NIH Scientists Find a Novel Mechanism that
Controls the Development of Autoimmunity
Scientists at the National Institutes of Health (NIH) have found
a mechanism in the immune systems of mice that can lead to the
development of autoimmune disease when turned off. The findings
shed light on the processes that lead to the development of autoimmunity
and could also have implications for the development of drugs to
increase the immune response in diseases such as cancer and HIV.
The study paper appears online today in the journal Nature.
The 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
immune system T cells — specifically the helper T cell, an
immune system component that helps other cells fight infection.
They focused on the protein furin, an enzyme that plays an important
role in the functioning of T cells.
Scientists have been limited in their ability to study the protein
furin, because other enzymes can perform some of the same functions.
Also, furin is essential to life, so scientists have been unable
to create a mouse without furin that lives past the embryo stage
of development. Since the NIH scientists were unable to see what
a mouse without furin would look like, they collaborated with Belgium
scientists to create a mouse without furin only in T cells. What
they discovered was that mice without furin in these cells developed
systemic autoimmune disease. This means that the immune systems
of the mice attacked their own cells and tissues throughout their
bodies.
"We already know that furin seems to have roles in a variety
of human diseases, such as cancer, cystic fibrosis and infectious
diseases," says lead author Marko Pesu, Ph.D., in the NIAMS’ Molecular
Immunology and Inflammation Branch. "These findings show that
having no furin in certain immune system cells can increase the
immune response and lead to autoimmune disease in mice."
The researchers found that deleting furin in helper T cells affected
the functioning of two types of T cells, regulatory and effector
T cells. The former cells, also called Tregs, promote immune tolerance
to the body’s own cells and tissues. Upon further examination,
the researchers found that 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.
"Inhibiting furin has been thought to reduce growth of malignant
cells or to block infections by preventing essential activation
of a pathogen," says study author and NIAMS’ Scientific Director
John J. O’Shea, M.D., chief of the NIAMS’ Molecular Immunology
and Inflammation Branch. "However, these results suggest that
the development of drug interventions could have an unexpected
side effect of increasing the risk of developing autoimmune disease."
Investigators from the NIH’s National Cancer Institute also contributed
to this study.
For more information about autoimmune diseases, visit the Medline
Plus Web site, a service of the NIH’s National Library of Medicine,
at http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html
For more information about the NIAMS’ Molecular Immunology and Inflammation
Branch, visit the NIAMS Web site at http://www.niams.nih.gov/Research/Ongoing_Research/Branch_Lab/Molecular_Immunology_and_Inflammation/default.asp For
more information about cancer, please visit the NCI website at http://www.cancer.gov,
or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies. News releases, fact sheets and
other NIAID-related materials are available on the NIAID Web site
at http://www.niaid.nih.gov.
The mission of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the Department of Health and
Human Services' National Institutes of Health (NIH), is to support
research into the causes, treatment, and prevention of arthritis
and musculoskeletal and skin diseases; the training of basic and
clinical scientists to carry out this research; and the dissemination
of information on research progress in these diseases. For more
information about NIAMS, call the information clearinghouse at
301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web
site at http://www.niams.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Reference: Marko Pesu, Wendy T. Watford, Lai Wei,
Lili Xu, Ivan Fuss, Warren Strober, John Andersson, Ethan M. Shevach,
Martha Quezado, Nicolas Bouladoux, Anton Roebroek, Yasmine Belkaid,
John Creemers, & John J. O’Shea. T-cell-expressed proprotein convertase
furin is essential for maintenance of peripheral immune tolerance. Nature Advance
Access published August 13, 2008, doi: 10.1038/nature07210. |