Measurement of serum levels of autoantibodies to type I interferons (IFNs) in patients with systemic mastocytosis (SM) do not appear to play a key role in the development or indicators of the disorder, according to findings from a cohort study published recently in the Journal of Allergy and Clinical Immunology: Global.
It is well known that autoantibodies to type I IFNs have been associated with a range of inflammatory and autoimmune disorders, including COVID-19 infection, systemic lupus erythematosus and chronic hepatic disease. Among individuals with SM, increased mast cell burden and mediator release are reported.
Recognizing that type I IFNs have shown inhibitory effects on “mast cell proliferation, degranulation, and bone marrow infiltration,” the researchers sought to establish whether autoantibodies to type I IFNs are seen in the sera of individuals with SM and whether they are linked to biomarkers of disease severity.
Sera were obtained from a total of 89 adults with SM. The investigators analyzed the concentrations of autoantibodies to type I IFNs by utilizing a “multiplex particle-based assay in which magnetic beads with differential fluorescence were covalently coupled to recombinant human proteins.” Signal neutralization capacity was tested via use of a signal transducer and activator of transcription 1 activity (STAT1) assay. The measurements obtained were compared with those contained in a database of information with a total of 1284 healthy controls.
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The median patient age was 56 years of age. Overall, 38 of the patients were male, and 51 were female. Participants’ median serum tryptase level—a marker of mast cell burden—was 80.7 ng/mL (range, 42.2-149.0 ng/mL). Among the 89 participants, 69 were diagnosed with indolent SM, 16 with smoldering SM and 16 with aggressive SM.
Overall, 13 of the patient samples obtained fulfilled the threshold for functional testing for autoantibodies against IFN-β, 3 samples attained the threshold for autoantibodies against IFN-ω, and no samples achieved the threshold for autoantibodies against IFN-α. Two of the samples met the threshold for both IFN-β and IFN-ω. Those individuals in whom their sera attained the threshold for autoantibodies to any subtype of type I IFN eventually were evaluated for in vitro neutralizing effects with the use of 10% sera.
Results showed that no sera blocked or partially blocked STAT1 signaling activity when stimulated with IFN-β 10 ng/mL. In fact, the percentage of signaling varied from 71% to 125% of the median healthy control signaling value. In a similar fashion, no participants exhibited blocking or partial blocking activity against IFN-ω .
Most of the adult patients with SM who were assessed harbored an activating mutation (D816V) in KIT. Moreover, neither autoantibody concentration nor signaling inhibition measurements was associated with tryptase concentrations or with D816V allele burden. In all, 94.4% (84 of 89) of the participants underwent KIT D816V analysis in peripheral blood or bone marrow, with 90.5% (76 of 84) of them testing positive.
“These findings support the conclusion that autoantibodies to type I [IFN] do not have a significant role in the pathogenesis or manifestations of SM,” the authors concluded.
