Researchers from the Australian National University (ANU) sought to understand the mechanisms that drive the creation of atypical B cells (ABCs) in the immune system, which were seen as “junk cells.” Using gene-editing technology on mice, the ANU researchers discovered a gene called Zeb2 is crucial to the production of ABCs. Manipulating the Zeb2 gene they found it disrupted the creation of ABCs in the immune system and that mice without the Zeb2 gene were unable to control malaria infection. Their findings show that ABCs play a crucial role in fighting malaria infections.

Their new study is published in Science Immunology in an article titled, “Zeb2 drives the formation of CD11c + atypical B cells to sustain germinal centers that control persistent infection.”

“CD11c+ atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood,” wrote the researchers. “Here we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single cell dataset.”

The discovery provides new insight into how the immune system fights infections and brings scientists a step closer to harnessing the body’s natural defenses to combat malaria. The scientists say ABCs could also be key to developing new treatments for chronic autoimmune conditions such as lupus. According to the researchers, ABCs have long been associated with malaria, as malaria patients have more of these cells in their system compared to the general population.

“Although ABCs are known to contribute to chronic inflammatory diseases and autoimmunity, we’ve discovered a previously unknown ability of these cells to fight disease,” lead author Xin Gao, PhD, a postdoctoral fellow at ANU, said. “In this sense, ABCs are like a double-edged sword. Contrary to past belief, ABCs are not junk cells; they are more important than we thought.”

Their research found that ABCs are also instrumental in developing T follicular helper cells.

“Antibodies can block parasites in the blood as they travel from the site of the infectious mosquito bite to the liver, where the infection is first established.”

The researchers say targeting ABCs could also pave the way for new treatments for certain autoimmune diseases such as lupus.

“ABCs also appear in large numbers in many autoimmune diseases, including lupus, which can be life-threatening in severe cases,” said study co-author Ian Cockburn, PhD, professor at the ANU John Curtin School of Medical Research.

“By developing a better understanding of the role of ABCs in the immune system and the cells’ role in fighting disease, it could bring us a step closer to one day developing new and more effective therapies.”

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