BTLA Archives - Sanford Burnham Prebys
Institute News

How our immune system controls gut microbes

AuthorMiles Martin
Date

April 6, 2022

And how this relationship could help fight autoimmune diseases

Sanford Burnham Prebys researchers including Carl Ware, PhD, and John Šedý, PhD, have discovered an immunological process in the gut that could help improve treatment for autoimmune and gastrointestinal diseases. The study, published March 22 in Cell Reports, found that this process regulates the activation of white blood cells in the intestines, which ultimately helps the body control the composition of the gut microbiome. 

“The immune system is like a gardener for our gut bacteria, gently monitoring and responding to their populations and keeping an eye out for unwanted pathogens” says Ware, who directs the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys. “This ultimately helps the immune system control these microbes.”

This “gardening” relies on a molecule called BTLA, one of several checkpoint proteins used by the body to control the immune system. 

“This is a signaling system we’ve known about for decades, but this is a totally new function for it that we’ve never seen before,” says Šedý, a Sanford Burnham Prebys research assistant professor, who co-led the study with Ware. “I helped discover this system two decades ago, so it’s exciting that we’re still making new discoveries about its function.”  

To explore the role of BTLA in the gut, the team zeroed in on specialized lymph nodes in the intestines called Peyer’s patches, which are full of white blood cells that help monitor and respond to pathogens and other microbes in the gut.

“Gut bacteria are in constant competition, and the populations of specific species can fluctuate,” says Ware. “In a healthy microbiome, there’s a balance, and disrupting that balance can contribute to autoimmune diseases, gastrointestinal disorders and even some brain disorders.”

The team found that BTLA is critical for maintaining this balance because it triggers white blood cells to release antibodies that control the populations of different gut bacteria.

“It’s a finely calibrated system that we’re still only just beginning to understand in detail,” adds Ware.

Immune checkpoints like BTLA are already used in immunotherapy for some cancers, and these results make the researchers confident that this system can be leveraged to treat diseases in the gut, especially those that are also autoimmune disorders, such as Crohn’s disease or ulcerative colitis. 

“The immune system is unimaginably complex, and understanding it gives us the ability to manipulate it, and that can help us treat diseases,” says Šedý. “This discovery is a step forward in that larger narrative.” 

Institute News

Viral tricks inspire autoimmune drug design

AuthorSusan Gammon
Date

November 20, 2017

In the U.S. alone, 24 million people, or eight percent of the population, have autoimmune diseases such as rheumatoid arthritis, lupus, multiple sclerosis, and psoriasis. Current treatments, including the new wave of biologic therapies, don’t work for all patients so effective new drugs are still desperately needed. Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP), publishing in the Journal of Biological Chemistry, may have found a way to make one by studying viral infections.

“Viruses find ways of turning off immune responses so they can avoid being recognized and attacked,” explains John Šedý, PhD, research assistant professor at SBP and lead author of the study. “We looked at the proteins that herpes viruses use to turn down the immune system to figure out how to make a new drug to treat autoimmune disorders.”

Šedý and his team focused on a human protein called HVEM (herpesvirus entry mediator). HVEM dampens immune responses by activating a receptor called BTLA (B and T lymphocyte attenuator).

“In healthy individuals, BTLA is an immune checkpoint—a brake that keeps the immune system from spiraling out of control and causing autoimmune disease,” says Šedý. “We are working toward a prototype drug that activates BTLA to keep the immune system from attacking healthy cells.”

“There is a substantial need for new therapies that can utilize the natural “brakes” of the immune system to turndown the immune system when it gets out of control, explains Carl Ware, PhD, professor and director of the Infectious and Inflammatory Diseases Center at SBP and the senior author of the research. “It has been difficult to design a molecule that turns a checkpoint receptor on, so we’ve sidestepped that hurdle by taking inspiration from biology.”

“HVEM itself won’t work very well as a BTLA-activating drug because it has other important immune regulatory responsibilities, so the side effects could be serious. Looking closely at the structure of a mimic—an HVEM-like protein in a virus—allowed us a way to make it selectively bind to BTLA,” explains Ware.

“Our study provides preliminary evidence that we can modify HVEM in a way that may be a starting point for an autoimmune disease drug,” adds Ware. “This version of HVEM inhibits a signaling process in B cells that has been shown to be essential for driving autoimmunity.”

“Right now we are continuing with our structural analysis of HVEM to design versions that will advance our preclinical studies,” says Ware. “Our goal is to develop an entirely new class of therapies for autoimmune diseases like inflammatory bowel disease and systemic lupus, and other conditions caused by too much inflammation,” says Ware.

Congratulations to Drs. Ware and Sedy! This paper has been viewed more that 250 times on the JBC website.