Background Type I interferons (IFN) are secreted molecules that play a major role in the response to viral infection. However, defective regulation of this pathway may result in an excessive α/β-IFN immunity presenting with severe inflammatory phenotype1. The two prototypic genetic diseases linked to increased α/β-IFN immunity are Aicardi-Goutières syndrome (AGS) and spondyloenchondrodysplasia with immune dysregulation (SPENCD). In the case of AGS, mutations in several genes have been identified leading to excessive type I IFN production as the result of inappropriate stimulation of the type I IFN response pathway. More recently, two new clinical phenotypes, STING associated vasculopathy with onset in infancy (SAVI)2 and a familial inflammatory syndrome with systemic lupus erythematosus (SLE)-like manifestations3, have also been linked to an increase of type I IFN – in both cases as a result of TMEM173 gain of function dominant mutations. All of these conditions have been grouped under the name of type I interferonopathies. Type I IFN has been also implicated in the development of the autoimmune and inflammatory complications characteristic of SLE.
Objectives To assess the predictive value of blood IFN signature for the identification of type I interferonopathies.
Methods We tested a cohort of pediatric rheumatologic patients using a qPCR based IFN gene signature assay4. Expression of 6 type I IFN-related genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) was quantified by standard RT-PCR techniques. An IFN score was calculated for each patient using the median fold change of gene expression related to a healthy control. Patients were selected based on the presence of the following features: i) atypical or incomplete SLE-like symptoms occurring in infancy or in preprepubertal age; ii) vasculopathy (skin ulcers, chilblains, strokes) iii) panniculitis with or without lypodistrophy iv) interstitial lung disease in the context of systemic inflammation.
Results We screened 8 patients from the rheumatology unit of the Gaslini Children's Hospital, Genova (Italy). 6 out of 8 patients had a positive signature with an IFN score ranging from 3.8 to 18.2. Based on the clinical presentation and the result of the IFN score we further analysed one patient for mutations affecting TMEM173 gene and we identified the previously reported V155M variant. Molecular screening for genes associated to type I Interferonopathies and whole exome sequencing is ongoing for selected patients.
Conclusions These preliminary results show that the blood IFN signature can be predictive of the diagnosis of type I interferonopathies and suggest that a genetic cause should be suspected in atypical cases of SLE-like disease and/or vasculopathy with skin chilblains and with an early onset. As already observed in the case of IL1-β and autoinflammatory conditions, knowledge of the defect responsible for a disease will allow the development of more effective targeted therapy.
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Disclosure of Interest None declared