Diversity may be the spice of life, but it’s also the key to an effective immune system, as B lymphocytes rely on extensive recombination to shuffle their antibody-coding genes to produce molecules that can recognize a diverse array of potential threats.
Antibodies with established targets can also undergo further alterations to modulate the immune response that they trigger upon antigen binding. Known as ‘class switch recombination’ (CSR), this process relies on activation-induced cytidine deaminase (AID), an enzyme that induces major rearrangements in antibody-coding loci.
Unregulated, AID can generate cancer-causing genomic rearrangements, and a team led by Tasuku Honjo and Hitoshi Nagaoka at the University of Kyoto, with Sidonia Fagarasan’s group at the RIKEN Research Center for Allergy and Immunology in Yokohama, recently set about exploring the mechanisms that help constrain expression of the Aicda gene.
“AID is tightly regulated in activated B cells and speculated to be a B cell-specific factor—however, the Aicda promoter is not lymphocyte specific,” says Thinh Huy Tran, lead author of the team’s recent article in Nature Immunology1. Comparison of the mouse and human versions of this promoter revealed four discrete segments that had been closely conserved throughout evolution. To assess their contributions to gene specificity, the researchers generated artificial promoters consisting of various subsets of these conserved regions, which they used to regulate a bioluminescence-producing ‘reporter’ gene in cultured lymphocytes.
They found that two of these four segments directly contribute to specificity. ‘Region 2’ contains binding sites for transcription factors known to guide B lymphocyte development, but also contains sequences that strongly inhibit Aicda expression. The other promoter segment, ‘region 4’, appears to participate in the strong induction of this gene in response to signaling factors that trigger CSR in vivo.
“Our results demonstrate for the first time that two separate regions contribute together to regulating Aicda expression, in which silencers are derepressed by B lineage-specific and stimulation-responsive enhancers,” says Tran. “The negative factors that restrict Aicda expression might contribute to retaining genomic stability, while region 4 is essential for Aicda response in B cells to environmental stimulation ... and is critical to generate antibody diversification.”
The investigators are now examining the individual importance of these various putative Aicda regulators, but also intend to further explore the bigger picture of the effects of AID dysregulation. “We plan to investigate the correlation between Aicda expression levels with mutation frequency in non-immune genes ... and the role of AID in tumor development,” says Tran.
The corresponding author for this highlight is based at the Laboratory for Mucosal Immunity, Research Center for Allergy and ImmunologyJournal information
Saeko Okada | Research asia research news
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences