Researchers at Northwestern Medicine have discovered how antibody responses are regulated by epigenetic factors that frequently mutate in cancer, according to a study published in Natural immunology.
“The mammalian Brg1/Brm-associated factor, or BAF, complexes are highly mutated in several cancers, and their role in normal cell physiology remains an active area of research,” said Vipul Shukla, PhD, assistant professor of cell and developmental biology and senior author of the study.
“The BAF complexes are known to be important for development in mammals and are also frequently mutated in cancers, including cancers that originate from B lymphocytes, the antibody-producing cells in our bodies,” said Shukla, who is also a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
In the study, Shukla and his colleagues wanted to understand how BAF complexes contribute to the physiology and function of B lymphocytes.
To better understand how the complexes affect immune responses, the researchers studied mice with genetic deletion of the BAF complex. They found that the gene Arid1a, This is an essential subunit of the mammalian BAF complex and is crucial for the normal function of B lymphocytes. In addition, B lymphocytes lack Arid1a exhibited molecular signatures associated with the activation of inflammatory genes that disrupted normal immune responses.
“The activation of inflammatory signatures in the absence of Arid1a was a really surprising finding considering that BAF complexes are primarily known to turn gene expression on, not off,” said Daniela Samaniego-Castruita, Ph.D., a postdoctoral fellow in the Shukla lab and one of the study’s first authors.
“Without this complex, inflammatory myeloid cells not normally found in secondary lymphoid tissue accumulate at these sites, leading to impaired immune response,” said Dr. Ajay Abraham, a member of the Shukla lab and co-first author of the study.
Next, the researchers tried to dampen inflammatory reactions in mice given Arid1a. To do this, they used two different approaches: They inhibited IL1b, a protein known to trigger inflammation in the body, and treated mice with dexamethasone, a known anti-inflammatory corticosteroid. After inhibiting IL1b or treating them with dexamethasone, the scientists observed that mice without Arid1a According to the study, the B cells partially began to produce normal antibody reactions again.
“One of the key findings of our study was the fact that uncontrolled inflammation can have paradoxical effects on the inhibition of adaptive immune responses,” Shukla said. “These findings confirm and complement an evolving conceptual paradigm in immunity that highlights that uncontrolled inflammation could determine the quality of the adaptive immune response.”
Such a mechanism could be crucial for preventing autoimmunity, he said.
These findings demonstrate how BAF complexes function in regulating immune responses and may provide insights into how modulating inflammatory responses could be useful in treating BAF complex mutant cancers, Shukla said. Shukla’s lab will continue to study how BAF affects inflammatory responses and alters the immune landscape.
“Our lab opened at Northwestern University just two years ago, and this work would not have been possible without the great research support and mentoring environment available to early career researchers at Northwestern University,” Shukla said.
The study was funded by the National Cancer Institute and with institutional seed funding from Northwestern University and the Lurie Cancer Center.
