Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

Immunology

Following lupus troublemaker cells, via DNA barcodes

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.

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Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.

Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?

Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.” It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.

The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.

When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.

“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,” Tipton says.

To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters). Read more

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Subset of plasma cells display immune ‘historical record’

You may have read about recent research, published in Science, describing a technique for revealing which viruses have infected someone by scanning antiviral antibodies in the blood.

Emory immunologists have identified corresponding cells in which long-lived antibody production resides. A subset of plasma cells keep a catalog of how an adult’s immune system responded to infections decades ago, in childhood encounters with measles or mumps viruses.

The results, published Tuesday, July 14 in Immunity, could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

“If you’re developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen,” says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare’s Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Lee says that her team’s research on plasma cells in humans provided insights unavailable from mice, since mice don’t live as long and their plasma cells also have a different pattern of protein markers. More here.

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Microbiome enthusiasm at Emory

At what point did the human microbiome become such a hot topic?

When it was shown that babies born by Cesarean section are colonized with different bacteria than those born vaginally? With the cardiovascular studies of microbial byproducts of meat digestion? With the advent of fecal transplant as a proposed treatment for Clostricium difficile infection?

The bacteria and other microbes that live within the human body are thought to influence not only digestive health, but metabolic and autoimmune diseases as well, possibly even psychiatric and neurodevelopmental disorders. The field is being propelled by next-generation sequencing technology, and Nature had to publish an editorial guarding against hype (a major theme: correlation is not causation).

At Emory, investigators from several departments are involved in microbiome-related work, and the number is expanding, and assembling a comprehensive list is becoming more difficult. Researchers interested in the topic are planning Emory’s first microbiome symposium in November, organized by Jennifer Mulle (read her intriguing review on autism spectrum disorders and the microbiome).

Microbial genomics expert Tim Read, infectious diseases specialist Colleen Kraft and intestinal pathologist Andrew Neish have formed an Emory microbiome interest group with a listserv and seminars.

Microbiome symposium sponsors: ACTSI, Hercules Exposome Center, Emory University School of Medicine, Omega Biotek, CFDE, Ubiome. Read more

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Pre-hospital recognition of severe sepsis

 

Severe sepsis, a consequence of the body’s response to infection, is a major cause of death in hospitals. The earlier that doctors recognize that a patient has sepsis, the earlier the patient can be treated with antibiotics, fluids and other measures, and the better the chance of survival.

That’s why critical care and emergency medicine researchers have been looking for ways to spot whether someone coming to the hospital might have sepsis, even before arrival.

At Emory, Carmen Polito, Jonathan Sevransky and colleagues recently published a paper in the American Journal of Emergency Medicine on an emergency medical services screening tool for severe sepsis. Polito and Sevransky are in the division of pulmonary, allergy, critical care and sleep medicine in the Department of Medicine. The tool was evaluated based on Grady emergency medical services data from 2011 and 2012.

“Sepsis is largely a face without a name in the EMS setting, “ Polito says. “The goal of our study was to create a tool to assist EMS providers in naming this deadly condition at the point of first medical contact. Similar to other life-threatening, time-sensitive conditions like stroke and heart attack, naming sepsis is the first step in developing coordinated care pathways that focus on delivering rapid, life-saving treatment once the patient arrives at the hospital.”

Read more

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Why checkpoint inhibitors fall short for some types of cancer

The big news from the recent American Society of Clinical Oncology meeting has been largely about immunotherapy drugs, also known as checkpoint inhibitors. These drugs have been shown to be effective in prolonging life in patients with some types of cancer, such as lung cancer and melanoma, but not others, such as colorectal and prostate cancer.

Lab Land asked oncologist Bradley Carthon and immunology researcher Haydn Kissick why. Both Carthon’s clinical work and Kissick’s lab research on prostate cancer are featured in the new issue of Winship magazine, but the prostate feature just touches on checkpoint inhibitors briefly.

Carthon says the reason checkpoint inhibitors haven’t moved the needle with prostate cancer is “likely due to the absence of infiltration of the prostatic tissue by tumor-associated lymphocytes.”

Checkpoint inhibitors are supposed to unleash the immune system, but if the immune cells aren’t in contact with the cancer cells so that the drugs can spur them into action, they won’t help much. Carthon says: “The answer may be to ‘prime’ the prostate with an agent, then introduce the checkpoint inhibitors.” Read more

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Why HIV’s cloak has a long tail

Virologists at Emory, Yerkes and Children’s Healthcare of Atlanta have uncovered a critical detail explaining how HIV assembles its infectious yet stealthy clothing.

Paul Spearman, MD

For HIV to spread from cell to cell, the viral envelope protein needs to become incorporated into viral particles as they emerge from an infected cell. Researchers led by Paul Spearman have found that a small section of the envelope protein, located on its “tail”, is necessary for the protein to be sorted into viral particles.

The results were published June 1 in Proceedings of the National Academy of Sciences. Read more

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HIV virions attached to cell membrane

The third winner of the Best Image contest from the Postdoctoral Research Symposium, from postdoc Joshua Strauss in electron microscopist Elizabeth Wright’s lab.

Strauss explains:

Tetherin is a host cell factor that mechanically links HIV-1 to the plasma membrane. This is the first time anyone has imaged tethered HIV-1 by cryo-electron tomography. In doing so, we were able to learn about the length and arrangement of the tethers.

Note: Tetherin also studied by Paul Spearman + colleagues.Joshua_Strauss_OPE_Image

Cryo-electron tomography is an imaging technique which enables scientists to look at biological specimens in a “native-like” (frozen hydrated) state, without the chemical fixatives or heavy metal stains typically used for conventional electron microscopy.

The 3D reconstruction was manually segmented to highlight the different viral and cellular components: HIV-1 virions (lavender), mature conical-cores (aqua blue), immature Gag lattice (pink), plasma membrane (peach), rod-like tethers (sea green).

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Test of megadose vitamin D in intubated critical care patients

Whether dietary supplementation with vitamin D is beneficial, in terms of preventing disease, has been controversial. However, vitamin D has been reported to increase immune cells’ production of microbe-fighting proteins. That’s why Emory doctors have been testing whether high doses of vitamin D could be helpful for critical care patients, who need to ward off infections.

The results of a small-scale clinical trial, presented in Denver this week at the American Thoracic Society meeting, suggest that high doses of vitamin D could decrease the length of hospital stays in critically ill patients with respiratory failure. Read more

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Spotlight on liver fibrosis

For a May explainer, we’d like to spotlight liver fibrosis. Two recent papers from Emory research teams in the journal Hepatology focus on this process.

Liver fibrosis is an accumulation of scar tissue and proteins outside cells that occurs as a result of chronic damage to the liver. It involves inflammation and immune cells, as well as activation of a type of cell in the liver (hepatic stellate cells), which usually stores fat and vitamin A. Fibrosis and cirrhosis are not the same. Think of it this way: cirrhosis is the late stage of the disease, but fibrosis is how someone can get there.

The liver has a remarkable, even mythical, ability to regenerate, but there is a long list of ways that someone can injure this most vital organ. Quickly – take too much acetaminophen (the most common cause of acute liver failure in the United States). More slowly – develop a hepatitis C infection. Drink large quantities of alcohol. Or something with more subtle effects: consume a diet high in sugar, which can lead to fatty liver. The relationship between fatty liver and more serious liver disease is currently under investigation.

One of the Hepatology papers comes at liver fibrosis from a malaria angle. Patrice Mimche, Tracey Lamb and colleagues show the involvement of EphB2 tyrosine kinase, a signaling molecule not previously known to be involved in liver fibrosis.

Malaria parasites have a complex life cycle, growing in the liver and then in the blood. Lamb says an important part of her paper was the finding that in mouse malaria infection, EphB2 is activated during the blood stage on immune cells infiltrating into the liver. EphB2 (an active drug discovery target) may be acting as a tissue-specific adhesion molecule, she says.

Read more

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Risk triangle: immune gene, insecticide, Parkinson’s

Genetic variation and exposure to pesticides both appear to affect risk for Parkinson’s disease. A new study has found a connection between these two risk factors, in a way that highlights a role for immune responses in progression of the disease.

The results are published in the inaugural issue of NPJ Parkinson’s Disease.

The findings implicate a type of pesticide called pyrethroids, which are found in the majority of commercial household insecticides, and are being used more in agriculture as other insecticides are being phased out. Although pyrethroids are neurotoxic for insects, exposure to them is generally considered safe for humans by federal authorities.

The study is the first making the connection between pyrethroid exposure and genetic risk for Parkinson’s, and thus needs follow-up investigation, says co-senior author Malu Tansey, PhD, associate professor of physiology at Emory University School of Medicine.

The genetic variation the team probed, which has been previously tied to Parkinson’s in larger genome-wide association studies, was in a non-coding region of a MHC II (major histocompatibility complex class II) gene, part of a group of genes that regulate the immune system.

“We did not expect to find a specific association with pyrethroids,” Tansey says. “It was known that acute exposure to pyrethroids could lead to immune dysfunction, and that the molecules they act on can be found in immune cells; now we need to know more about how longer-term exposure affects the immune system in a way that increases risk for Parkinson’s.”

“There is already ample evidence that brain inflammation or an overactive immune system can drive the progression of Parkinson’s. What we think may be happening here is that environmental exposures may be altering some people’s immune responses, in a way that promotes chronic inflammation in the brain.”

For this study, Emory investigators led by Tansey and Jeremy Boss, PhD, chair of microbiology and immunology, teamed up with Stewart Factor, DO, head of Emory’s Comprehensive Parkinson’s Disease Center, and public health researchers from UCLA led by Beate Ritz, MD, PhD. The first author of the paper is MD/PhD student George T. Kannarkat.

The UCLA researchers used a California state geographical database covering 30 years of pesticide use in agriculture. They defined exposure based on proximity (someone’s work and home addresses), but did not measure levels of pesticides in the body. Pyrethroids are thought to decay relatively quickly, especially in sunlight, with half-lives in soil of days to weeks. Read more

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