In Systemic Mastocytosis, What’s the Impact of Type I Interferon Autoantibodies?
—Investigators from the National Institutes of Health recently tackled the challenge of determining whether autoantibodies to type I interferon detected in the serum of patients with systemic mastocytosis are markers of disease severity.
A team of researchers from the National Institutes of Health, in Bethesda, Maryland, recently investigated the presence of type I interferon autoantibodies in the serum of patients with systemic mastocytosis, and, if found, the extent to which these autoantibodies correlate with biomarkers of disease severity.1
“On the basis of . . . findings indicating that type I interferons influence mast cell homeostasis, we hypothesized that autoantibodies to type I interferons may play a role in disease activity,” the authors noted in the Journal of Allergy and Clinical Immunology: Global.1
Study design and patient characteristics
This prospective cohort study included serum samples drawn from 89 adults with systemic mastocytosis (median age 56 years; 57.3% female; 94.4% White).1 Of these, 69 patients were classified as having indolent systemic mastocytosis, 16 with smoldering disease, and four with aggressive disease; 84 patients had concurrent maculopapular cutaneous mastocytosis.
The median serum tryptase level, which is a mast cell burden marker, was 80.7 ng/mL (interquartile range 42.2 to 149.0 ng/mL). Of the 84 patients who had any form of KIT D816V analysis performed, 76 (90.5%) were classified as positive. Of the 60 patients with peripheral blood evaluated for D816V burden using allele-specific quantitative polymerase chain reaction (PCR), 49 (81.7%) were classified as positive.
The results of autoantibody testing
The threshold for interferon (IFN) alpha (IFN-α) autoantibody functional testing was not met for any patients. Samples from 13 and three patients met the threshold for IFN-β and IFN-ω, respectively; samples from two patients met the threshold for both.
Patients with serum samples that met the threshold for any type I interferon autoantibodies were analyzed for neutralizing effects. Less than 20% signaling activity was considered blocking; 20% to 65%, partially blocking; and greater than 65%, not blocking. When stimulated with 10 ng/mL of IFN-β, no patient serum samples blocked or partially blocked STAT1 signaling activity, with the percentage of signaling ranging between 71% and 125% of the median value of healthy controls. Similar results were observed for IFN-ω, with the percentage of signaling ranging between 103% and 136%.
No correlation was observed between the concentration of type I interferon autoantibodies and serum tryptase levels (IFN-α, P=.33 and R2=.01; IFN-β, P=.10 and R2=.03; IFN-ω, P=.20 and R2=.02).
“Thus, according to this assay, which is the most relevant analysis, there was no evidence of a functional consequence,” the authors wrote.1
Sorting through various correlations
A slightly positive correlation between STAT1 signaling activity and tryptase value was observed following testing for IFN-β autoantibody signal neutralization; however, the small R2 value is suggestive of limited clinical significance. No correlation was found between STAT1 signaling activity and tryptase value following testing for IFN-ω autoantibody signal neutralization.
This same finding—no correlation—held for KIT D816V mutation values and type I interferon autoantibody levels, as well as for KIT D816V mutation values and STAT1 activity. Comparison of type I interferon autoantibody levels in those positive for the KIT D816V mutation and those negative for it revealed no significant differences (IFN-α, P=.50; IFN-β, P=.35; IFN-ω, P=.48). Moreover, no significant differences in type I interferon autoantibody levels were found based on severity of systemic mastocytosis, age, or medication use.
A history of mast cell activation (MCA)-related symptoms, including anaphylaxis, chronic gastrointestinal issues, and consistent flushing episodes, was reported in 40.5%, 92.1%, and 76.4% of patients, respectively. No difference in the proportion of patients with and without a history of MCA-related symptoms was observed among those positive for IFN-β autoantibodies.
“Thus, MCA-related symptoms were not associated with elevations in concentrations of autoantibodies to IFN-β,” the authors noted.1
Breaking new ground
The authors believe that their study is the first to report measurement of serum type I interferon autoantibodies and their correlation with disease manifestation or illness severity in patients with systemic mastocytosis. While type I interferon autoantibodies were detected in 14.6% of patients, there was no observation of type I interferon signaling inhibition via autoantibodies.
“These findings support the conclusion that autoantibodies to type I interferon do not have a significant role in the pathogenesis or manifestations of systemic mastocytosis,” the authors concluded.1
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