University Times

Virus can trigger celiac disease

Infection with reovirus, a common but otherwise harmless virus, can trigger the immune system response to gluten that may lead to celiac disease, according to new research from Pitt’s School of Medicine and the University of Chicago.

The study, published in Science, further implicates viruses in the development of autoimmune disorders such as celiac disease and type 1 diabetes, and raises the possibility that vaccines eventually could be used to prevent these diseases.

The study demonstrates that a virus that is not clinically symptomatic still can adversely affect the immune system and set the stage for an autoimmune disorder, and for celiac disease in particular. However, the specific virus and its genes, the interaction between the microbe and the host, and the health status of the host are all important factors as well.

Celiac disease affects one in 133 people in the United States, although it is believed that only 17 percent of those with the disease have been diagnosed. It is caused by a weak immune response to the protein gluten, found in wheat, rye and barley, which damages the lining of the small intestine. There is no cure for celiac, and the only effective treatment is a gluten-free diet.

Gluten is a dietary protein that is naturally poorly digested, and therefore more likely to engage the immune system than other proteins, even in people without celiac. However, the way inflammatory immune responses to gluten work is not well understood. In a 2011 study in Nature, researchers from the Chicago laboratory reported that IL-15, a cytokine upregulated in the intestinal lining of celiac disease patients, can break oral tolerance to gluten. However, not all celiac disease patients overexpress IL-15.

The current study, a collaboration with Terence Dermody, chair of Pitt’s Department of Pediatrics and physician-in-chief and scientific director at Children’s Hospital, shows that intestinal viruses can induce the immune system to overreact to gluten and trigger the development of celiac disease. Using two different reovirus strains, the researchers showed how genetic differences between viruses can change how they interact with the immune system. Both reovirus strains induced protective immunity and did not cause overt disease. However, when given to mice, one common human reovirus triggered an inflammatory immune response and the loss of oral tolerance to gluten, while another closely related but genetically different strain did not.

Said Dermody: “We have been studying reovirus for some time, and we were surprised by the discovery of a potential link between reovirus and celiac disease. We are now in a position to precisely define the viral factors responsible for the induction of the autoimmune response.”

The study also found that celiac disease patients had much higher levels of antibodies against reoviruses than those without the disease. The celiac patients who had high levels of reovirus antibodies also had much higher levels of IRF1 gene expression, a transcriptional regulator that plays a key role in the loss of oral tolerance to gluten. This suggests that infection with a reovirus can leave a permanent mark on the immune system that sets the stage for a later autoimmune response to gluten.

The study suggests that infection with a reovirus could be a key initiating event for developing celiac. For example, in the United States, babies usually are given their first solid foods — often containing gluten — and weaned from breastfeeding around six months of age. Children with immature immune systems are more susceptible to viral infections at this stage, and for those genetically predisposed to celiac disease, the combination of an intestinal reovirus infection with the first exposure to gluten could create the right conditions for developing celiac.

The Chicago team is collaborating with graduate student Judy Brown and additional members of Dermody’s team at UPMC to study the common critical features of host-viral interactions driving loss of tolerance to dietary antigens. Members of the Chicago laboratory also are investigating the possibility that other viruses can trigger the same series of events. Together, their work provides more evidence that viruses can trigger development of complex immune-mediated diseases, and raises the possibility that vaccines targeting viruses infecting the intestine could be used to protect children at risk for celiac and other autoimmune disorders.

The study was supported by the National Institutes of Health (NIH), the University of Chicago Celiac Disease Center and Digestive Disease Research Core Center, the Bettencourt Schueller Foundation, the Dutch Sophia Research Foundation and the Austrian Science Fund.

Additional authors were from Vanderbilt University; University of Naples Federico II and CeInGe–Biotecnologie Avanzate, Naples, Italy; Erasmus University Medical Center Rotterdam, Netherlands; Massachusetts General Hospital; Harvard Medical School; the Broad Institute at MIT; Harvard University; the University of Montreal and the Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal; CHU Sainte-Justine Research Center; and Stanford University.

Brain pathway for hand movements identified

Picking up a slice of pizza or sending a text message: Scientists long believed that the brain signals for those and related movements originated from motor areas in the frontal lobe of the brain, which controls voluntary movement.

But that may not always be true. A new brain pathway has been identified by neuroscientists at the School of Medicine and the University of Pittsburgh Brain Institute (UPBI) that could underlie our ability to make the coordinated hand movements needed to reach out and manipulate objects in our immediate surroundings. The discovery was made in a non-human primate model, but researchers believe that a similar pathway is likely to be present in humans as well.

The results, published in Proceedings of the National Academy of Sciences, show that the neural pathway originates not from the frontal lobe but from the posterior parietal cortex (PPC), a brain region that scientists previously thought was involved only in associating sensory inputs and building a representation of extrapersonal space.

Said senior author Peter Strick, Thomas Detre Professor of Neuroscience, distinguished professor and chair of neurobiology in the School of Medicine and scientific director of UPBI: “The findings break the hard-and-fast rule that a furrow in the brain called the central sulcus — a Mississippi River-like separation — splits up the areas controlling sensory and motor function. This has implications for how we understand hand movement and may help us develop better treatments for patients in whom motor function is affected, such as those who have had a stroke. Our study also will have a direct impact on the efforts of researchers studying neural prosthetics and brain computer interfaces.”

More than three decades ago, neuroscientist Vernon Mountcastle proposed the presence of a movement control center in the PPC and termed it a “command apparatus” for operation of the limbs, hands and eyes within immediate extrapersonal space.

In the current study, Strick and his team confirm that such a command apparatus exists and demonstrate a new pathway that connects the PPC directly to neurons in the spinal cord that control hand movement.

The research team conducted three separate experiments in a non-human primate model to make the discovery. They first showed that electrical stimulation in a region of the PPC called “lateral area 5” evoked finger and wrist movements in the animal. When they injected a protein marker into lateral area 5, they found that the marker made its way to the spinal cord and ended in the same location where the neurons controlling hand muscles are known to be present, suggesting a connection.

Said Jean-Alban Rathelot, a research associate in Strick’s laboratory and the lead author of the new study: “The wiring and the connections from the PPC to the spinal cord and the hand look extremely similar to those from the frontal lobe that have been extensively studied. Similar form suggests similar function in controlling movement.”

For their final experiment, they used a strain of rabies virus as a “tracker” since it has the ability to jump across connected neurons. The team found that when they injected the virus into a hand muscle, it was transported back to neurons in the same region of PPC where stimulation evoked hand movements. This result demonstrated the existence of a direct pathway from lateral area 5 to spinal cord regions that control hand muscles.

Said Richard Dum, a research faculty member in neurobiology and a co-author of the study: “We know from previous research that individuals who have suffered brain injuries in this area have trouble with dexterous finger movements like finding keys in a bag containing many other things, which strongly supports our findings.”

Strick and his team believe that the multiple pathways for controlling hand movement from the frontal lobe and the PPC could work together to execute one complex hand task or could work in parallel to speed up movement, much like multiple processors in a computer can enhance efficacy.

The research was supported by NIH and the Pennsylvania Department of Health.

Treatment options for depressed older adults studied

As part of a $13.5 million grant from the Patient Centered Outcome Research Institute (PCORI), researchers at the School of Medicine have launched OPTIMUM, a national multi-institutional study of antidepressant medication regimens for older adults with treatment-resistant depression.

Difficult-to-treat depression is very common among older adults and takes a considerable toll on their quality of life and may increase their risk of developing dementia, feelings of loneliness, serious falls, worsening of other medical conditions and earlier death.

Said Jordan F. Karp, faculty member in psychiatry, anesthesiology and clinical and translational science in the School of Medicine and lead researcher of the Pittsburgh study site: “Depressed older adults often see little benefit from the medications that we typically use to treat depression. At least 50 percent of older adults don’t respond to their existing antidepressant medications and we don’t yet know what the safe and effective treatment options are for these patients. Older adults likely respond differently to medications than younger people, and this study will break new ground by identifying those differences and finding better treatment options that may improve their quality of life.”

Participants in the OPTIMUM study will either be switched to a new drug or have a drug added to their existing antidepressant medication regimen. For those who still do not respond to treatment, they may be switched to a different medication.

In addition to comparing the clinical benefits of these treatments, the researchers also will explore how aging-related factors, such as cognitive changes and medical illnesses, affect the benefits and risks of these different antidepressant strategies.

The Pittsburgh study site aims to recruit 300 participants aged 60 and older. Participants also will receive phone-based assessments from the research team, who will provide simple recommendations and will collaborate with each patient’s primary care physician or psychiatrist.

Other Pitt study researchers included Bruce Rollman and Charles F. Reynolds III.

Said Reynolds: “It’s normal to be concerned about maintaining brain health and independence as you age. A way to preserve these functions and keep people more active and healthy in their community is to reduce risk factors. By finding ways to treat difficult depression, we can reduce a potent risk factor for many of these concerns that plague older adults.”

OPTIMUM will last five years, and is a collaboration among researchers at Pitt’s School of Medicine, Washington University School of Medicine in St. Louis, UCLA, the University of Toronto and Columbia University.

For study details, see www.OPTIMUMstudy.org.

Telomere length may predict cancer risk

The length of the telomere “caps” of DNA that protect the tips of chromosomes may predict cancer risk and be a potential target for future therapeutics, University of Pittsburgh Cancer Institute (UPCI) scientists reported at the American Association for Cancer Research (AACR) annual meeting.

Longer-than-expected telomeres — which are composed of repeated sequences of DNA and are shortened every time a cell divides — are associated with an increased cancer risk, according to research led by scientists from Pitt and Singapore.

Said Jian-Min Yuan, Arnold Palmer Endowed Chair in Cancer Prevention at UPCI and lead or senior author on two studies presented at AACR: “Telomeres and cancer clearly have a complex relationship. Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”

Yuan and his colleagues analyzed blood samples and health data on more than 28,000 Chinese people enrolled in the Singapore Chinese health study, which has followed the health outcomes of participants since 1993. As of the end of 2015, a total of 4,060 participants had developed cancer.

Participants were divided into five groups, based on how much longer their telomeres were than expected. The group with the longest telomeres had 33 percent higher odds of developing any cancer than the group with the shortest telomeres, after taking into account the effect of age, sex, education and smoking habits. That group also had 66 percent higher odds of developing lung cancer, 39 percent higher odds of developing breast cancer, 55 percent higher odds of developing prostate cancer and 37 percent higher odds of developing colorectal cancer. Of all the cancers, pancreatic had the largest increase in incidence related to longer telomeres, with participants in the highest one-fifth for telomere length having nearly 2.6 times greater risk of developing pancreatic cancer, compared to those in the lowest one-fifth for telomere length. Only the risk of liver cancer went down with longer telomeres.

For three cancers, the risk was greatest for both the groups with extremely short and extremely long telomeres — creating a “U-shaped” risk curve. Participants in the group with the shortest telomere length had 63 percent higher odds of stomach cancer, 72 percent higher odds of bladder cancer and 115 percent higher odds of leukemia than the group in the middle of the curve. The group with the longest telomeres had 55 percent higher odds of stomach cancer, 117 percent higher odds of bladder cancer and 68 percent higher odds of leukemia.

“We had the idea for this study more than seven years ago, but it took the laboratory three months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” said Yuan, also a faculty member in epidemiology in the Graduate School of Public Health. “Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”

Additional Pitt authors on these studies are Zhensheng Wang, Renwei Wang and Jennifer Adams-Haduch. Colleagues from the University of Minnesota, the Health Promotion Board, Singapore, and the Duke-National University of Singapore also contributed.

This research was supported by NIH.

 

—Compiled by Marty Levine

The University Times Research Notes column reports on funding awarded to Pitt researchers and on findings arising from University research.

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