Inflammatory protein may distinguish Sjögren’s disease subtype: Study
With high levels detectable years before symptoms, it could be a risk marker
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More than half of people with Sjögren’s disease have high levels of an inflammatory protein called interferon-alpha (IFN-alpha) and a distinct pattern of immune system dysregulation, according to data from people living in the U.K.
Study findings suggest that IFN-alpha may be a critical marker to distinguish between different biological subtypes of Sjögren’s.
“For a long time, … there’s been the suspicion that an inflammatory mediator, specifically interferon alpha, is dysregulated in people affected by the disease,” Rayk Behrendt, PhD, the study’s co-senior author at the University of Bonn in Germany, said in a university news story. “The combination of data from [people with and without the disease] and our studies on mice enabled us to demonstrate that there is a causal link between interferon alpha and characteristic changes in the immune system.”
In addition, in the subset of patients with elevated IFN-alpha, high levels of this molecule were detectable years before symptom onset, suggesting that IFN-alpha may be a useful marker to help identify people at risk of developing Sjögren’s before the disease manifests.
“These findings have the potential to support precision prevention approaches in Sjögren’s disease, which might enable the identification of at-risk individuals early in their disease course who might benefit the most from targeted treatment,” researchers wrote. “Therefore, this work developed tools that are of practical use for disease stratification, trial design, and risk prediction.”
The study, “Interferon-[alpha] as a precision medicine tool in Sjögren’s disease: a cohort and experimental medicine study,” was published in The Lancet Rheumatology.
IFN-alpha plays key roles in driving inflammation
Sjögren’s is an autoimmune disorder that characteristically causes damage to the glands that produce tears and saliva. However, it can also affect many other systems in the body, leading to a wide array of possible symptoms.
Although it’s been established that Sjögren’s develops because the immune system becomes dysregulated and starts to attack the body’s own healthy tissues, the specific biological mechanisms that drive the disease remain obscure.
IFN-alpha is a signaling molecule that plays key roles in driving inflammation. Normally, its levels are quite low, but if the body senses a threat such as infection, IFN-alpha levels shoot up, sounding the alarm for the immune system to go on the attack.
Previous studies have indicated that blood IFN-alpha levels are elevated in people with Sjögren’s. However, it hasn’t been clear whether elevated IFN-alpha contributes to the disease or is simply a byproduct of immune dysregulation. It also hasn’t been clear if IFN-alpha is elevated in all Sjögren’s patients or just a subset of patients.
High IFN-alpha group showed patterns of immune dysregulation
To learn more, an international team of scientists analyzed blood IFN-alpha levels in 177 Sjögren’s patients in a study called the U.K. Primary Sjögren’s Syndrome Registry. Data from a large database, called the UK Biobank, were also used to validate the results, including those from more than 250 Sjögren’s patients who had blood samples on file from years before the onset of symptoms.
Data showed that 61% of the 177 Sjögren’s patients had higher-than-normal blood IFN-alpha levels, while the rest of the patients had levels within normal ranges. Clinical manifestations and disease severity measures were comparable between these two groups.
However, the high IFN-alpha group showed distinct patterns of immune dysregulation, including lower counts of certain immune cells and higher levels of specific types of antibodies. Notably, patients with high IFN-alpha often had self-reactive antibodies targeting the TRIM21 protein. These antibodies have been previously implicated in Sjögren’s development.
There was a significant association between higher IFN-alpha levels and lower levels of TRIM21. Also, IFN-alpha was significantly elevated in patients positive for anti-TRIM21 antibodies compared with those without these antibodies.
“Subpopulations of Sjögren’s disease with elevated or normal [IFN-alpha] [had] distinct immunological [signatures] yet similar patterns of disease activity and organ involvement,” the researchers wrote.
The scientists then created a mouse model that produced high IFN-alpha levels. These mice showed patterns of immune dysregulation similar to what was seen in Sjögren’s patients with elevated IFN-alpha.
Now, for the first time, we can take treatments geared toward suppressing the interferon effect and trial them really specifically on patients with elevated interferon levels. We might also find new approaches to treatment that will help at least a large percentage of patients over the long term.
These findings imply that IFN-alpha is actively driving immune dysregulation, not merely a byproduct of other disease processes. However, in the mouse model, drugs to block IFN-alpha reduced only some signs of disease activity, suggesting that this molecule’s role in established Sjögren’s is complex.
Also, in patients with high IFN-alpha, elevated levels were detectable more than a decade prior to symptom onset, suggesting that this immune marker may help identify people at risk of developing Sjögren’s.
Overall, the data show that high IFN-alpha levels are found in some, but not all, people with Sjögren’s. And because immune activity differs in patients with high or normal IFN-alpha levels, it may be necessary to tailor treatment strategies to each specific biological subtype.
“Now, for the first time, we can take treatments geared toward suppressing the interferon effect and trial them really specifically on patients with elevated interferon levels,” Behrendt said. “We might also find new approaches to treatment that will help at least a large percentage of patients over the long term.”
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