Garrett-Sinha Using NIH Grant to Study B Cell Signaling Pathways

The grant is funded by the National Institute of Allergy and Infectious Disease.

The research is aimed at shedding light on new therapeutic approaches to either increase antibodies to promote immune responses against harmful pathogens or decrease autoantibodies in autoimmune diseases.

B cells can make antibodies to fight infection, and they can differentiate into plasma cells, which are antibody-producing factories that secrete huge amounts of antibodies each day. These antibodies bind to bacteria and viruses and help eliminate them from the body.

However, this process must be tightly controlled since B cells can also sometimes secrete antibodies, called autoantibodies, that bind to a person’s own tissues and cause damage.

“This is a project we have been working on for a while,” Garrett-Sinha says. “We are working on the protein Ets1 that is highly expressed in the immune system.”

Her lab has been studying mice that lack Ets1 as a model for human autoimmune disease, she says.

There are mutations in the human genome that lead to low expression of Ets1, and those mutations are associated with autoimmune disease in humans such as SLE.

“In mice, when we knock out Ets1, they also get autoimmune disease,” Garrett-Sinha says. “So we are trying to understand that and what Ets1 does in the immune system.”

Better understanding of the negative and positive pathways controlling B cell differentiation will provide new clues into how they might be manipulated to limit B cell activation in autoimmune diseases, she notes.

“We know that these signaling pathways control the expression of Ets1, which binds to DNA in the nucleus to regulate genes important for preventing autoantibody generation,” Garrett-Sinha says.

The grant has three main goals:

• to further characterize the signaling mechanisms controlling Ets1 expression in B cells

“We are looking at what signals inside the B cell control Ets1 and how it is controlled,” Garrett-Sinha says.

• to determine the consequences of failure to downregulate Ets1 in B cells for both anti-pathogen immune responses and for the development of autoimmunity

“Normally when a B cell gets stimulated, Ets1 goes down, and when the Ets1 is down, the B cells can make antibodies,” Garrett-Sinha says.

“But we are trying to find out what happens if you prevent Ets1 from getting downregulated,” she says. “Can you still make antibodies? Can you make an immune response?”

• to determine whether Ets1 is regulated by the same signaling pathways in human B cells as it is in mouse B cells and whether B cells from SLE patients have altered Ets1 expression

“Our lab has mostly done mouse studies, but we are going to start looking at human B cells to see if what we have described in mice really applies to humans or not,” Garrett-Sinha says.

“Another thing we are going to do is to look at B cells from people who have lupus and see if Ets1 is not regulated properly in those human B cells,” she says.

Garrett-Sinha says lupus and rheumatoid arthritis are the most well-established autoimmune diseases linked to reduced expression of Ets1.

Garrett-Sinha is co-principal investigator of the grant along with Anne Satterthwaite, PhD, of the University of Texas Southwestern Medical Center in Dallas.

Approximately half of the total grant funding will be directed to the University at Buffalo, according to Garrett-Sinha.