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 New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience

nachricht Wintering ducks connect isolated wetlands by dispersing plant seeds
22.02.2017 | Utrecht University

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

Positrons as a new tool for lithium ion battery research: Holes in the electrode

22.02.2017 | Power and Electrical Engineering

New insights into the information processing of motor neurons

22.02.2017 | Life Sciences

Healthy Hiking in Smart Socks

22.02.2017 | Innovative Products

VideoLinks
B2B-VideoLinks
More VideoLinks >>>