Anti-TFAM antibodies linked to blood clot risk in SLE, study finds
Antibodies seen as potential biomarkers for clotting-based complications
People with systemic lupus erythematosus (SLE) who have antibodies that target the mitochondrial transcription factor A (TFAM) protein are more likely to develop certain blood clotting complications, a study found.
The antibodies were a risk factor for blood clots, or thrombotic events, even when accounting for other factors that could play a role, such as smoking or the presence of other types of self-reactive antibodies (autoantibodies) linked to SLE.
They could ultimately serve as biomarkers to help clinicians identify SLE patients who are at an increased risk of experiencing serious blood clotting complications, including stroke, heart attack, or antiphospholipid syndrome (APS), another blood clotting condition commonly seen in lupus, the researchers said.
“When we discovered the anti-TFAM antibodies, we had no idea how crucial they were,” Felipe Andrade, MD, PhD, associate professor of medicine at the Johns Hopkins University School of Medicine and the study’s senior author, said in a university news story.
The study, “Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE,” was published in Annals of the Rheumatic Diseases.
Exploring the role of TFAM
The study “adds a new idea to the pathogenesis [disease mechanisms] of thrombosis in lupus: that anti-TFAM antibodies are associated with thrombotic events independently of other factors and other autoantibodies,” Andrade said.
SLE, sometimes referred to simply as lupus, is an autoimmune disorder in which the immune system launches erroneous attacks on the body’s healthy tissues and damages them.
Central to these autoimmune attacks are self-reactive antibodies — autoantibodies — produced by immune cells. A variety of different types, each with different targets within the body, can be found.
Some of these antibodies target parts of mitochondria, the organelles responsible for producing cellular energy, and damaged mitochondria are believed to play a role in SLE.
When mitochondria are harmed, they release molecules to alert the immune system that the cell is injured or stressed and in need of repair, called damage-associated molecular patterns, or DAMPs. The immune system can mistakenly generate autoantibodies to attack these molecules, contributing to autoimmunity.
TFAM is a protein critical for maintaining the integrity of mitochondrial DNA, and is among the molecules mitochondria release as a stress signal. But the potential role of TFAM in driving SLE-related autoimmune responses hadn’t yet been explored.
To learn more, the scientists looked for anti-TFAM antibodies in the blood of 158 SLE patients and 98 healthy people. They found that about a third of SLE patients had such antibodies.
These antibodies did not appear to be associated with overall SLE disease activity, but were linked to an increased risk of certain blood clot-related events. For example, people with these autoantibodies were at about a three times increased risk of thrombosis, or having blood clots form within blood vessels.
They were also at a more than five times higher risk of experiencing APS, a condition linked to an elevated risk of blood clots that commonly occurs secondarily to autoimmune diseases like lupus.
Anti-TFAM antibodies were also found in people without SLE who had primary antiphospholipid syndrome, in which APS occurs independently of any other autoimmune disease. Researchers believe this suggests that these antibodies play a role in APS, but not necessarily SLE development.
Anti-TFAM antibodies were also associated with blood clot-related gene activity profiles and elevated type III interferons, a group of immune proteins, in people with SLE.
‘Surprising and exciting’
“The results of this work are very surprising and exciting,” said Eduardo Gómez-Bañuelos, MD, PhD, assistant professor at Johns Hopkins and the study’s first author. “We originally were looking at these antibodies’ involvement in lupus nephritis. Instead, we saw a different clinical manifestation with our analysis — a strong association between anti-TFAM antibodies and thrombotic events in lupus patients that can be very serious.”
Lupus nephritis is a serious complication of lupus wherein autoimmune attacks target the kidneys.
“Anti-TFAM antibodies identify a distinct … disease subset associated with mitochondrial damage, thrombosis, and APS in SLE,” the researchers wrote.
The scientists said they will work to better understand whether these antibodies contribute to thrombotic events in SLE, or if they are a biomarker of them.
“This is a new and exciting topic for our lab and others interested in this area of lupus,” Andrade said. “We plan to see what this role of anti-TFAM is in lupus and in mitochondria — maybe even in other conditions associated with thrombosis.”
The scientists, in unpublished analyses, identified that anti-TFAM antibodies may be associated with other serious outcomes in SLE, including cancer development and death.
The study was supported by the National Institutes of Health and the Jerome L. Greene Foundation.
