NIH researchers probe key to autoimmune disease development

Scientists at the NIH recently discovered a mechanism in the immune systems of mice that can lead to the development of autoimmune disease when turned off, a finding that could lay the groundwork for the development of drugs to increase immune response in diseases such as cancer and HIV.

Amy Swinderman
BETHESDA, Md.—Scientists at the National Institutes of Health (NIH) recently discovered a mechanism in the immune systems of mice that can lead to the development of autoimmune disease when turned off, a finding that could lay the groundwork for the development of drugs to increase immune response in diseases such as cancer and HIV.

In a study published recently in Nature, scientists from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Allergy and Infectious Diseases (NIAID), both part of the NIH, studied helper T cells, an immune system component that helps other cells fight infection.  Specifically, they focused on the protein furin, an enzyme that plays an important role in the functioning of T cells. Collaborating with a team of scientists from Belgium, the NIH researchers created a mouse without furin only in T cells.

According to the study, the immune systems of the mice without furin attacked their own cells and tissues, leading to the development of systemic autoimmune disease. The researchers further found that deleting furin in helper T cells affected the functioning of two types of T cells, regulatory (Treg) and effector T cells. Mice lacking furin in Tregs had lower levels of a specific protein, TGF-ß1, which is produced by these cells and is important for their ability to preserve immune tolerance. However, the researchers noted that effector T cells also produce TGF-ß1. They found that furin is also needed for TGF-ß1 production by effector T cells, and that the absence of furin in effectors makes these cells more aggressive in causing autoimmune disease and tissue damage.

"Our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non-redundant, essential function in regulating TGF-ß1 production," the researchers wrote. "Targeting furin has emerged as a strategy in malignant and infectious disease. Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance."

The results suggest that the development of drug interventions could have an unexpected side effect of increasing the risk of developing autoimmune disease, the scientists say.

"Furin activity has been linked to the pathogenesis of several diseases, including metastatic cancers, cystic fibrosis and infectious diseases," the researchers wrote. "Consequently, furin inhibitors have been proposed as possible therapies for such diseases. However, our findings suggest that interfering with furin activity might have the unexpected consequence of promoting autoimmunity. In principle, this might be beneficial in that it might boost T-cell-mediated immune responses and be advantageous in treating cancer and infections."

The study, T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance, was a joint effort by the NIH and Katholieke Universiteit Leuven's Laboratory for Biochemical Neuroendocrinology in Leuven, Belgium.

Amy Swinderman

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