To B or Not To B: Determining The Fate of a B Cell

Date: May 7, 2021 By:

by: Rachel Leeson. Image Credit: staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436


Ragon scientists discover epigenetic changes unique to B cells and B cell subtypes. 


Antibodies are a vital part of our immune system, but they don’t just appear when they’re needed. They are made in immune cells called B cells. Most B cells, known as B2 cells, produce antibodies in response to a pathogen or a vaccine, providing defense and immunity against infections. But a small subset of long-lived B cells, known as B1 cells, are quite different from their short-lived cousins, the B2 cells. Instead of producing antibodies in response to invaders, they spontaneously make antibodies that perform vital housekeeping functions, such as removing waste like oxidized LDL cholesterol from the blood.


Like all the cells in the body, B1 and B2 cells have the same DNA, and therefore the same starting set of instructions. It is through epigenetic modifications, which open and close different areas of the genome to the machinery that reads the genetic instructions, that the same genome can be used to create unique instructions for each cell type. Understanding how the different epigenetic landscapes – the changes in instructions – allows for these differences in such similar cells is both an important fundamental question in immunology and can help scientists better understand diseases linked to B cells dysregulation. 


By carefully studying the DNA modifications present in both cell types, and their precursors, during different stages of development, Ragon Institute Core Member Shiv Pillai, MD, PhD, was able to identify an epigenetic signature that may determine whether a cell becomes a B1 or a B2 cell, published recently in the journal Nature Communications.


“We analyzed a specific type of epigenetic marker, known as CpG methylation,” says Vinay Mahajan, MD, PhD, an Instructor in Pathology at the Ragon Institute and first author on this paper. “This revealed that the fate of a B cell is determined by epigenetic markers driven by a protein called DNMT3A. Genetic studies in humans link the genomic regions with these marks to a variety of immune-mediated disorders.” 


The team studied CpG methylation, a type of epigenetic modification that opens up specific areas of DNA and marks regulatory elements that can turn genes on or off. Their analysis revealed a set of regulatory elements with unique features in these B1 and B2 cells. In most cases, CpG methylation is permanent and, once added, is even passed on if the cell replicates. But in B cells, the protein DNMT3A had to continually work to maintain the epigenetic markers. If DNMT3A was removed from B1 cells, the epigenetic modifications were lost, and chronic lymphomic leukemia (CLL), a cancer that caused by the uncontrolled replication of B1 cells, would arise. 


“These unique B1 cells are vitally important to our ability to stay healthy,” says Pillai, who is also Program Director of the Autoimmune Center of Excellence at the Massachusetts General Hospital. “The antibodies they create help prevent 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 other diseases.”


Co-authors: Hamid Mattoo, Na Sun, Vinayak Viswanadham, Grace J. Yuen, Hugues Allard-Chamard, Maimuna Ahmad, Samuel J. H. Murphy, Annaiah Cariappa, Yesim Tuncay



This work was supported by NIH AI110495 and Ragon Institute Strategic Funding (Shiv Pillai) and support from NIH AI113163 (Vinay Mahajan) 

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