CINCINNATI - Why do genetic variants that increase the risk of autoimmune disease remain so common in the population?
A new study, published Sept. 11, 2026, in The American Journal of Human Genetics provides one possible answer: some genetic variants that increase the risk of lupus may also make the immune system better at fighting viruses.
In this study, a research team led by Leah Kottyan, PhD , Matthew Weirauch, PhD , and Stephen Waggoner, PhD focused on a common lupus-associated genetic haplotype linked to IRF7, a transcription factor that plays a central role in the antiviral immune response.
Systemic lupus erythematosus, or lupus, is a complex autoimmune disease in which the immune system attacks the body's own tissues. Genetics plays an important role in determining who develops lupus, and many of the genetic regions associated with disease risk have been known for years. A major challenge, however, has been moving from association to mechanism. It is challenging to understand exactly what these inherited variants do inside immune cells and why they increase disease risk, and not just for lupus.
"Our team's findings help explain why a genetic variant linked to lupus remained so common and how, biologically, it affects the immune system more broadly." says Sam Virolainen, PhD, first author of the study and graduate of the Immunology Graduate Program . "During my PhD training in the Kottyan/Weirauch lab, I learned to appreciate that many genetic risk factors can contribute to multiple diseases, especially when the immune system is involved."
A Bridge From Immunity To Autoimmunity
IRF7 helps cells respond to viral infection by activating production of type I interferons, including interferon-alpha (IFN-α). These molecules are essential components of our antiviral defenses. But type I interferon signaling is also strongly implicated in lupus. Many patients with lupus have chronically elevated interferon activity, sometimes referred to as the "interferon signature," and therapies that target this pathway are now used to treat the disease. The new findings help explain how these two observations may be connected.
The team found that the lupus risk haplotype increases IRF7-dependent induction of IFN-α. In other words, individuals carrying this genetic configuration can mount a stronger interferon response under the conditions studied. That heightened response can improve antiviral defense; however, the same biology can also promote excessive or inappropriate immune activation that contributes to lupus.
This suggests an important biological tradeoff.
A more vigorous antiviral immune response may have been beneficial during human evolution, particularly when infectious diseases represented an enormous threat to survival. But an immune system that is particularly sensitive or responsive to viral signals may also have a greater tendency to cross the line from protective immunity into autoimmunity.
That idea changes how we think about at least some lupus risk variants. They may not simply be "defective" versions of immune genes. Instead, they may represent versions of the immune system that perform differently. They may provide an advantage in one context while increasing disease susceptibility in another.
Connecting Genetics, Viruses, And Lupus
This work also fits into a larger question: how inherited genetic risk interacts with viral infection. For years, researchers have recognized a strong relationship between Epstein-Barr virus (EBV) and lupus . Nearly everyone is exposed to EBV during their lifetime, yet only a small fraction of people develop lupus. Genetics may help explain why the consequences of the same viral exposure differ so dramatically from person to person.
The research team's previous work has examined how viral proteins, including those produced by EBV, interact with the human genome at regions associated with autoimmune disease. The new IRF7 study approaches the gene–virus relationship from another direction. Rather than asking how a virus interacts with genetically susceptible cells, the team asked how inherited genetic variation changes the antiviral response itself.
"Together, these studies support a model in which genetic susceptibility and viral exposure are not independent risk factors. They can converge on the same regulatory pathways," says Kottyan.
A person's inherited genome can influence how strongly their immune system reacts to infection. Viral infection, in turn, can activate molecular pathways that are already influenced by a person's genetic makeup. In some individuals, that interaction may help explain how a normal antiviral immune response develops into chronic autoimmune inflammation.
Looking Ahead
The study does not immediately change how lupus is diagnosed or treated, and carrying this genetic haplotype does not mean that someone will develop lupus. Lupus results from the combined effects of many genetic variants together with environmental exposures and other biological factors.
However, the research demonstrates how scientists can move beyond identifying genetic risk factors to understanding how those variants affect immune function. Studies like this help build a foundation for future research into what drives disease and why it develops differently from person to person.
"I am hopeful that our work will increase our understanding of not just lupus biology but other diseases with similar genetic and immunologic complexities," says Virolainen.
Many disease-associated genetic variants have already been identified, but their biological effects remain unclear. By clarifying the molecular pathways involved, studies like this one may ultimately help guide the development of therapies that target disease more precisely while preserving normal immune function.
About The Study
Cincinnati Children's investigators on this study included experts from the Divisions of Allergy & Immunology, Human Genetics, Rheumatology, Immunobiology and Biomedical Informatics, as well as the Center for Autoimmune Genomics and Etiology (CAGE).
The publication reflects a collaboration among researchers from institutions across 13 U.S. states and territories and six countries.
This study was funded by the National Institutes of Health (R01 AR073228, R01 DK107502, R01 AI148276, U01 HG011172, U19 AI070235, R01 HG010730, R01 GM055479, U01 AI130830, U01 AI150748, P01 AI150585, U24 HG013078, P30 AR070549, R01 NS099068, R01 AI024717, and R01 DK134625), the U.S. Department of Defense Impact Award, the National Research Foundation of Korea (NRF-2021R1A6A1A03038899), and the Korean Ministry of Education. Additional support was provided by Cincinnati Children's Office of Academic Affairs and Career Development.
