A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Abstract

Identification of autoimmune processes and introduction of new autoantigens involved in the pathogenesis of multiple sclerosis (MS) can be helpful in the design of new drugs to prevent unresponsiveness and side effects in patients. To find significant changes, we evaluated the autoantibody repertoires in newly diagnosed relapsing-remitting MS patients (NDP) and those receiving disease-modifying therapy (RP). Through a random peptide phage library, a panel of NDP- and RP-specific peptides was identified, producing two protein data sets visualized using Gephi, based on protein--protein interactions in the STRING database. The top modules of NDP and RP networks were assessed using Enrichr. Based on the findings, a set of proteins, including ATP binding cassette subfamily C member 1 (ABCC1), neurogenic locus notch homologue protein 1 (NOTCH1), hepatocyte growth factor receptor (MET), RAF proto-oncogene serine/threonine-protein kinase (RAF1) and proto-oncogene vav (VAV1) was found in NDP and was involved in over-represented terms correlated with cell-mediated immunity and cancer. In contrast, transcription factor RelB (RELB), histone acetyltransferase p300 (EP300), acetyl-CoA carboxylase 2 (ACACB), adiponectin (ADIPOQ) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) had major contributions to viral infections and lipid metabolism as significant events in RP. According to these findings, further research is required to demonstrate the pathogenic roles of such proteins and autoantibodies targeting them in MS and to develop therapeutic agents which can ameliorate disease severity.

Keywords: autoantibodies; disease-modifying therapies; relapsing-remitting multiple sclerosis; systems medicine approach; therapeutic targets.

Figure 1

Monoclonal phage enzyme‐linked immunosorbent assay (ELISA) and the number of proteins predicted by each selected peptide. (a) Newly diagnosed relapsing–remitting MS patients (NDP) phage clones which showed the highest signal intensities in monoclonal phage ELISA (orange). (b) MS patients receiving disease‐modifying therapy (RP) phage clones which exhibited strong binding to purified immunoglobulin (Ig)G of RP (dark orange). The controls [bovine serum albumin (BSA)] are shown in grey. All data are presented as the mean ± standard deviation (s.d.). (c) Peptides identified with purified IgG of NDP (orange) and RP (dark orange) are plotted against the number of human proteins matched with each sequence after blasting (cut‐off, 18·5). [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Network visualization of newly diagnosed relapsing–remitting MS patients (NDP) and MS patients receiving disease‐modifying therapy (RP) data sets. (a) The NDP network. (b) The RP network. The NDP and RP protein data sets were introduced into STRING and protein–protein interactions were visualized by Gephi. The node size represents betweenness centrality and each colour displays a module. The significant pathways for the top three modules of each group enriched based on the KEGG and WikiPathways databases are shown in coloured circles. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

The B cell receptor (BCR) signalling pathway. Newly diagnosed relapsing–remitting MS patients (NDP)‐ and MS patients receiving disease‐modifying therapy (RP)‐specific proteins and pathways are shown as coloured boxes in the BCR signalling pathway taken from the KEGG database 28. Pathways associated with B cells were also added into the network. Complement and coagulation cascades, the common pathway between NDP and RP, is coloured blue. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

The AMP‐dependent protein kinase (AMPK) signalling pathway. MS patients receiving disease‐modifying therapy (RP)‐specific proteins and pathways are shown as colored boxes in the AMPK signalling pathway taken from the KEGG database 28. SP = signalling pathway. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 5

Binding assessment of the selected hubs to the newly diagnosed relapsing–remitting MS patients (NDP) and MS patients receiving disease‐modifying therapy (RP) sera. Results of hepatocyte growth factor receptor (MET) and adiponectin (ADIPOQ) binding to the sera of 10 NDP and 20 RP in addition to 20 age‐matched healthy controls (HC), as controls, are presented (*P < 0·001). [Color figure can be viewed at wileyonlinelibrary.com]