Type I interferon appears to play a role in disease susceptibility and pathogenesis in several classic connective tissue diseases, at least in some patients. Below, I present evidence supporting this connection, explore potential missing links in pathogenesis and discuss biological treatments that target the pathway.
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Explore This IssueJuly 2019
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The Type I Interferon Pathway
Interferons are a class of cytokines thought to play important roles in immunity, autoimmunity, inflammation and cancer. Each of the three subtypes of interferon triggers a distinct receptor complex. Type I interferons all send their signals via the type I interferon receptor (IFNAR). Interferon-α and interferon-β are the two type I interferons most studied in rheumatic diseases, but three other subtypes also exist. Though interferon-α and interferon-β signal via the same receptor, their binding permits different downstream signaling. Once triggered, IFNAR can activate kinases, such as Janus kinase 1 and tyrosine kinase 2, ultimately leading to the expression of different gene programs.1
The main producers of interferon-α are plasmacytoid dendritic cells. In contrast, many different cell types produce interferon-β, including fibroblasts, epithelial cells, dendritic cells and phagocytes. The production of type I interferon is highly dependent on cell type and specific environmental circumstances. For example, type I interferon production might be initiated after toll-like receptors detect local microbial products, partly mediated through a family of transcription factors called interferon regulatory factors. These factors also help modulate the effects of type I interferon on target cell gene expression.1,2
Elevated Activity in Rheumatic Disease
A 1979 study first noted elevated interferon activity in the blood of lupus patients, as well as in scleroderma, Sjögren’s syndrome and rheumatoid arthritis. The lupus findings were particularly robust.3
Timothy Niewold, MD, is the director of the Colton Center for Autoimmunity and the Judith and Stewart Colton professor of medicine at NYU School of Medicine in New York City. He notes that type I interferon has anti-viral activity: “It’s interesting, because some of the features of lupus, like the myalgias and the fatigue, are similar to those observed in a viral infection.”
Dr. Niewold says it wasn’t clear what to do with this information, and interest in the topic lagged. Part of the reason was the difficulty of the tests used to measure type I interferon. He notes, “It has been hard to reliably measure protein levels of type I interferon in human blood. For high levels, standard methods seem to work well, but when you get to more subtle determinations, most of the assays have been tricky. There aren’t really good commercially available tests for type I interferon.”
More studies might have included this measure over the years if the test had not proved so challenging to perform.
A renaissance of interest in the type I interferon pathway occurred in the 2000s, when technology became available that could study gene expression patterns. “There was an ‘interferon signature’ in many patients with lupus,” explains Dr. Niewold. “They call it a ‘signature’ because what you are seeing is the response to interferon in the blood cells, where it looks like the interferon receptor has been ligated, and you can observe the downstream events. You see the messenger RNA transcripts that you would expect after a type I interferon receptor is engaged.” In other words, one saw upregulation of type I interferon-stimulated genes. “It jumped off the page in lupus,” he adds.
Other studies soon followed. Shervin Assassi, MD, is an associate professor in rheumatology at the University of Texas Health Science Center in Houston. He notes, “When we look at the gene expression profile in peripheral blood of patients with systemic sclerosis, we detect that the most prominently dysregulated profile is an upregulation of interferon I gene expression. We see similar findings to a lower degree when we look at tissue level, such as in the skin.” An interferon signature is also commonly found in samples taken from Sjögren’s patients, and literature documents high levels of type I interferon in both pediatric and adult dermatomyositis.
Similarities exist among many of the conditions that show increased type I interferon response. “A lot of them are classic connective tissue diseases—lupus, Sjögren’s, scleroderma, myositis. They are unified by anti-nuclear antibodies as well,” says Dr. Niewold. He adds, “This raises more questions than it answers. We have this diverse group of ANA-positive diseases that have many different physical manifestations but some similarities in autoantibodies. Why are they all related to type I interferon?”
Phenotype, Severity & Autoantibodies
Not all patients with these diseases display interferon signatures indicative of high interferon I activity. “Several studies have shown that not all systemic sclerosis patients have the interferon signature,” explains Dr. Assassi. “It’s thought to be positive in around half of them.” Similarly, around half of lupus patients have elevated type I interferon levels. In other words, type I interferon is probably not an important pathogenic factor for all patients with these diseases.1
“An interferon signature does appear to be associated with more severe lung disease and more severe skin disease in systemic sclerosis,” says Dr. Assassi. In Sjögren’s syndrome, an interferon signature identifies patients with higher levels of disease activity.1
Dr. Niewold says elevated type I interferon levels probably indicate a subset of a sicker group of patients with lupus. “If you look at a large group of patients and you measure disease activity, the people that have high interferons will tend to have higher disease activity than the group that doesn’t,” he says. These patients are also more likely to have kidney, central nervous system or hematological involvement.
However, the correlation with type I interferon is not as strong if one looks at the individual lupus patient and their disease activity over time. Dr. Niewold explains, “You can find patients who always have high interferons, and their disease flares can come and go without change in interferon. You can also find patients who seem to always have low levels, and it might be that interferon is just not part of their disease. It does seem like interferon levels fluctuate in a subgroup of lupus patients, but it hasn’t been useful as a major predictor of disease activity.”
In contrast, several studies have demonstrated that type I interferon correlates with muscle enzyme levels in inflammatory myositis, suggesting that elevated type I interferon might play more of a role in flare activation in that condition.1
Interferon Signature & Rheumatic Antibodies
High type I interferon activity seems to be associated with positivity of certain autoantibodies as well. “Type I interferon has been associated with autoantibodies, like the anti-Ro and anti-La antibodies in Sjögren’s syndrome and lupus—patients who have those autoantibodies are more likely to have an interferon signature than those who don’t,” says Dr. Niewold. In myositis, a similar correlation has been found between anti-RNA binding protein antibodies (such as anti-Ro).1