Heightened Immunity To Colds Makes Asthma Flare-Ups Worse, U-M Research Shows

Tempering the immune response — rather than enhancing it — in asthma patients might be a better strategy when combating cold symptoms

People often talk about “boosting” their immunity to prevent and fight colds. Nutritional supplements, cold remedies and fortified foods claim to stave off colds by augmenting the immune system.

A new University of Michigan study shows this strategy might actually be flawed. The results may hold important implications for individuals with asthma, who often experience life-threatening flare-ups due to infections with cold viruses.

The study, using a novel mouse model, shows that, in the airways, the immune response to the common cold is actually maladaptive. Mice that were engineered to have a reduced innate immune response to the common cold actually showed less – not more – airway inflammation and bronchoconstriction (airway spasm) following infection.

The results of this study appeared online ahead of print in the journal PLoS Pathogens, currently available online. Marc B. Hershenson, M.D., professor of pediatrics and communicable diseases and director of the division of pediatric pulmonology, is the study’s senior author.

“You often hear that people want to boost their immunity to prevent and fight colds,” says Hershenson. “However, boosting the immune response could increase inflammation. Up to now there have been no convincing data supporting the theory that the immune response might be deleterious. In our study, we offer the first direct evidence that limiting the immune response reduces the manifestations of rhinovirus infection.”

“In our model, cold-induced asthma flare-ups were caused by the body’s immune response to the virus, not the virus itself. Chemicals produced by the immune system inflame cells and tissues, causing asthma symptoms such as cough and wheeze,” Hershenson explained.

Hershenson and his group hypothesized that limiting the immune response to viral infection would actually reduce their symptoms. Using a rhinovirus 1B, a cold virus strain that replicates in mouse lungs, they infected mice deficient in MDA5 and TLR3 – two receptors that trigger the protective defenses of the immune system against viruses and other pathogens.

MDA5-deficient mice showed a delayed defensive response to the infection, leading to a small increase in the level of virus in the lungs. Nevertheless, these mice showed less airway inflammation and bronchoconstriction following infection compared to wild-type mice. TLR3-deficient mice also showed diminished airway responses.

In addition, MDA5- and TLR3-null mice that were made asthmatic by exposure to allergen showed decreased airway inflammatory and contractile responses in response to rhinovirus infection compared to normal mice. These results suggest that, in the context of rhinovirus infection, reducing the mouse’s innate immune system led to reduced inflammatory signaling pathways and reduced airways inflammation and hyper-responsiveness.

“This study shows that, once you have a cold, elements of the immune response actually make the symptoms worse,” Hershenson adds. “A better strategy might be to modulate the immune response in asthma patients with colds.”

Contacts and sources:

Written by Margarita Wagerson

University of Michigan Health System

Authors: Qiong Wang, Ph.D., David J. Miller, M.D., Ph.D., Emily R. Bowman, Deepti R. Nagarkar, Ph.D., Dina Schneider, Ph.D., Ying Zhao, Marisa J. Linn, Adam M. Goldsmith, Ph.D., J. Kelley Bentley, Ph.D., Umadevi S. Sajjan, Ph.D, Marc B. Hershenson, M.D., all of the University of Michigan

Funding: National Institutes of Health

Disclosures: None

Citation: Wang Q, Miller DJ, Bowman ER, Nagarkar DR, Schneider D, et al. (2011) MDA5 and TLR3 Initiate Pro-Inflammatory Signaling Pathways Leading to Rhinovirus-Induced Airways Inflammation and Hyperresponsiveness. PLoS Pathog 7(5): e1002070. doi:10.1371/journal.ppat.1002070

The University of Michigan C.S. Mott Children’s Hospital is consistently ranked as one of the best hospitals in the country. It was nationally ranked in all ten pediatric specialties in the U.S. News Media Group’s 2011 edition of “America’s Best Children’s Hospitals” including third in the country for heart and heart surgery. In November, the hospital moves to a new 1.1 million square feet, $ 754 million state-of-the-art facility that will be home to cutting-edge specialty services for newborns, children and women.

Research discovers frequent mutations of chromatin remodeling genes in TCC of the bladder

BGI, the world’s largest genomics organization, Peking University Shenzhen Hospital and Shenzhen Second People’s Hospital, announced today that the study on frequent mutations of chromatin remodeling genes in transitional cell carcinoma (TCC) of the bladder was published online in Nature Genetics. This study provides a valuable genetic basis for future studies on TCC, suggesting that aberration of chromatin regulation might be one of the features of bladder cancer. Bladder cancer is the ninth most common type of cancer worldwide, which affects three times as many men as women. Almost all bladder cancers originate in the urothelium, so they are also known as one of the most common tumors of the genitourinary tract. Each year, about 360,000 new cases of bladder cancer are expected, and about 150,000 people will die of this disease in the world. In North America, South America, Europe, and Asia, TCC is the most common type of bladder cancer diagnosed, accounting for 90% of all bladder malignancies in those regions.
“Considering the high risks of TCC and the lack of comprehensive analysis, we and our partners initiated this project to identify other previously unidentified genes associated with the bladder cancer.” said Professor Zhiming Cai, President of Shenzhen Second People’s Hospital and the former President of Peking University Shenzhen Hospital. “I hope our unexpected discoveries in this study can provide more important insights into potential diagnoses and the therapeutic applications.” he added.
In this study, the exomes of nine patients with TCC were sequenced with BGI’s exome sequencing platform. Then, all the somatically mutated genes were screened in a prevalence set of 88 additional patients with TCC at different tumor stages and grades. “After the detections and statistical analysis, we discovered 49 new significantly mutated genes associated with TCC, and these genes are previously unknown to be mutated in TCC.” said Professor Yaoting Gui，the co-leading author of the study and Vice-Director of the Institute of Urology at Peking University Shenzhen Hospital, “Another interesting finding is that eight genes among them are associated with chromatin remodeling, which could be related with frequent mutations in the majority of TCCs.”
“We identified the genetic aberrations of the chromatin remodeling genes in 59% of the 97 individuals with TCC, and discovered one gene, UTX, could be altered substantially more frequently in tumors with low stages and grades.” said Guangwu Guo, one of the co-leading authors of the study and PI of this project at BGI. “This study indicates UTX may pose a potential role in the classification and diagnosis of bladder cancer.”
As we all know, aberrations of the chromatin remodeling genes may directly lead to the misregulation of multiple downstream effector genes, consequently promoting the tumor genesis process. “In our study, the newly discovered genetic mutations in the chromatin remodeling genes, except for UTX, are previous unknown in the primary tumors of TCC.” said professor Cai. “Our results demonstrate that the disruption of the chromatin remodeling machinery may be one of the main mechanisms that lead to TCC.”
Professor Jun Wang, Executive Director of BGI, said, “This study provides further understanding of bladder cancer and other human cancers through the comprehensive analysis of genetic alterations in TCC. It also implicates the necessity to enhance the epigenomics research in the field of cancer studies in the future. “

**Source: Beijing Genomics Institute

Current Peanut Allergy Research

This week on NoPeanuts we have had discussion on whether the food allergy focus should be on peanuts. There was debate about whether I should focus on peanuts so much or instead balance my comments and articles across all forms of food allergy. Though I am certainly empathetic to all food allergies, especially when we think of stories such as that of Sabrina Shannon, the NoPeanuts family is primarily concerned with peanut allergy right now as that is what triggered the events of Boxing Day.

As part of our journey I have been extensively reading, pondering and discussing the ongoing research into the causes and possible treatments of peanut allergy anaphylaxis. As I get deeper in to the research I will certainly pass along what I learn on other food allergies – remember, we are also challenged with anaphylaxis to uncooked egg-white.

Though somewhat dated, I think it is worth highlighting a great article in the Wall Street Journal in October 2006 titled “Researchers Uncertain How To Tame Peanut Allergy” by Jame Zhang. The article covers many possible solutions but three jumped out as being of particular interest:

- Drug Development
- Immunotherapy
- Genetically Modified Peanuts

In the quoted, highlighted text below I have taken excerpts the WSJ article:

Drug development:
“An approved asthma drug, Xolair, may be useful in treating peanut and other food allergies; injected into patients, it would reduce certain antibodies that are thought to cause anaphylactic food allergy. Last year, though, clinical trials came to a halt after two children, who had been given peanut protein in a screening to gauge the severity of their allergy, experienced anaphylactic reactions. The drug’s makers — Genentech, Novartis and Tanox — are working with the Food and Drug Administration to design a new trial, Genentech says.”

This drug has actually had a controversial history. It ‘took over’ from TNX-901 after a legal battle between multiple drug development partners – as documented by Time in 2003. Given that it is one of the only drugs I am aware of geared toward peanut allergy it will be interesting to see if anything actually transpires. Based on the halting of the clinical trial (see above) and the fact that Xolair did not begin life as a peanut allergy drug in the first place, I would not hold out on waiting for this drug to hit a pharmacy near you. It is also worth noting that, per the Time article, the annual cost of treatment would be a whopping $ 10,000!

So if there is not a drug treatment available (not that I would necessarily take that option for our daughter anyway), what about the possibility of a vaccination or immunotherapy? The research actually seems quite promising in this area:

Immunotheraphy / Vaccination:
Two researchers — Wesley Burks, chief of pediatric allergy and immunology at Duke University Medical Center, and Hugh Sampson, his counterpart at New York’s Mount Sinai School of Medicine — are trying to create a vaccine. They have slightly modified the three peanut proteins responsible for most reactions so they don’t trigger such strong reactions from human mast cells. By administering the modified proteins to subjects in slowly increasing doses, they hope to condition their immune systems to tolerate more. They have tested the therapy on mice and plan to start on humans in a year or so.

Another experimental therapy aims to reduce the severity of reactions. Burks’s team administers powdered or liquid peanut proteins to patients in incrementally increasing doses, starting with 0.001 peanut the first day, to one whole peanut six months later. They hope one day to develop a drug or a physician-administered therapy. In a trial completed on eight patients, Burks says the subjects tolerated 13 peanuts before experiencing a reaction — enough, in theory, to save an allergic child’s life in case of accidental ingestion.”

I actually have communication into Dr. Burks and I will let you know if I learn more from him on this research as it seems to be more within reach than a $ 10,000 a year unproven prescription drug. The difference between 0.1mg of peanut protein, the allergen threshold for those with a severe peanut allergy, and 13 peanuts could the difference between life and death. It is reasonable to expect accidental exposure to 1mg of peanut protein or even a whole peanut, but I suspect it would be a lot less likely to be accidentally exposed to 13 peanuts before you realized it was happening!

Genetically Modified Peanuts:
Peanut interests have helped to fund the work of Peggy Ozias-Akins, a horticulture professor at the University of Georgia, Tifton. She wants to develop a plant whose peanuts are free of the three major protein allergens.

Screening the genetic structure of peanuts harvested on an experimental farm, Ozias-Akins is searching for ones with a defunct Ara h 2 gene, which is responsible for a protein that causes reactions in about 90 percent of patients with peanut allergy. When she finds plants with the defunct gene, she’ll use them in a traditional breeding program to produce less-allergenic plants. She expects it will take at least three years to breed the plants and test them in animals.

Ozias-Akins’s team also is trying to disable the Ara h 2 gene by modifying the peanut plant’s genetic structure. She shoots cloned copies of the gene into a peanut, which can create a disabled gene that suppresses the function of the original one. Her team is growing plants with a disabled Ara h 2 gene in the greenhouse and testing whether the peanuts contain the allergy-causing protein.

Success is a long way off. Without the protein, other genes may compensate for its loss, making the new plants more, not less, allergenic than regular peanuts. As a result, any new genetically modified food product would have to go through animal testing and human clinical trials.

And even if Ozias-Akins gets there, it isn’t clear that the world will embrace the results of her work. Says Duke’s Burks, “If you take out all those proteins that cause allergic reactions to the peanut, then you no longer have a peanut.”

While this is interesting, I will let you eat the first bag of genetically modified peanuts and wait to see what happens! I also am not sure that people need to eat peanuts this badly. While peanuts are a healthy source of protein, if you are training your daughter to avoid peanuts then you run the risk of confusing her by saying these modified peanuts (which probably look identical to allergen-laden peanuts) are fine while these other peanuts are bad. This is a similar line of caution that the former head of Anaphylaxis Canada expressed in reaction to the release of the peanut butter replacement, PeaButter. Seems to me that there is no market for this product unless allergenic peanuts are banned and we all eat the genetically modified variety.

While these projects are very interesting, what strikes me is the seemingly small aggregate pool of research on peanut allergy and food allergy as a whole. A 2002 study found only 33 food allergy research projects in the U.S. and less than $ 7M in total annual funding. I suspect that there is more happening now and I am trying to get better data to share with you. According to the WSJ article above, ‘peanuts farmers and food processors have given $ 5.6M over the past decade to eight scientists, mainly for peanut-allergy work’.

I think that this area of research is fascinating. Parents of anaphylactic children should stay current on developments from these and other researchers. While sites and blogs (such as NoPeanuts) will have commentary and information, make sure you also ask your allergist or physician as they may have information that is even more current.