The innate immunity in clinically isolated syndrome (CIS) and Multiple Sclerosis (MS) is poorly studied, but very important for both initiation and progression of the disease. In a predisposed subject, the activation of damage-associated molecular patterns (DAMPs) mediated by Toll-like receptors provides a micro-chemical inflammatory environment resulting in the self-maintaining neuroinflammation. IFN-beta is one of the most prescribed agents for MS’ treatment. Its heterogeneous response is individual and urges defining biological marker. The Rio Score (RS) provided a clinical assessment tool for predicting the one year-response in IFN-treated MS, but no pharmacodynamic biomarker is available. Interferon induced protein 35 (IFP35) is a zinc-finger factor correlating with the biological IFN activity, also serving as proinflammatory DAMP via the Janus kinase/signal transducers on the transcription of JAK-STAT protein.
The primary aim of this study is to profile the IFP35 expression in CIS and clinically defined MS (CDMS) patients; furthermore, to assess the IFP35 differential profile to individuate the responder (RS=0) and non-responder (RS≥1) subjects among the IFN-treated MS group.
30 CIS-patients, 50 relapsing remitting (RR) MS-patients treated with IFNbeta-1b and IFNbeta-1a, 10 Secondary Progressive (SP) MS-patients along with 20 healthy controls (HCs) were enrolled. All patients underwent the blood sample, clinical and MRI evaluation, obtaining lesion load (LL), white/grey matter fraction (W/GMF) and RS definition over a 30-months observational period. Quantitative assessment of IFP35 was obtained by western-blot technique from peripheral blood mononuclear cells.
IFP35 from the CIS-patients was 2.06-fold up-regulated than HCs (p<0.0001) and 1.67-fold up-regulated than SPMS-patients (p=0.035); IFP35 from IFNbeta-1a-treated patients was higher than IFNbeta-1b (p=0.006). Furthermore, IFP35 from the RS=0 group was 1.88-fold up-regulated than RS ≥ 1 (p<0.0001). IFP35 expression also inversely correlated to RS (r=0.60; p<0.0001), WMF (r=-0.50; p=0.0017) and LL (r =-0.51; p=0.0026). Finally, Kaplan-Meier analysis sorted a cut-off value of IFP35 ≥ 65% for RS=0 (p<0001).
We demonstrated for the first time the IFP35 biological pattern as predictive indicator of drugs efficacy in IFN-treated MS, but also of disease activity, thus reflecting the innate immunity-dependent neuroinflammation.