Identifying the mechanism of virus-induced lupus

Tarin Bigley, M.D., Ph.D., Washington University 

While the causes are unclear, genetic factors and environmental exposures (like viral infections) contribute to the development of systemic lupus erythematosus (SLE). A type of herpes virus called roseolovirus typically infects children from six months to three years old, causing two to three days of fever before remaining inactive throughout life. Roseolovirus has been associated with the development of SLE; but understanding how viral infection can cause SLE is difficult due to the time between the initial infection and the development of SLE symptoms as well as the lack of animal models for studying this process. Dr. Bigley will study how immune cells change after a viral infection to understand the transition from health to lupus. 

Overactive immune cells called T and B cells play a major role in lupus by mistakenly targeting a person’s own cell contents as foreign invaders, leading to inflammation and organ damage. The toll-like receptor (TLR7) pathway is overactive in people with SLE and is triggered by viral infection. Dr. Bigley will test whether roseolovirus infection changes TLR7 activity in T and B cells and cause these cells to cause autoimmune disease. He predicts that these changes underlie the development of SLE in children. Dr. Bigley recently found that mice infected with roseolovirus early in life develop autoimmunity and, after being given a chemical that activates TLR7, develop lupus-like disease. He will use this model to understand how viral infection causes long-term changes in T and B cells. He will then compare cells from healthy children, children with autoimmune features but no apparent disease symptoms, and those with lupus to understand the features of T and B cells that define the transition from health to lupus. 

What this study means for people with lupus 

How early-life infections cause long-lasting immune changes is not well understood, but the immune system is believed to be altered years before symptoms arise and SLE is diagnosed. Findings from Dr. Bigley’s study could lay the groundwork for understanding lupus development and progression, enabling the identification of new therapeutic targets. 

The cause of systemic lupus erythematosus (SLE) remains unknown, but genetic and environmental factors are thought to play an important role. Viral infections have been proposed to contribute to onset and flares in SLE but few studies have looked at how viral infection early in life could predispose some people to developing SLE later in life. Human roseoloviruses, which causes a common childhood infection called roseola, have been studied in patients that have SLE but most people are infected as children and have minimal illness. This makes demonstrating roseoloviruses as a cause of SLE difficult. Interestingly, studies suggest that people with SLE develop autoantibodies and changes in their immune system years before other symptoms, suggesting that perhaps events early in life may be a predisposing factor. We have found that infection of mice with murine roseolovirus (MRV) early in life results in development of autoimmune disease. Moreover, these mice develop a lupus-like disease when given a chemical that stimulates a protein that senses viral infection called toll-like receptor 7 (TLR7). This suggests that early infection with MRV predisposes mice to autoimmunity and abnormal response toTLR7 stimulation, resulting in lupus like disease.

We plan to study how MRV infection early in life leads to long term changes in T and B cells, both of which play an important role in SLE. Furthermore, we will study the characteristics of T and B cells that define the transition from health to SLE. Taken together, we have found an exciting new way to study how roseoloviruses, a common infection in humans, skews the development of the immune system toward autoimmune disease and SLE.