce the risk of allergies in their babies. Previously, some experts have suggested that perhaps pregnant and breastfeeding women should avoid nuts to lower allergy risk. But the new findings contradict that recommendation. From a JAMA press release on an editorial about the new research:

…pregnant women should not eliminate nuts from their diet as peanuts are a good source of protein and also provide folic acid, which could potentially prevent both neural tube defects and nut sensitization. So, to provide guidance in how to respond to the age-old question “To eat or not to eat?” mothers-to-be should feel free to curb their cravings with a dollop of peanut butter!

Previously: Food allergies and school: One mom’s perspective, Ask Stanford Med: Pediatric immunologist answers your questions about food allergy research and A mom’s perspective on a food-allergy trial
Photo by Matias-Garabedian

Bioengineering, Global Health, Immunology, Public Health, Stanford News

Working to create a universal flu vaccine

Working to create a universal flu vaccine

Swartz

Exactly one week ago, I found myself unable to get out of bed. I was shaking despite being tucked under mountains of blankets; my head was pounding despite having taken numerous doses of Tylenol. I had gotten the flu and was bitter: Not only was my illness going to derail my weekend’s plans, but I had gotten a flu shots several weeks prior. How unfair, I thought.

The flu shot, of course, doesn’t provide protection against every strain of influenza, and scientists have been on a quest for years for a “universal vaccine” that can offer broader protection. Earlier this week, Stanford researchers announced that they’ve taken important steps towards the creation of such a vaccine. “Their approach arises from a better understanding of the structure of a key protein on the surface of the flu virus and a new process for making vaccines based on that understanding,” Tom Abate writes in this School of Engineering release, which goes on to describe the details of the work.

Abate cautions in the piece that “many steps remain before the research community knows whether this… approach yields a better flu vaccine.” But the lead researcher said he and colleagues are committed to the effort. “This is an important project for world health,” James R. Swartz, PhD, said.

Previously: Flu-vaccine study participant shares his experience, Ask Stanford Med: Answers to your questions about seasonal influenza, Dynamic duo: Flu vaccine plus adjuvant bolsters immunity, European experts debunk six myths about flu shot and Universal influenza vaccine, maybe – eternal, maybe not
Photo of Swartz by Joel Simon

Health and Fitness, Immunology, In the News, Public Health

Should people with allergies get a flu vaccine?

Should people with allergies get a flu vaccine?

FluToday, many of my colleagues took advantage of one of Stanford’s free flu vaccination clinics. Since I’m feeling a bit under the weather – and I’m terrified of needles – I sat this particular vaccination clinic out.

Yet, my caution tinged with cowardliness brings up an interesting point: When should you forgo the flu vaccine? As discussed in this article from Medical News Today, one group of people that should carefully weigh the risks and benefits of flu vaccines are people with allergies such as gelatin.

From the article:

As flu vaccine coverage is on the rise in the U.S., experts from the American College of Allergy, Asthma and Immunology (ACAAI) warn that individuals who are allergic to gelatin could have a mild to severe reaction to the flu vaccine.

“Gelatin is used in the flu shot, as well as other vaccines, as a stabilizer. Because it is found in the vaccine, those with a known allergy to gelatin can experience allergic reactions, such as hives, sneezing and difficulty breathing.”

The article explains that a swollen tongue or itching after eating foods, such as gummy bears, that contain gelatin could signify a gelatin allergy. But, it is it a true allergy, or a food intolerance? President of the ACAAI, Richard Weber, MD, explains:

“Those who believe they might have an allergy should be tested and diagnosed by an allergist before taking extreme avoidance measures or skipping vaccinations. The flu shot is an important vaccine and can even be life-saving for individuals who are at an increased risk for severe side effects associated with the flu.”

Previously: CDC: More U.S. adults need to get recommended vaccinationsFailure to vaccinate linked to pertussis deaths and Ask Stanford Med: Pediatric immunologist answers your questions about food allergy research
Photo by USACE Europe District

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