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Tolerating yourself

Carolina Wallace
PHOTO: SARAH PACK | Caroline Wallace |

A novel pathway to regulate B cell activity and prevent autoimmunity

BY MATTHEW GRESETH

Autoimmune diseases result from an abnormal immune response against a normal self-tissue. There are over 80 types of autoimmune disease involving all parts of the body, and an estimated 24 million Americans are affected.

The immune system has several strategies to prevent autoimmune disease, known as tolerance, and MUSC researchers have identified a novel checkpoint of peripheral tolerance, specifically in B cells. In an article published online April 5, 2018 by JCI Insight (doi: 10.1172/jci.insight.99863), the researchers showed that a specific form of transforming growth factor (TGF)-beta binds the membrane receptor glycoprotein-A repetitions predominant (GARP) to regulate B cell activity.

“This pathway is very important in balancing immunity against pathogens and tolerance against self,” says Zihai Li, M.D., Ph.D., professor and chair of the Department of Microbiology and Immunology at MUSC, co-leader of the Cancer Immunology Research Program at the MUSC Hollings Cancer Center, and senior author on the article. Caroline Wallace, a graduate student in Li’s laboratory when the study was conducted, is first author on the article.

TGF-beta has been studied for more than 40 years and is a master cytokine that regulates inflammation and tolerance. More recently, the membrane receptor GARP was shown to bind to TGF-beta on regulatory T cells and platelets to modulate their activity. Although it was known that GARP is expressed on B cells, it was unknown whether and how the GARP:TGF-beta axis contributes to peripheral B cell tolerance.

The study by Li’s laboratory showed that GARP was expressed upon activation of B cells and may therefore act as an important checkpoint for B cell tolerance. To address the contribution of the GARP:TGF-beta axis to B cell biology, the Li lab generated two preclinical models: one in which GARP was overexpressed and one in which GARP expression was reduced. Overexpression of GARP reduced the proliferation and activation of B cells. Interestingly, loss of GARP led to the development of spontaneous lupus-like disease. Furthermore, in a lupus-prone model, loss of GARP exacerbated the lupus symptoms.

The findings by Li’s laboratory demonstrated the importance of this pathway in lupus, but the GARP:TGF-beta axis is likely a key regulator of peripheral B cell tolerance in preventing all autoimmune disease. Follow-up studies will closely examine how the GARP:TGF-beta axis functions in patients with autoimmune diseases, such as systemic lupus erythematosus (SLE), scleroderma and rheumatoid arthritis, to see whether this pathway is indeed as important as they found it to be in their lupus model system. Over the long term, the Li laboratory will pursue the GARP:TGF-beta pathway as a potential therapeutic target for autoimmune diseases.

There is no cure for autoimmune diseases and treatment generally focuses on reducing the activity of the immune system. The current study lays the groundwork for improving the outcomes of patients with these diseases. Monitoring the levels of GARP on B cells may provide a very useful diagnostic marker for autoimmune disease. Moreover, this pathway, specifically GARP, may be a potential future therapeutic target for treatment.