For three decades, Betty Tsao has been on the trail of lupus, tracking down the cause of the autoimmune disease that primarily affects women of childbearing age.
She was a young woman herself when she started, the SmartState and Richard M. Silver Endowed Chair for Inflammation Research said with a slight smile, and she was intrigued by this disease about which so much wasn’t known.
“I’ve been studying lupus forever,” she said.
She said the last decade has produced breakthroughs in lupus research thanks to the ability to conduct genome-wide association studies, enabling scientists to scan the human genome to find common markers that appear more frequently in people with a particular disease. In the last 10 years, research has gone at “lightning speed” in identifying more genetic risk factors, she said. Now, about 100 genes have been implicated as possible risk loci for lupus.
Still, there are still a lot of unknowns with lupus, starting with the number of people it affects. Because lupus isn’t a reportable condition and diagnosis can be difficult, researchers over the years have come up with wildly differing estimates for annual new cases, with as much as a 10-fold difference between the lowest and highest estimates.
Researchers know that lupus primarily affects women, and it’s two to three times more common among blacks than whites. Asians, Hispanics and American Indians also have shown an increased risk. With lupus, the body’s immune system fails to differentiate between foreign invaders and the body’s own system and thus attacks healthy cells, tissues or organs. It seems to be caused by a combination of genetics and environmental factors. The disease goes through periods of flare-ups and remissions, but it also can lead to chronic damage to organ systems. There’s no cure, so health care providers focus on managing symptoms.
Because of the organ damage the disease causes, people with lupus are at risk for early death from kidney disease, heart attacks and cardiovascular disease, according to the National Resource Center on Lupus. And immunosuppressive drugs, prescribed to control inflammation, can make it harder for patients to fight off colds and infections.
It was a paper cut that killed a family member of Tsao’s. Tsao had already been studying lupus for years when the young relative was diagnosed. When the 25-year-old got a paper cut, she didn’t take it seriously at first. Her mother persuaded her to go to the emergency department after the young woman developed a fever, but as they waited to be seen, her condition quickly deteriorated. She ended up dying, Tsao said.
“That was just so sudden and so devastating,” Tsao said. “It just shouldn’t happen.”
A hub of activity
Tsao, who was recruited to MUSC in 2015 from UCLA, said she was attracted to MUSC because it has a number of researchers looking at lupus.
In April Tsao was awarded a $3.5 million National Institutes of Health grant, “Transancestral Fine Mapping and Functional Dissection of Autophagy-Related SLE risk Loci,” to map out autophagy-related gene loci associated with lupus. Autophagy is a process of removing cell debris, degrading them within intracellular organelles and reusing the components; it helps maintain cellular homeostasis and provide a means for cellular survival during stressful conditions. Recently, the autophagic machinery has been recognized to function in innate immune defenses, which could be important for autoimmune diseases, Tsao said.
Previous studies have shown a link between the autophagy pathway and lupus, but researchers aren’t sure how they’re linked. In this study, Tsao intends to exploit the different patterns of chromosomes amongst ancestry groups — white, blacks, Asians and Hispanics — that have been handed down through time due to historical migration. Then she will narrow down which genes and cells are involved in lupus by searching for the variants that appear the same across all groups.
“We are looking for the commonality,” she said.
This study is one of three she’s working on.
Tsao also was awarded a $2.5 million NIH grant in May. “Predictive Biomarkers for Disease Activity and Organ Damage in Patients with Lupus” is a longitudinal biomarker study she is conducting along with Jim Oates, M.D., associate director of the Division of Rheumatology, and colleagues at The Ohio State University. The study poses three main questions: Is there a biomarker that would alert doctors that a patient is about to experience a flare-up so doctors could block it from even happening? Is there a way to predict which patients will respond to certain drugs? If so, “then you can give the right drug to the right patient,” Tsao said. And lastly, is there a way to tally a personal risk factor of end-stage renal disease for each patient?
There are about 100 loci, or fixed positions within the chromosome, identified with lupus. Tsao wants to know whether researchers can score the genetic risk factors, along with other risk factors for kidney disease, to identify those patients most at risk of end-stage renal failure. All drugs have side effects, but doctors can better justify more aggressive treatment if they know the drugs are going to patients with the propensity to develop renal damage, she said.
This kind of longitudinal study hasn’t been done before, she said.
The Lupus Research Alliance is funding a third study with a $600,000 grant. In this study, Tsao is building on earlier work that showed a certain gene variant that frequently linked to lupus appeared more often in Asians. Now, they’re genetically modifying mice to give them this gene variant and see if, when exposed to environmental stressors, the mice develop lupus.
The research also has the possibility of helping people with other diseases. Tsao said the genes they’ve found might affect other autoimmune diseases like rheumatoid arthritis or Sjỏgren’s syndrome . The question for researchers is whether the same mechanism turns on the gene in each disease or if each disease has a different mechanism.
There’s no shortage of intriguing questions being asked in Tsao’s lab.
“It’s easy to ask. It takes a long time to answer,” she said.
For those who like to investigate answers to such questions, Tsao added that currently she is looking for postdoctoral researchers.
The transancestral fine mapping grant is NIH project No. 1R01AR071410-01A1 and the biomarker study is NIH project No. 1R01AR071947-01A1.