To perform its myriad functions, the immune system must, above all, differentiate between self and non-self — a remarkable selective ability that allows it to detect and disable harmful agents while sparing the body’s own tissues.

If the immune system fails to make this distinction, it can mistakenly launch an assault against the body, causing autoimmune disorders.

Researchers have known the general principle underlying this selective ability for some time, but exactly how immune cells learn to distinguish friend from foe has remained less well understood.

Now, a new study led by researchers at Harvard Medical School identifies a new mechanism that explains how the body’s most powerful immune troops — T cells — learn to tell self and non-self apart.

The work, conducted mainly in mice, was published online June 16 in Cell and is scheduled to appear in the July 7 print issue.

The research shows that the thymus gland — the organ where T cells are born and trained — educates nascent immune cells by exposing them to proteins made by thymus cells that mimic various tissues throughout the body. Specifically, the research demonstrates that by assuming different identities, these specialized thymus cells preview for the maturing T cells self-proteins they would encounter once they leave their native thymus gland.

“Think of it as having your body recreated in the thymus,” said study senior author Diane Mathis, professor of immunology at Harvard Medical School. “For me, it was a revelation to be able to see with my own eyes muscle-like cells in the thymus or several very different types of intestinal cells.”

The findings, Mathis said, shed light on how the adaptive immune system acquires its ability to discern friend from foe. Glitches in this critical recognition system can have grave consequences.

“Our immune system is super powerful. It can kill any cell in our body, it can control any pathogen we encounter, but with that power comes great responsibility,” said study first author Daniel Michelson, an MD/PhD student at Harvard Medical School and a researcher in the Mathis/Benoist lab. “If that power is left unchecked, it can be lethal. In some autoimmune diseases, it is lethal.”

School for T cells

T cells, so named because they mature and learn to do their job in the thymus before they are released into the body, are the immune system’s elite forces charged with multiple functions. They recognize and eliminate pathogens and cancer cells; they form long-term memory of viruses and bacteria encountered in the past; they regulate inflammation and tamp down hyperactive immunity.

But how does a newborn T cell that’s never left the thymus know which proteins are the body’s own and which herald enemy presence?

“T cells get educated in the thymus, but the thymus is not a gut, it’s not a pancreas,” Michelson said. “There’s no reason why these T cells should be able to recognize these organs before they leave the thymus.”

Researchers knew that this early training does take place in the thymus, but the precise teaching tools the gland uses have eluded them.

A molecular explanation for a centuries-old observation

Until the mid-1900s, the thymus provoked little scientific interest because it was deemed vestigial, Michelson said. But as far back as the mid-1800s — well before scientists knew what the thymus does or that an adaptive immune system existed — biologists had already noticed cells in the thymus that looked out of place. Peering into their microscopes throughout the decades, they saw cells that looked like they came from muscle, intestine, and skin. Yet, the thymus was none of the above. The observations made no sense.

The newly published research hearkens back to a very old finding and puts it into a whole new molecular context, Michelson said.

The study showed that these teacher cells, dubbed mimetic cells for their ability to mimic different tissues, work by co-opting various transcription factors — proteins that drive the expression of genes unique to specific tissues. When they do so, the mimetic cells effectively adopt the identities of tissues such as skin, lung, liver, or intestine. They then present themselves to immature T cells to teach them self-tolerance, the team’s experiments showed.

The work shows that T cells-in-training that mistakenly react against self-proteins either receive a command to self-destruct or get repurposed into other types of T cells that don’t kill but instead restrain other immune cells from attacking.

“The thymus says: This cell is autoreactive, we don’t want it in our repertoire, let’s get rid of it,” Michelson said.

Plot twist

Until now, the elimination of self-reactive T cells was thought to be regulated largely by a single protein called AIRE. The Mathis/Benoist lab was critical in elucidating the function of AIRE. Defects in this protein can lead to a serious immune syndrome characterized by the development of multiple types of autoimmune disorders.

Mathis and Michelson went into their current research seeking to map the molecular pathways involved in AIRE function. Instead, they found many cells in the thymus that did not express the AIRE protein but were still capable of adopting the identities of different tissue types. AIRE, the researchers realized, was only part of the story.

The researchers say the newly identified mimetic cells are likely to play a role in various autoimmune diseases associated with the tissue types they mimic, a hypothesis they plan to pursue.

“We think it’s an exciting discovery that may open up a whole new vision of how certain types of autoimmune diseases arise and, more broadly, of the origins of autoimmunity,” Mathis said.

The researchers said their next steps are to acquire an even deeper understanding of the molecular mechanisms that underlie T cell education, to study the association between individual mimetic cell types and T cell function and dysfunction, and to determine how the mechanism plays out in the human thymus.

Study co-authors included Koji Hase of Keio University, Tsuneyasu Kaisho of Wakayama Medical University, and Christophe Benoist of HMS.

The work was funded by National Institutes of Health grants R01AIo88204, Ro1DKo60027, and T32GM007753.

This research has been ongoing in School of Physics Professor Flavio Fenton’s lab with his student Noah DeTal and research scientist Abouzar Kaboudian. Their latest findings are published in the paper, “Terminating Spiral Waves with a Single Designed Stimulus: Teleportation as the Mechanism for Defibrillation,” in the journal Proceedings of the National Academy of Science.

The Problem with Spiral Waves

Electrical waves enable the heart to contract and send blood throughout the body. When a wave becomes a spiral, its rotation is faster than the heart’s natural pacemaker and suppresses normal cardiac function. Instead, one spiral wave can spawn more spirals until the heart is overtaken by multiple spiral waves, leading to disorganized contraction, and preventing the heart from supplying the body with blood.

For years, scientists and doctors have worked to find the best way to stop spiral waves before they get out of control. Yet for over half a century the best method has been a single strong electric shock. The 300 joules of energy required for defibrillation excites not just the heart cells, but the entire body, making it very painful for the patient.

Over the years researchers have experimented with using weaker shocks to reorganize arrythmias.

“We still did not have a clear understanding of how defibrillation worked,” said Fenton. “This research explains the minimum energy required to actually terminate an arrhythmia and I believe it clarifies the mechanism for defibrillation.”

The Symmetrical Solution

The researchers determined that because spiral waves develop in pairs, they must also be terminated in pairs. Every spiral wave is connected to another spiral going in the opposite direction. Bringing the spiral waves together through an electric shock instantly eliminates both waves.

The researchers used a mathematical method to identify the key regions for electrical shock stimulation to target spiral waves. They determined that a stimulus delivered to the tissue areas a spiral wave just left and were able sustain a new wave could defibrillate the heart.

In the process of terminating the spiral waves, the researchers were actually moving them, as well, through a concept they named “teleportation.”

“We call it teleportation because it’s very similar to what you see in science fiction where something is moved instantaneously from one place to another,” Fenton said.

Spiral waves can be teleported anywhere in the heart using this approach. In particular, spiral waves can be moved so that they collide with their partners, which extinguishes them. Fenton explained that for successful defibrillation to occur, all pairs of spiral waves must be eliminated in this manner.

The researchers plan to further test this concept using two-dimensional cultures of heart cells.

“The next step is to is to prove experimentally that what we did numerically is possible,” Fenton said.

Eventually, Fenton added, they want to develop methods that could be used clinically, and are partnering with cardiologists at Emory University on this work.

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Materials provided by Georgia Institute of Technology. Note: Content may be edited for style and length.

Most biological materials, for example, amino acids, fossils, sedimentary rocks, plants, microbes, proteins and lipids, have strong organic fluorescence signals that can be detected by specialized scanning cameras. In a study published in Nature Scientific Reports recently, the research team reported that the Biofinder is so sensitive that it can accurately detect the bio-residue in fish fossils from the 34-56 million year-old Green River formation.

“The Biofinder is the first system of its kind,” said Anupam Misra, lead instrument developer and researcher at the Hawai’i Institute of Geophysics and Planetology at the UH Manoa School of Ocean and Earth Science and Technology (SOEST). “At present, there is no other equipment that can detect minute amounts of bio-residue on a rock during the daytime. Additional strengths of the Biofinder are that it works from a distance of several meters, takes video and can quickly scan a large area.”

Though the Biofinder was first developed in 2012 by Misra, advances supported by the NASA PICASSO program culminated in the latest color version of the compact Biofinder.

Finding evidence of biological residue in a vast planetary landscape is an enormous challenge. So, the team tested the Biofinder’s detection abilities on the ancient Green River fish fossils and corroborated the results through laboratory spectroscopy analysis, scanning electron microscopy and fluorescence lifetime imaging microscopy.

“There are some unknowns regarding how quickly bio-residues are replaced by minerals in the fossilization process,” said Misra. “However, our findings confirm once more that biological residues can survive millions of years, and that using biofluorescence imaging effectively detects these trace residues in real time.”

The search for life — which may be existing or extinct — on planetary bodies is one of the major goals of planetary exploration missions conducted by NASA and other international space agencies.

“If the Biofinder were mounted on a rover on Mars or another planet, we would be able to rapidly scan large areas quickly to detect evidence of past life, even if the organism was small, not easy to see with our eyes, and dead for many millions of years,” said Misra. “We anticipate that fluorescence imaging will be critical in future NASA missions to detect organics and the existence of life on other planetary bodies.”

“The Biofinder’s capabilities would be critical for NASA’s Planetary Protection program, for the accurate and no-invasive detection of contaminants such as microbes or extraterrestrial biohazards to or from planet Earth,” said Sonia J. Rowley, the team biologist and co-author on the study.

Misra and colleagues are applying to have the opportunity to send the Biofinder on a future NASA mission.

“The detection of such biomarkers would constitute groundbreaking evidence for life outside of planet Earth,” said Misra.

Story Source:

Materials provided by University of Hawaii at Manoa. Original written by Marcie Grabowski. Note: Content may be edited for style and length.

A new study published today reveals that population declines have been greatest among species that migrate to areas with more human infrastructure — roads, buildings, power lines, wind turbines — as well as higher population densities and hunting levels.

Habitat degradation and climate change have also played a part in driving long-term declines.

The research team hope their work will help inform how best to target conservation efforts.

Dr James Gilroy, from UEA’s School of Environmental Sciences, said: “We know that migratory birds are in greater decline than non-migratory species, but it’s not clear why.

“We wanted to find out where in their life cycles these migratory species are most exposed to human impacts.”

The research team identified 16 human-induced threats to migratory birds, including infrastructure associated with bird disturbance and collisions, conversion of land from natural habitat to human land use, and climate change.

Advances in satellite imagery allowed the team to map each of the 16 threats across Europe, Africa and Western Asia. The team also created the first ever large-scale map of hunting pressure across the region.

A total of 103 species of migrating birds were studied, including many rapidly declining species like the Turtle Dove and the Common Cuckoo, using large-scale datasets.

The team calculated ‘threat scores’ for factors such as habitat loss and climate change, across breeding locations, as well as non-breeding ranges.

They then explored the relationships between these threat scores and bird population trends calculated from 1985 to 2018 by the Pan-European Common Bird Monitoring Scheme (PECBMS).

Dr C,laire Buchan from UEA’s School of Biological Sciences, said: “We found that human modification of the landscape in the birds’ distribution ranges in Europe, Africa and Western Asia is associated with declining numbers of over 100 Afro-Eurasian migratory birds.

“When we talk about modification of the landscape, we mean things like roads, buildings, powerlines, wind turbines — anything that isn’t naturally there.

“One of the biggest impacts seems to be caused by things that would kill a bird outright — for example flying into a wind turbine, a building, being electrocuted on a powerline, hit by a vehicle or hunted. We found that exposure to these human-induced ‘direct mortality’ threats in the bird’s wintering ranges are reflected in population decreases in breeding birds.”

Dr Aldina Franco, also from UEA’s School of Environmental Sciences, said: “Our findings are important because we need to understand where declining species are being most impacted by humans across their seasonal migrations. Pinpointing where birds are most exposed to these threats could help us target conservation actions.”

This research was led by UEA (UK) in collaboration with the University of Porto and the University of Lisbon (both Portugal), and the Czech Society for Ornithology (Czech Republic).

Researchers working on this project have received funding from the Natural Environment Research Council (NERC), the European Commission and the Portuguese Foundation for Science and Technology.