B cells are the immune cells responsible for making antibodies, and most B cells, called B2 cells, produce antibodies in response to a pathogen or vaccine, providing defense and immunity against infections. But a small subset of long-lived B cells, called B1 cells, are quite different from their short-lived cousins, B2 cells. Instead of producing antibodies in response to invaders, they spontaneously make antibodies that perform essential household functions, such as removing wastes like oxidized LDL cholesterol from the blood.
Like all cells in the body, cells B1 and B2 have the same DNA, and therefore the same set of starting instructions. It is through epigenetic modifications, which open and close different areas of the genome to the machinery that reads genetic instructions, that the same genome can be used to create unique instructions for each type of cell. Understanding how different epigenetic landscapes – changes in instructions – enable these differences in these similar cells is both an important fundamental question in immunology and can help scientists better understand diseases related to B cell deregulation.
Shiv Pillai, MD, PhD, a senior fellow of the Ragon Institute of MGH, MIT, and Harvard, studied DNA changes found in both types of cells at different stages of development to identify an epigenetic signature that can determine whether a cell becomes B1 or a cell B2. This work was recently published in the journal Nature communications.
“Through our analysis, we discovered that the fate of a B cell is determined by epigenetic changes driven by a protein called DNMT3A,” explains Vinay Mahajan, MD, PhD, pathology instructor at the Ragon Institute and first author of the article. “Genetic studies in humans link genomic regions with these markers to a variety of immune-mediated disorders.”
The team studied the methylation of CpG, a type of epigenetic modification that opens up specific areas of DNA and marks regulatory elements that can turn genes on or off. They discovered a set of regulatory elements with unique characteristics in these B1 and B2 cells. In most cases, methylation of CpG is permanent and, once added, is even passed on as the cell replicates. But in B cells, the DNMT3A protein had to work constantly to maintain these epigenetic changes. If DNMT3A were cleared from B1 cells, epigenetic changes were lost and chronic lymphomic leukemia (CLL), a cancer caused by the uncontrolled replication of B1 cells, would occur.
“These unique B1 cells are vitally important to our ability to stay healthy,” says Pillai. “The antibodies they create help prevent blood clots and heart attacks. At the same time, understanding what genetic factors regulate them can help us better understand what happens when their regulation goes awry and leads to CLL and d ‘other diseases. “
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