Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New understanding of tiny RNA molecules could have far-ranging medical applications

01.07.2013
A team led by scientists at The Scripps Research Institute (TSRI) has identified a family of tiny RNA molecules that work as powerful regulators of the immune response in mammals. Mice who lack these RNA molecules lose their normal infection-fighting ability, whereas mice that overproduce them develop a fatal autoimmune syndrome.

"This finding gives us insights into immune regulation that could be very helpful in a range of medical applications, from viral vaccines to treatments for autoimmune diseases," said Changchun Xiao, assistant professor in TSRI's Department of Immunology and Microbial Science and senior investigator for the study, which appears in the June 30, 2013 issue of Nature Immunology.

Unraveling a Crucial Process

The finding concerns a key interaction between T cells and B cells, the allied lymphocyte armies that make up most of the adaptive immune system of mammals. B cells, which produce antibodies, usually lie in wait for pathogens in special zones called follicles within lymph nodes and the spleen. But to start proliferating normally and pumping out antibodies to fight an infection, these B cells have to be assisted, in effect, by T cells known as "follicular helper" T cells (TFH cells). "The TFH cells have to migrate into the B cell follicles and physically contact the B cells in order to provide help to them," said Xiao. "However, the molecular pathways that control TFH cell differentiation and migration have not been well understood."

In 2009, other researchers proposed that this crucial process requires the suppression of the miR-17~92 family of RNA molecules. These are among the thousands of short RNA molecules (often known as micro-RNAs, miRs, or miRNAs) that are made by mammalian cells and are meant to do their jobs while in RNA form. Typically an miRNA works inside the cell as a basic regulator or "dimmer switch" for the activity of tens to hundreds of genes—it binds to transcripts of those genes and slows down their translation into proteins.

Xiao, who had been studying the miR-17~92 family since 2005, decided to examine their role in TFH differentiation. His team began by measuring the levels of these miRNAs in young, "naïve" T cells and in the TFH cells to which these T cells gave birth after exposure to foreign antigens.

Surprising Finding

To the researchers' surprise, the miR-17~92s showed the opposite pattern of expression than expected: their levels jumped as the naïve T cells began differentiating into TFH cells, but fell back by the time the process was finished. The finding suggested that, far from acting as a brake on TFH differentiation, miR-17~92s work as enablers of the process.

To confirm their suspicion, team members developed mutant mouse lines in which some or all of the miR-17~92 miRNAs were knocked out of T cells. These miR-17~92-deficient T cells turned out to be much less able to differentiate into TFH cells. As a result, the follicle-dwelling B cells that depend on TFH assistance also lost much of their ability to respond to an immune challenge. "These mutant mice showed a deficient antibody response to a standard immune-provoking protein," said Seung Goo Kang, a postdoctoral research associate in the Xiao laboratory who was the leading author of the study.

Collaborating TSRI scientists led by John Teijaro, a senior research associate in the laboratory of Michael B. A. Oldstone, professor in the Department of Immunology and Microbial Science, showed further that these transgenic mice—unlike ordinary lab mice—could not clear a chronic virus infection that is used as a standard challenge in immunological experiments.

By contrast, when the team raised transgenic mice whose T cells produced four to six times the normal amount of miR-17~92s, these T cells differentiated into TFH cells spontaneously—that is, without an immune-stimulating inoculation.

These mice developed antibody responses to their own tissues, and died young, with swollen spleen and lymph nodes. "The accumulation of autoantibodies is also seen in lupus and other autoimmune diseases in humans," said Wen-Hsien Liu, another postdoctoral research associate in the Xiao laboratory and a co-first author of the paper.

Important Targets

Liu and Kang were able to track down a key target gene of miR-17~92s, which the miRNAs suppress to enable TFH cell differentiation. The targeted gene codes for Phlpp2, a recently discovered signaling inhibitor. "Lowering Phlpp2 protein levels in our miR-17~92-knockout T cells restored much of their ability to become TFH cells," Kang said.

"Phlpp2 is one important target, but we believe there are others too, and we are now looking for those," Xiao said. He and his colleagues also plan to investigate methods for manipulating miR-17~92s and their TFH cell-related pathways, in order to boost antibody responses – to vaccines for example—or alternatively to lower autoantibody productions in people with autoimmune diseases.

The study, "miR-17~92 family microRNAs are critical regulators of T follicular helper cell differentiation," was a collaboration that also involved the laboratory of Hai Qi at Tsinghua University in Beijing and the laboratory of Eric Verdin at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. A co-first author of the study was Peiwen Lu of the Qi laboratory; other co-authors were Hyung W. Lim of the Verdin laboratory, Daniel Fremgen of the Oldstone laboratory and Hyun Yong Jin and Jovan Shepherd of the Xiao laboratory.

The study was funded by the PEW Charitable Trusts, the Cancer Research Institute, the Lupus Research Institute, the American Heart Association (grant 11POST7430106 ), the National Institutes of Health (R01AI019484 and R01AI087634) and the National Natural Science Foundation of China (81161120405).

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>