New Regulation Mechanism Controls Survival Of Immune Cells And Influences The Diversity Of Antibodies
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 a germ is detected, the cell produces specific antibodies, which directly attack the pathogens. 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 fragments of the B cell receptor genes.
The research groups of the Harvard Medical School and the MDC have now been able to detect another regulation mechanism of B lymphocyte development. They could show that microRNAs, tiny RNA fragments, 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. Those small RNA fragments 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 fragments. 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, the 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
References
1. Immune Disease Institute and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
2. Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany
3. New York University, Department of Physics, 4 Washington Place, New York, NY 10003, USA
4. The Dana-Farber Cancer Institute, Department of Cancer Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA
5. Lymphocyte Development Group, Medical Research Council Clinical Sciences Center, Imperial College London, W12 0NN England, United Kingdom
Photos can be downloaded from the internet here.
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Un nou regulament de control mecanism de supravieþuire a celulelor imune ºi influenþe de o diversitate de anticorpi anti - - New Regulation Mechanism Controls Survival Of Immune Cells And Influences The Diversity Of Antibodies - articole medicale engleza - startsanatate