Systemic lupus erythematosus (SLE), an autoimmune disease in which the immune system produces antibodies to cells within the body, leads to widespread inflammation and tissue damage. Although the causes of SLE remain unknown, the disease is believed to be linked to genetic, environmental and hormonal factors, and is marked by periods of illness and remission.
SLE has a variety of clinical manifestations and can affect joints, skin, brain, lungs, kidneys and blood vessels. The lupus anticoagulant is one of three primary antiphospholipid antibodies that are associated with an increased risk of thrombosis and antiphospholipid antibody syndrome (APS), an autoimmune disorder characterized by excess blood clot formation and pregnancy complications.
APS can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as SLE.
Today, physicians treat SLE using a wide variety of medicines, ranging in strength from mild to extremely strong. Unfortunately, many patients with SLE experience ongoing disease activity, despite treatment, and researchers continue to look for new treatment options.
Recently, UT Southwestern Medical Center researchers have made headway in understanding the body's immune defense system by identifying a common signaling mechanism to produce interferon — one of the main proteins used to signal the immune system when the body needs to defend itself against a virus, tumor or other diseases.
Dr. Zhijian Chen, professor of molecular biology in the Center for the Genetics of Host Defense at UT Southwestern and a Howard Hughes Medical Institute (HHMI) investigator, believes this mechanism will facilitate the design and development of medications to treat human diseases such as SLE.
The study results show how a protein called interferon regulatory factor 3 (IRF3), which controls the production of type I interferons, is activated and how this pathway is tightly controlled. The failure of this control system can lead to autoimmune disorders such as SLE.
A normal function of interferons is to defend the body against infections from viruses, bacteria and parasites. Previous research identified specific pathways that induce interferons in response to distinct infectious agents, but how these different pathways converge on IRF3 to induce interferons was not understood.
In 2005, Chen and his team studied a protein called MAVS, revealing that it is an adaptor protein essential for interferon induction by RNA viruses such as influenza virus. In the new study, they found that MAVS is modified by the addition of a phosphate group (phosphorylated) by an enzyme called TBK1 when cells are infected by a virus, and this modification is important for IRF3 activation.
The research team found that the amino acid sequence that is phosphorylated in MAVS is similar to those of two other adaptor proteins, STING and TRIF, which mediate interferon induction in response to DNA viruses and bacteria, respectively. Further research confirmed that all three adaptor proteins are phosphorylated at the common sequence motif and that this phosphorylation allows each of the adaptor proteins to bind IRF3, thereby facilitating IRF3 phosphorylation by TBK1.
Although TBK1 is required for IRF3 activation, TBK1 alone is not sufficient. Phosphorylation of the adaptor proteins provides a license for TBK1 to phosphorylate IRF3.
These findings are important for understanding the body's immune defense system and searching for compounds to turn the immune system on or off. Ultimately, this will help combat autoimmune diseases in which overactive immune cells attack healthy tissues. Chen and his researchers believe that understanding this mechanism will facilitate the design and development of medications to treat human diseases such as SLE.
