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Scientists identify potential key to therapeutic treatments for autoimmune diseases

September 27, 2017

From left to right: Kaitlin Read, Kenneth Oestreich, Michael Powell
Kenneth Oestreich (center), an assistant professor at the Virginia Tech Carilion Research Institute, and his team found a new molecular complex that helps develop and regulate immune responses. Kaitlin Read, a research specialist and Oestreich’s lab coordinator, and Michael Powell, a doctoral student in Virginia Tech’s translational biology, medicine, and health graduate program, are co-first authors on the paper.

A collaborative team of scientists led by Kenneth Oestreich, an assistant professor at the Virginia Tech Carilion Research Institute, has identified a novel combination of immune response factors involved in the body’s fight against invading pathogens.

This new finding could provide insight into the development of better vaccines or even into chronic autoimmune diseases, such as lupus or rheumatoid arthritis.

In a study in the October edition of the Journal of Immunology, the research team described how it discovered a novel transcription factor involved in the development of a specific kind of T helper cells, called T follicular helper (Tfh) cells.

T helper cells in the body develop, or differentiate, into a number of different subtypes to coordinate immune responses to a particular pathogen. One type helps fight viral and intracellular bacterial infections, such as Salmonella, while another protects the body from larger pathogens, like parasitic worms. Tfh cells, though, can develop in response to several different infections.

“As you can imagine, this is an extremely important branch of the immune system,” said Oestreich, who is also an assistant professor of biomedical sciences and pathobiology in the Virginia-Maryland College of Veterinary Medicine. “Tfh cells activate B cells, which produce antibodies to neutralize either viruses, bacteria, or larger pathogens, such as parasites. If we know how these cells form normally, we could potentially use this information to design stronger vaccines.”

There’s a dark side to this cell type, though. They can also become confused and activate the production of antibodies that target the body’s own tissue. This kind of cell confusion leads to autoimmune disease, such as lupus and rheumatoid arthritis.

Better understanding the development of Tfh cells could potentially allow researchers to target the development pathways in an effort to destroy mis-primed cells or at least disrupt the activities that result in autoimmune disease, according to Oestreich.

That’s where the novel transcription factor, named Aiolos, comes in. In their recent study, Oestreich and his team determined that Aiolos activates another protein, Bcl-6, that is required for the development of Tfh cells.

“We did several mechanistic studies to figure out exactly how Aiolos is involved in activating Bcl-6 expression, and that’s where we came across this novel transcription factor complex,” Oestreich said.

The researchers found that Aiolos doesn’t act alone to activate Bcl-6; instead it works in cooperation with another transcription factor, called STAT3. This is the first evidence of members of these two transcription factor families interacting to influence gene expression.

While still not fully understood, it’s clear the complex plays a key role in pushing T helper cells to become Tfh cells. “A unique mechanism between Aiolos and the protein STAT3 seems to propagate Tfh cell differentiation.”

The finding earned Oestreich and his team a grant from the National Institute of Allergy and Infectious Disease, of the National Institutes of Health. They’re now working to understand exactly how Aiolos and STAT3 interact to influence Tfh cell activities.

“Is this complex the driver of cell type differentiation? We’re extremely excited to explore that, and now we have significant federal funding to further pursue this research avenue,” Oestreich said. “If we can promote or inhibit these immune responses, it really does open up a lot of potential therapeutic targets to treat autoimmune disease, as well as promote immune responses against specific pathogens.”

Kaitlin Read, a research specialist and Oestreich’s lab coordinator, and Michael Powell, a doctoral student in Virginia Tech’s translational biology, medicine, and health (TBMH) graduate program, are co-first authors on the paper.

Other contributors include Chandra Baker, a research associate at the VTCRI; Bharath Sreekumar and Veronica Ringel-Scaia, both students in Virginia Tech’s TBMH graduate program; Holly Bachus, a research assistant at the University of Alabama at Birmingham; Ian Cooley, a resident physician at the University of North Carolina who conducted research in the Oestreich lab as a Virginia Tech Carilion School of Medicine student; Coy Allen, an assistant professor of biomedical sciences and pathobiology at the Virginia-Maryland College of Veterinary Medicine; and Andre Ballesteros-Tato, an assistant professor of medicine at University of Alabama at Birmingham.

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