The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to Read more

A push for reproducibility in biomedical research

At Emory, several scientists are making greater efforts to push forward to improve scientific research and combat what is being called “the reproducibility crisis.” Guest post from Erica Read more

Exosomes as potential biomarkers of radiation exposure

Exosomes = potential biomarkers of radiation in the Read more

antibodies

Lampreys and the reverse spy problem

Call it the reverse spy problem. If you were a spy who wanted to gain access to a top secret weapons factory, your task would be to fit in. The details of your employee badge, for example, should look just right.

As described in this 2016 JCI Insight paper, Emory and University of Toronto investigators wanted to do the opposite. They were aiming to develop antibody tools for studying and manipulating plasma cells, which are the immune system’s weapons factories, where antibody production takes place. The situation is flipped when we’re talking about antibodies. Here, the goal is to stand out.

Do these guys look like good spies?

Monoclonal antibodies are classic biomedical tools (and important anticancer drugs). But it’s tricky to develop antibodies against the places where antibodies themselves are made, because of the way the immune system develops. To guard against autoimmune disease, antibodies that would react against substances in the body are often edited out.

To get around this obstacle, researchers used organisms that have very different immune systems from humans: lampreys. Emory’s Max Cooper and colleagues had already shown how lampreys have molecules — variable lymphocyte receptors or VLRs — that function like antibodies, but don’t look like them, in terms of their molecular structure.

From the paper:

We reasoned that the unique protein architecture of VLR Abs and the great evolutionary distance between lampreys and humans would allow the production of novel VLRB Abs against biomedically relevant antigens against which conventional Abs are not readily produced because of structural or tolerogenic constraints.

Senior author Goetz Ehrhardt, now at University of Toronto, used to be in Cooper’s lab, and their two labs worked together on the JCI Insight paper. Read more

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How antiviral antibodies become part of immune memory

Weapons production first, research later. During wartime, governments follow these priorities, and so does the immune system.

When fighting a bacterial or viral infection, an otherwise healthy person will make lots of antibodies, blood-borne proteins that grab onto the invaders. The immune system also channels some of its resources into research: storing some antibody-making cells as insurance for a future encounter, and tinkering with the antibodies to improve them.

In humans, scientists know a lot about the cells involved in immediate antibody production, called plasmablasts, but less about the separate group of cells responsible for the “storage/research for the future” functions, called memory B cells. Understanding how to elicit memory B cells, along with plasmablasts, is critical for designing effective vaccines.

EbolaBcells

Activated B cells (blue) and plasmablasts (red) in patients hospitalized for Ebola virus infection, with a healthy donor for comparison. From Ellebedy et al Nature Immunology (2016).

Researchers at Emory Vaccine Center and Stanford’s Department of Pathology have been examining the precursors of memory B cells, called activated B cells, after influenza vaccination and infection and during Ebola virus infection. The Ebola-infected patients were the four who were treated at Emory University Hospital’s Serious Communicable Disease Unit in 2014.

The findings were published Monday, August 15 in Nature Immunology.

“Ebola virus infection represents a situation when the patients’ bodies were encountering something they’ve never seen before,” says lead author Ali Ellebedy, PhD, senior research scientist at Emory Vaccine Center. “In contrast, during both influenza vaccination and infection, the immune system generally is relying on recall.”

Unlike plasmablasts, activated B cells do not secrete antibodies spontaneously, but can do so if stimulated. Each B cell carries different rearrangements in its DNA, corresponding to the specificity and type of antibody it produces. The rearrangements allowed Ellebedy and his colleagues to track the activated B cells, like DNA bar codes, as an immune response progresses. Read more

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Mulligan WABE interview on Ebola vaccine research

A recent WABE “Closer Look” interview with Mark Mulligan, executive director of the Emory Vaccine Center’s Hope Clinic, covers a lot of ground. It starts off with a segment — also aired on Marketplace — from reporter Michell Eloy, who visited the Hope Clinic’s lab. We hear a machine processing blood samples from a study testing an experimental Ebola vaccine and a roundup of Ebola vaccine developments.

We also hear from Carl Davis, postdoc in Rafi Ahmed’s lab, who is part of the DARPA-funded team research project studying the utility of antibodies from Ebola survivors. [Other recent news on this topic from The Scientist.]

Then, reporters Rose Scott and Jim Burress discuss several different Ebola vaccines with Mulligan. One is based on chimpanzee adenovirus, was tested at the Hope Clinic and elsewhere in the USA and the UK, and then in Liberia. While this vaccine was safe and it appears to stimulate the immune system appropriately, the outbreak fizzled out (a good thing!) before it was possible to tell if the vaccine protected people from Ebola infection. Read more

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Galectins defend against bacterial wolves in sheeps’ clothing

To prevent auto-immune attack, our bodies avoid making antibodies against molecules found on our own cells. That leaves gaps in our immune defenses bacteria could exploit. Some of those gaps are filled by galectins, a family of proteins whose anti-bacterial properties were identified by Emory scientists.

In the accompanying video, Sean Stowell, MD, PhD and colleagues explain how galectins can be compared to sheep dogs, which are vigilant in protecting our cells (sheep) against bacteria that may try to disguise themselves (wolves).

The video was produced to showcase the breadth of research being conducted within Emory’s Antibiotic Resistance Center. Because of their ability to selectively target some kinds of bacteria, galectins could potentially be used as antibiotics to treat infections without wiping out all the bacteria in the body. Read more

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Decoding lupus using DNA clues

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.

A team of Emory scientists has been investigating some fundamental questions about lupus: where do the cells that produce the self-reactive antibodies come from? Are they all the same?

In the accompanying video, Kelli Williams, who helps study the disease and has lupus herself, describes what a flare feels like. In addition, Emory researchers Iñaki Sanz, MD and Chris Tipton, PhD explain their findings, which were published this summer in Nature Immunology.

Judging by the number and breadth of abstracts on lupus at the Department of Medicine Research Day (where Tipton won 1st place for basic science poster), more intriguing findings are in the pipeline. Goofy Star Wars metaphors and more explanations of the science here.

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Progress on universal flu vaccine

Flu viruses are constantly mutating and every year the seasonal flu shot is updated to keep up with the viruses that are making people sick. Readers interested in the prospect of a “universal flu vaccine” may have noticed some experimental progress on that theme this week.

The reports build on findings some years ago from Emory Vaccine Center researchers led by Rafi Ahmed. Ahmed’s team had showed that people infected by the 2009 H1N1 flu strain developed broadly protective antibodies, and separately, so did volunteers immunized against the H5N1 avian flu virus.

Some background: the head region of the flu virus’s mushroom-like hemagglutinin protein is more variable, and more exposed to the immune system, while the stem/stalk region is less variable.

The underlying idea is: if someone’s immune system is exposed to flu viruses different enough than what it has seen before (like in the 2009 H1N1 outbreak and the H5N1 study), the antibodies to the stem region become more important and more prominent.

The NIAID team fused the flu hemagglutinin to ferritin to make nanoparticles

The NIAID team fused the flu hemagglutinin to ferritin, a platform for further protein engineering.

This week, what the researchers from NIAID (Nature Medicine) and Scripps/J&J (Science) showed is that experimental vaccines made from the stem region only can be broadly protective in several animal models. This required some protein engineering and reconstruction because chopping off the head of the hemagglutinin protein makes it fall apart.

Emory Vaccine Center’s Walter Orenstein, in comments for Genetic Experts News Service, wrote:

These are animal studies, so we are some way off for development and testing of a vaccine in humans. The technique is promising and a step in the right direction. 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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Carbohydrates not silent to immune system

Donor antibodies, administered intravenously or subcutaneously, make up a commercial product used to treat both immunodeficiencies and inflammatory or auto-immune diseases.

These preparations contain a complex mix of antibodies against glycans, the carbohydrate molecules on the outsides of cells, a Jan. 7 paper in Science Translational Medicine reveals.

At first glance, the findings are remarkable because:

A. Immunologists have long thought that carbohydrates, by themselves, are not good at provoking the immune system. (The assumption was: you need some protein for antigen presentation and getting T cells interested.) The data shows exceptions to the rule.

B. Some of the antibodies react against human carbohydrate structures. Instead of attacking them in an auto-immune fashion, they may actually be blocking viruses or bacteria from using those structures as gateways to infection.

The lab of Stephan von Gunten at the University of Bern collaborated with the National Center for Functional Glycomics led by biochemists Rick Cummings and David Smith at Emory to analyze the spectrum of carbohydrate structures bound by donor antibodies. Read more

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Max Cooper celebrated in Nature for 50 yrs of B cells

Emory’s Max Cooper was celebrated this week in Nature for his discovery of B cells in the 1960s, while working with Robert Good at the University of Minnesota.

Cooper in Good’s laboratory in the 1960s (source: National Library of Medicine)

B cells are immune cells that display antibodies on their surfaces, and can become antibody-secreting plasma cells. Without B cells: no antibodies to protect us against bacteria and viruses. Where B cells come from, and how they can develop such a broad repertoire of antibody tools, was a major puzzle of 20th century immunology, which Cooper contributed to solving. (See the Nature piece to learn why the “B” comes from the name of an organ in chickens.)

The authors did not mention that Cooper is now at Emory studying lampreys’ immune systems, which are curiously different from those of mammals. The similarities and differences provide insights into the evolution of our immune systems. In addition, scientists here are exploring whether lamprey’s antibody-like molecules might be turned into anticancer drugs.

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Alternative antibody architecture

This complex diagram, showing the gene segments that encode lamprey variable lymphocyte receptors, comes from a recent PNAS paper published by Emory’s Max Cooper and his colleagues along with collaborators from Germany led by Thomas Boehm. Lampreys have molecules that resemble our antibodies in function, but they look very different at the protein level. The study of lamprey immunity provides hints to how the vertebrate immune system has evolved.
PNAS-2014-Das-1415580111_Page_4

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