An important cellular reaction mediates part of the immune system responsible for tolerance. Without tolerance, the immune system would target harmless “self” cells like it does in the case of autoimmune disease. From the Medical University of South Carolina, scientists uncover a new checkpoint involved in regulating B cells.
Tolerance in the immune system is vital for preventing autoimmune reactions against harmless substances that the immune accidentally recognizes as dangerous. There are more than 80 types of autoimmune diseases, and there are 24 million people affected by autoimmune diseases in the United States. Women are more likely than men to have an autoimmune disease.
Researchers from the present study have historically been focused on cellular mechanisms that regulate the adaptive, or specific immune response, and the innate, or non-specific immune response. They are especially interested in uncovering the role of the immune system in cancer and autoimmune disease. Two proteins are especially important to their studies: TGF-beta and GARP.
TGF-beta is a “master cytokine” that regulates inflammation and tolerance. Recent research described GARP binding TGF-beta on regulatory T cells and platelets, affecting their activity. But the present study is the first to describe how GARP and TGF-beta binding affects activity of peripheral B cells in the context of immune tolerance.
Researchers found that when B cells are activated, GARP is expressed, indicating it might be a potential checkpoint for B cell tolerance. They used two preclinical models to understand more about the effect of GARP, one with GARP overexpressed and one with GARP underexpressed.
When GARP was overexpressed, B cells proliferated and activated less, and underexpression of GARP led to the development of spontaneous lupus-like disease, an autoimmune disease. Researchers also compared GARP expression across different populations of B cells.
"If you look at GARP expression on B cells, usually it's only expressed on activated B cells in the periphery,” Zihai Li, MD, PhD. “But in the gut, it looks like, even in the steady state, GARP is expressed.”
Why the gut? Researchers explain that because it is exposed to the environment, tissues of the gastrointestinal (GI) tract have to keep track of bacteria, viruses, food antigens, and self-antigens. B cells in an area called “Peyer’s patches” have an increased level of GARP expression. And without GARP, B cell proliferation and activation increased. Researchers theorize that the interaction between GARP and TGF-beta is most important in the gut because B cells need to be able to tolerate harmless food and self antigens.
"Our work started from a very simple question: What does GARP do? But as you can see, we have now shown that this pathway is important for autoimmune disease in a mouse model,” Li said. “And our work in humans suggests that this pathway is really relevant to human health.”
The present study was published in the journal JCI Insight.