The pathophysiology of lupus is somewhat less murky than it was at last year’s Annual Meeting.
A growing body of research points to genetic variability and epigenetic changes as key factors in the development of lupus.
“We believe that a DNA methylation defect in T cells can cause lupus in genetically susceptible individuals,” said Amr Sawalha, MD, Marvin and Betty Danto Research Professor of Connective Tissue Research and Professor of Internal Medicine at the University of Michigan Medical School. “Our genome-wide epigenetic data provided a mechanistic explanation of type 1 interferon hyperresponsiveness in lupus. We know that type 1 interferon is a major player in the pathogenesis of lupus.”
Dr. Sawalha will discuss the series of discoveries that led to the current understanding of lupus pathogenesis during the Rheumatology Research Foundation Edmund L. Dubois, MD, Memorial Lectureship on Tuesday. Changes in DNA methylation can not only trigger the development of lupus, they may also be useful as biomarkers of specific disease manifestations and disease progression.
A variety of factors and events can trigger changes in DNA methylation, Dr. Sawalha said. In some individuals, pathogenic methylation changes may be the result of genetics, which could help explain why lupus is more common in African Americans than in other ethnic groups in the United States.
“If you look at African Americans who do not have lupus, you can see genetic evidence contributing to some epigenetic variability that we think might explain at least in part why African Americans are more likely to develop lupus compared to European Americans” he said. “Our most recent data suggest that the DNA methylome in African Americans tends to make their T cells more pro-inflammatory or more active compared to other populations. Some of these methylation changes are due to the underlying genetics.”
Emerging data also point to environmental factors as important players in the development of lupus. Some epigenetic factors that contribute to the development of lupus are relatively stable over time, suggesting an underlying genetic cause. Other epigenetic factors are dynamic, suggesting a role for environmental factors that can change over time.
Confirming that environmental factors play a role in lupus is one step, Dr. Sawalha said. The next step is unraveling which environmental factors are important. Chemical exposures and infectious incidents are prime candidates for triggering pathogenic epigenetic changes, but the precise exposures and mechanisms remain unknown.
“What we know for sure is that some of these epigenetic changes are more stable and probably represent epigenetic susceptibilities that are influenced by genetics,” he said. “Other epigenetic changes are more dynamic and are probably more heavily influenced by the environment.”
Continuing research into epigenetic changes is revealing novel factors that are unlikely to have been recognized using other methods, Dr. Sawalha said. Genome-wide studies his group performed revealed that certain types of T cells are primed to be hypersensitive to type 1 interferon even before they are activated by some other event.
Similar population studies pointed to ethnic-specific methylation changes that might potentially explain why individuals in certain ethnic groups are more likely to develop autoimmunity. The same work identified specific methylation changes as potential biomarkers or even prognostic markers for the development of specific disease states.
Other recent research shows similar promise. Oxidative stress is the end point for several of the factors thought to trigger lupus. Double strand DNA breaks are increased in lupus cells and are a direct measure of oxidative stress, Dr. Sawalha said.
Genome-wide studies to localize these breaks in lupus are underway in his lab.
“Many of these triggers increase oxidative stress, and oxidative stress can cause double strand DNA breaks,” he said. “We have data on one particular epigenetic mark to show that lupus T cells and monocytes have more double strand DNA breaks than controls, and that the number of these breaks correlates with disease activity in lupus. The goal is to map where these breaks tend to localize and which genes they might disrupt in lupus patients.”