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Researchers from UCLA and the Seattle Children's Research Institute worked together to advance our understanding of the genes governing the synthesis and release of immunoglobulin G, the most prevalent class of antibody in the human body.
The discovery could progress both the development of medical therapies that rely on the creation of antibodies and the manufacturing of antibody-based therapeutics for conditions including cancer and arthritis. A collection of proteins known as antibodies are essential to the immune system. IgG, or immunoglobulin G, marks harmful microorganisms so that immune cells may remove them. It also carries memories of previous infections. IgG from mothers is essential for the immune system of their babies. For many years, researchers have understood that a subset of white blood cells known as plasma B cells produces IgG. More than 10,000 IgG molecules are produced by plasma B cells every second, demonstrating their great productivity. However, the molecular processes by which antibodies are secreted into the bloodstream by plasma cells remain poorly understood. In order to learn more about those mechanisms, the researchers performed an analysis that had never been done before: They captured thousands of single plasma B cells as well as their individual secretions, and then connected the amount of proteins each individual cell released to an atlas mapping tens of thousands of genes expressed by that same cell. To collect the cells and their secretions, the researchers used microscopic, bowl-shaped hydrogel containers callednanovials, which were developed in prior UCLA research. Their analysis found that genes involved with producing energy and eliminating abnormal proteins were even more important for high IgG secretion than the genes containing instructions for making the antibody itself. They also discovered that the presence of CD59, a gene that had not previously been linked to IgG secretion, is a better predictor of high-producing plasma cells than other genetic markers already associated with this cell type. These processes in cells are like an assembly line for making proteins, and there are lots of places where you could see bottlenecks, said Dino DiCarlo, the Armond and Elena Hairapetian Professor of Engineering and Medicine at theUCLA Samueli School of Engineeringand a co-corresponding author of the study. Things have to be moving smoothly in sync across the cell. If a cell is making a lot of proteins, its using a lot of energy and needs a way to correct the proteins that get messed up. The study was publishedin the journalNature Communications. DiCarlo, who is also a member of theCalifornia NanoSystems Institute at UCLAand theUCLA Jonsson Comprehensive Cancer Center,said the findings could not only advance fundamental understandings of biology but also could have applications in biomedicine. For instance, knowing which genes are associated with higher secretion of an antibody could be used by pharmaceutical makers to engineer cells that secrete large volumes of the antibody. That knowledge could also be applied to an emerging strategy that introduces engineered cells directly to patients bodies, such as the potential cell therapies under development by University of Washington immunologist Richard James, a co-corresponding author of the paper. The new way in which nanovials and a standard laboratory setup were used in the study also opens up new possibilities for understanding how the instructions contained in DNA are translated into the behaviors of cells. Each nanovial contains molecules tailored to bind with proteins on the surface of the cells that the researchers are investigating, which enables the nanovial to capture a single cell at a time. Once that cell is immobilized and protected within the nanovial bowl, its secretions also accumulate and are attached to specific antibodies engineered to capture them. In the study, the investigators trapped tens of thousands of plasma cells, along with the IgG they released, in nanovials with a diameter about one-third the thickness of a sheet of paper. The nanovials were then run through an instrument to analyze each cells messenger RNA, or mRNA. Every cell in an individuals body carries the same blueprint written in DNA. So scientists detect which genes are active by looking at the mRNA, which translates those instructions so that each cell can build proteins that are specific to its functions. There are multiple layers of information in each cell, DiCarlo said. Were able to link the final layer the amount of proteins actually secreted that have a clear function throughout the bodyback to the more fundamental layer of genetic code. Theres currently no other technique that is available to do that. Now that we have this approach, the most interesting thing, to me, is which question to ask next. (ANI)
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