Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis

Abstract

AbstractInterferon-beta (IFN-[Formula: see text]) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN-[Formula: see text] responsiveness. This research attempted to develop an IFN-[Formula: see text] responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN-[Formula: see text] treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN-[Formula: see text] injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN-[Formula: see text] treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN-[Formula: see text] responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN-[Formula: see text]-associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN-[Formula: see text] responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN-[Formula: see text] responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN-[Formula: see text] treatment early and determine whether a current treatment plan should be continued.

Keywords

• Multiple sclerosis
• IFN- therapy
• drug responsiveness
• prognostic model construction
• survival analysis