Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

The structure behind the switch

07.04.2003


USC researchers uncover mechanism of class- switching in antibodies



A team of scientists from the Keck School of Medicine of USC has, for the first time, described a new, stable DNA structure in both mouse and human cells-one which differs from the standard Watson-and-Crick double helix and plays a critical role in the production of antibodies, or immunoglobulins.
The research will be published online in the journal Nature Immunology this week, and will appear in print in the journal’s May issue.

"The way in which the five different immunoglobulin classes are created is a nearly perfect system," notes Michael Lieber, M.D., Ph.D., professor of pathology and biochemistry and the study’s principal investigator. "And yet, the DNA mechanism for how a cell switches from producing one class to producing another has remained a mystery for almost 20 years."



The typical antibody molecule is shaped like the letter Y. The region at the end of each of the two short arms houses the receptors that recognize and bind with a specific foreign object, or antigen. These receptors are created via a well-described cutting-and-splicing mechanism that occurs within the nuclear DNA of B cells, which are key components of the immune system.

The long stem, or handle, of the Y determines to which immunoglobulin class an antibody belongs. It, too, is created via a B-cell nuclear cut-and-paste job, but the mechanics here are much more complicated-and until now, much less well understood.

An immunoglobulin’s class is important because it determines where in the body the antibody’s efforts will be concentrated. While immunoglobulin M (IgM) works mostly in the bloodstream, for instance, IgG can easily slip through a capillary’s walls and cross the placenta, and IgA can make itself at home in the lungs, the digestive tract and the body’s secretions (saliva, sweat, tears).

Although antibodies are needed in all areas of the body, they all begin life as IgM, explains Kefei Yu, Ph.D., the paper’s first author and a research associate at the USC/Norris Comprehensive Cancer Center. In order to go where they’re needed, the antibodies need to change their class-to go from being IgM to being IgG or IgA or IgE or IgD.

By undergoing this so-called class switch, Lieber explains, the body can send "the same antibody missile to different areas of the body."

The switch is made by cutting the DNA so that the code for IgM and any of the other class types that might precede the desired immunoglobulin class are abolished.

What Lieber, Yu and their colleagues have found is that, in order for such a cut to be made, the DNA that codes for the desired class must first form a stable, relatively permanent bond with the RNA strand that is transcribing it. Only when this aptly named R-loop is present can the DNA be cut and spliced to create an antibody of a different immunoglobulin class.

This is not the normal process by which DNA is cut. Usually, an enzyme cuts DNA based on a particular nucleotide sequence; the sequence acts as a signal to the enzyme, pointing to the precise place the cut is to be made. But in immunoglobulin class switching, Yu explains, there is no specific signaling sequence-instead, as the Keck School scientists proved in their paper, it is the mere physical presence of the R-loop that tells the enzymes where the cut is to be made. "The protein enzyme is not recognizing a sequence, but rather an altered DNA structure," Yu says.

This is also not the normal process by which DNA is transcribed. Generally, DNA being transcribed serves as a template for the creation of a protein or enzyme. The double-stranded DNA separates, and then an RNA strand begins to pair up with each individual DNA nucleotide on one of those strands, creating a sort of mirror image of the DNA; this is the transcript. During this process, only the leading edge of the RNA remains bonded to the DNA nucleotides it’s transcribing. The rest of the RNA strand hangs off like the tail of a kite; when the RNA reaches the end of the stretch of DNA to be transcribed, the entire RNA strand drops away from the DNA and leaves the nucleus.

Not so in immunoglobulin production, says Yu. For one thing the part of the DNA that’s transcribed during immunoglobulin class switching doesn’t actually produce anything-it’s called a silent transcript. And for another, the RNA strand remains firmly attached to each and every DNA nucleotide it touches-creating a sort of permanent RNA sandwich, with the RNA between two strands of DNA, though only attached to one of them. That’s the R-loop. And it is what makes immunoglobulin class switching remarkable and unique.

"The whole process is more sophisticated than we first thought," Yu remarks.

And it may also be more illuminating than they thought. According to Yu and Lieber, the discovery of the R-loop may shed light on the development of B-cell cancers like myelomas. "We believe something may be going wrong during this class-switching recombination event that activates an oncogene," says Yu. "That is not proven yet, but it is something we will be looking at in the laboratory."

Kefei Yu, Frederic Chedin, Chih-Lin Hsieh, Thomas E. Wilson, Michael R. Lieber, "R-loops at immunoglobulin class switching regions in the chromosomes of stimulated B cells." Nature Immunology, www.nature.com/natureimmunology.


Lori Oliwenstein | EurekAlert!
Further information:
http://www.usc.edu/

More articles from Life Sciences:

nachricht Closing in on advanced prostate cancer
13.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht Visualizing single molecules in whole cells with a new spin
13.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

A whole-body approach to understanding chemosensory cells

13.12.2017 | Health and Medicine

Water without windows: Capturing water vapor inside an electron microscope

13.12.2017 | Physics and Astronomy

Cellular Self-Digestion Process Triggers Autoimmune Disease

13.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>