Researchers Continue Search for Role of Type-1 Interferon Pathway in Rheumatic Disease

According to a publication from the Rheumatologist, past studies have suggested that type 1 interferons may play a significant role in determining susceptibility to several classic connective tissue diseases. Although the non-conclusive evidence for this has been cobbled together piecemeal over decades, advances in medical science have provided new insights that keep some scientists confident in the pathway’s involvement.

About Interferon and the Type I Interferon Pathway

Interferons are an important kind of cytokine — a class of protein that acts as “messengers” to the rest of the body, prompting the activation or deactivation of certain pathways as necessary.

Specifically, interferons are immune system cytokines. Their presence is one of the first steps of a cascading immune response. Interferons have also been identified as a potential factor in inflammation, immunity/autoimmunity, and the growth of certain cancers.

Type 1 interferons are a group of five subtypes of interferon that are all capable of binding to the same interferon 1 receptors (IFNAR). Although these interferons bind to the same receptors, they can bring about the activation of significantly different pathways. The subtype of an interferon produced by a cell is highly dependent on the cell’s type and certain environmental factors.

Interferons Linked to Rheumatic Disease

Rheumatic diseases can have numerous symptoms throughout the human body, but most generally, they are characterized by repeated episodes of inflammation and pain, especially in joints and ligaments.

The first time elevated interferon activity was detected in rheumatic disease patients was back in 1979. It wasn’t until the 2000s, however, that technology would progress to the point where researchers could search genomes for “signatures” related to interferon activity.

And it wasn’t long before researchers found one. In one study, a number of lupus patients were found to have this “interferon signature.” These signatures, found in “mRNA transcripts” in the blood, suggested that type-1 interferon receptors were being activated — and therefore that something was activating them.

Although this interferon signature isn’t found in all rheumatic disease patients, it is observed regularly in patients with lupus and systemic sclerosis — occurring in about 50% of cases. However, whether interferon-1 plays a direct role in the severity of these conditions is still up for scientific debate. The activity of interferon-1 in lupus patients is, over time, not necessarily a reliable indicator of the severity of the case. Patients with naturally high interferon levels may not experience symptomatic changes as interferon levels fluctuate. Similarly, some patients have naturally low interferon levels — suggesting that the disease is not necessarily reliant on interferon activity.

Scientists have a lot of questions about interferon. The scientific community has yet to determine what factors lead to elevated interferon levels, and what mechanisms those levels affect “downstream.” Research on the pathway is robust and growing — a few clinical trials targeting the interferon-1 pathway have already been run in labs (with mixed results).

The recent failures of the TULIP-1 and TULIP-2 studies of AstraZeneca’s experimental lupus drug treatment has proved frustrating to researchers in the field, as definitive success remains elusive. Dr. Shervin Assassi, associate professor at the University of Texas Health Science Center, wants to gain a better understanding of “the role of RNA interferon signature” when predicting patient outcomes. Despite disheartening studies, Assassi hasn’t given up on interferon-1 targeting treatments. “We… need to identify patients who are more likely to benefit from interferon blockade,” so trials of the drugs have better odds of success.

Despite mixed results in studies of the effects of type-1 interferons on rheumatic disease patients, some remain convinced that the pathway is somehow involved, and that its manipulation might be able to improve patient outcomes. Do you share their optimism? Why or why not? Patient Worthy wants to know!

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