Why lupus may be relieved as some older people age

Systemic lupus erythematosus has been difficult to predict for decades.

Its immune-powered attack on the kidneys, heart, skin, and joints usually strikes in early adulthood and lasts for many years. But for some older people, lupus symptoms mysteriously relieved in the 1960s and 1970s. Now, UC San Francisco scientists think they know why: The antiviral defense of the immune system is beginning to become quieter as they age.

Reject the volume on interferon

In a published study Scientific Translation MedicineThe researchers analyzed blood samples from nearly 300 lupus patients over the entire age range and compared them with more than 900 healthy control groups. They focus on a group of genes called interferon-stimulated genes (ISGs), which produce powerful antiviral proteins but can also trigger autoimmune damage in lupus.

“I see signs of serious illness being performed on my young lupus patients in their 20s, 30s and 40s every few months, but many of my older patients are exposed to the foundation only once a year,” said Dr. Sarah Patterson, assistant professor of medicine at UCSF rheumatology. “If patients succeed through those decades of risk, they sometimes see tremendous improvement.”

The study shows that in healthy individuals, the expression of genes associated with inflammation slowly increases over time, a trend known as “inflammatory.” But in patients with lupus, these same immune genes start to be abnormally high in middle age and then decrease with age, especially those associated with interferon.

Major findings from the study

• In patients with lupus, expression of interferon-stimulated genes decreases significantly with age
• Plasma levels of interferon-alpha-2, a major inflammatory molecule, have also decreased
• These changes are associated with specific DNA methylation patterns, suggesting epigenetic switches
• Only patients with lupus (rather than healthy controls) show these unique age-related changes

“Inflammation in patients with lupus appears to have been reversed,” said UCSF senior author and associate professor of medicine. “But this is not completely reversed. Lupus patients have higher levels of inflammatory signaling than healthy adults in older adults.”

Epigenetics and the Way of Relief

The team found that interferon-related genes not only expressed less, but also showed signs of epigenetic silencing by DNA methylation. This suggests that aging may trigger changes in gene regulation of natural dialing lupus inflammation.

Both the health and lupus groups showed expected age-related T cell declines, which are important for immune defense. However, only patients with lupus see a specific subset of specific natural killer cells as they age, which may lead to symptoms relief.

Next: Timing therapy for age

The UCSF team now plans to explore whether interferon drugs should be tailored to patients’ age. Because young adults with lupus have high interferon activity, they may benefit more from these drugs than older people whose immune systems have calmed down.

The researchers also hope that their multi-structural approach can be used to study other age-related diseases that have immune components including rheumatoid arthritis, atherosclerosis, and COPD.

“We learned that aging not only increases inflammation in everyone in the same way,” Patterson said. “For certain diseases like lupus, age can actually bring relief.”

Journal and Funding Information

Magazine: Scientific Translation Medicine

title: Epigenetic attenuation of interferon signaling is related to improvements in aging of systemic lupus erythematosus

doi: 10.1126/scitranslmed.Adt5550

funds: NIH (R01 AR069616, K23AT011768, P30 AI027763), CDC and Chan Zuckerberg Biohub

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