microRNA-155 and B-lymphocytes: mutate, but in moderation!
DNA modification is an undesirable event for the body. Exceptions to this rule include situations in which the body needs to fight infections. To encode antibodies to all possible microbial and viral antigens in advance is an impossible task, therefore, when encountering an antigen unfamiliar to the immune system, B lymphocytes resort to a complex and potentially unsafe strategy to create antibodies specific to it – they purposefully change part of their DNA.
Two groups of scientists at Rockefeller University (New York), working under the leadership of Dr. Nina Papavasiliou and Michael Nussenzweig, independently identified a tiny microRNA-155 molecule that directly binds and blocks a powerful gene mutator, the AID enzyme. By controlling the level of this enzyme, microRNA-155 occupies a very responsible position – it regulates the fight of the immune system against microbes, while preventing the formation of very aggressive malignant diseases: leukemia and B-cell lymphomas.
Previously, microRNA-155 was known for its role in the development of malignant diseases, but using different approaches and methods, two groups of researchers proved the same fact: microRNA-155 directly controls the level of AID.
In B-lymphocytes, AID binds specifically to a small fragment of DNA encoding variable sections of the antibody molecule. Minor mutations of this fragment lead either to the appearance of new antibodies to fight previously unknown pathogens, or to an increase in the affinity of antibodies to the main target, which increases their effectiveness. By providing the necessary level of the AID enzyme in the cell, microRNA-155 prevents mutations of other DNA fragments.
Papavasiliou group researchers have found that the lack of the AID enzyme reduces the ability of the immune system to fight infections. At the same time, its excess does not ensure the synthesis of a more heterogeneous and effective repertoire of antibodies. Instead, an excess of the enzyme causes fragments of genes encoding antibodies to swap places with genes located on other chromosomes. This process – the translocation of genes – in certain conditions can lead to the development of malignant diseases.
As part of a parallel study, the scientists of the second group worked with two lines of transgenic mice. In animals of one line, microRNA-155 did not bind to the AID enzyme due to modification of its binding center, and in animals of the second line, microRNA-155 was absent altogether. The authors found that instead of increasing the number of mutations in the genes encoding antibodies, the uncontrolled synthesis of AID increases the activity of the translocation mechanism by 15%, leading to the movement of the oncogene c-myc from its usual position into the DNA fragment encoding antibodies. The strong gene activity characteristic of this region can lead to a significant increase in the expression of this oncogene and the development of Burkitt's lymphoma, a very aggressive malignant blood disease.
While other types of lymphomas are characterized by overexpression of microRNA-155, there is no expression of this molecule in Burkitt lymphoma cells. According to the authors, cells of different types of lymphomas differ significantly in their characteristics, therefore, knowledge of the role of microRNA-155 in the formation of these diseases will help to understand their features and improve the effectiveness of treatment.
Articles by TENG et al. "microRNA-155 Is a Negative Regulator of Activation-Induced Cytidine Deaminase" and DORSETT et al. "microRNA-155 Suppresses Activation-Induced Cytidine Deaminase-Mediated Myc-Igh Translocation" published in the May issue of the journal Immunity.
Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of ScienceDaily
16.06.2008