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New Regulation Mechanism Controls Survival of Immune Cells and Influences the Diversity of Antibodies

Cooperation of the Laboratories of Klaus and Nikolaus Rajewsky at Harvard Medical School and the MDC

B cells are important elements of the immune system. In the course of an infection, they produce antibodies that systematically fight bacteria, viruses, and other pathogens. The power of these cells depends on the diversity of their antibodies. Scientists at Harvard Medical School in Boston, Massachusetts, USA and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, have now discovered a new mechanism which controls the development of these immune cells and influences the arsenal of antibody variants. The results of Sergej Koralov, Stefan Muljo, Klaus Rajewsky (all of them at Harvard), Azra Krek, Nikolaus Rajewsky (both MDC) and colleagues have been published in the current issue of the journal Cell* (Vol. 132, Nr. 5, pp. 860-874, 2008).

B cells are a subtype of white blood cells (lymphocytes) which are generated in the bone marrow. Before a B cell is able to produce antibodies, it must go through various complex steps to eventually generate a B cell receptor. This sensor enables the B cell to recognize pathogens. Once such pathogens are detected, the cell produces specific antibodies, which directly attack them. The huge diversity of antibodies, upon which the body depends to fight a huge variety of pathogens, is based on the random combination of DNA segments of the B cell receptor genes.

The research groups of the Harvard Medical School and the MDC have now discovered  another regulatory mechanism controling B lymphocyte development. They could show that microRNAs, tiny RNA molecules, are important for the survival of developing B cells and also play a role in the production of antibody variants.

Ribonucleic acid (RNA) is a chemical relative of DNA. It is the carrier of the genetic information which the cell needs to produce proteins. That is, the cell translates the construction plan for proteins from the language of genes, the DNA, into the language of RNA, and delivers it to the cell’s protein factories.

Aside from this messenger RNA, there is another RNA variety called microRNA. MicroRNAs bind to specific regions of messenger RNA and, thus, block the production of the corresponding protein. This way, microRNAs regulate which proteins are produced by the body.

To investigate the influence of microRNAs on the development of B cells, the researchers blocked a protein (Dicer) in immature B cells which is responsible for the production of all microRNAs. These modified cells generate more proteins whose production is normally inhibited by microRNAs. As a result, the cells could not develop into mature B cells and, therefore, could not generate antibodies.

The researchers applied an exemplary approach to the emerging field of systems biology. They combined experimental and bioinformatical mathematical methods and were then able to make precise predictions about which microRNAs are of vital importance for developing B cells and why the cells die in  the absence of the small RNA molecules.

With evolutionary sequence analysis and statistical modelling, they could identify microRNAs which inhibit a protein called Bim. High concentrations of Bim cause cell death, a process which is prevented by these microRNAs stop and, thus, cells survive.

The researchers could verify these predictions with a second experiment. When microRNAs and Bim were both blocked, some cells developed into mature B cells. Examination of these B cells led the scientists to the conclusion that, in the absence of microRNAs, antibody variants are generated which are not found in normal B cells.

*Dicer Ablation Affects Antibody Diversity and Cell Survival in the B
Lymphocyte Lineage

Sergei B. Koralov1, Stefan A. Muljo1, Gunther R.
Galler1, Azra Krek2, Tirtha Chakraborty1, Chryssa
Kanellopoulou4, Kari Jensen1, Bradley S. Cobb5, Matthias Merkenschlager5, Nikolaus Rajewsky2, and
Klaus Rajewsky1


Disease Institute and Department of Pathology, Harvard
200 Longwood Avenue, Boston,

for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany

3New YorkUniversity,
Department of Physics, 4 Washington Place, New York, NY10003, USA

Dana-Farber Cancer Institute, Department of Cancer Biology, Harvard Medical
School, 44 Binney Street, Boston, MA 02115, USA

Development Group, Medical Research Council Clinical Sciences Center, Imperial
College London, W12 0NN England, United Kingdom

Stefan Muljo, Sergei Koralov, Klaus Rajewsky, Tirtha Chakraborty (Photo: private)

Nikolaus Rajewsky , group leader at the MDC (Photo: David Ausserhofer, Copyright: MDC)

Azra Krek from the MDC Photo: private

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Robert-Rössle-Straße 10; 13125 Berlin; Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax:  +49 (0) 30 94 06 - 38 33

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