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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 2018 Jan 25;192(1):18–32. doi: 10.1111/cei.13087

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

M Pazhouhandeh 1, M‐A Sahraian 2, S D Siadat 1,3, A Fateh 1,3, F Vaziri 1,3, F Tabrizi 1, F Ajorloo 1,4, A K Arshadi 1, E Fatemi 5, S Piri Gavgani 1, F Mahboudi 5, F Rahimi Jamnani 1,3,✉
PMCID: PMC5842404  PMID: 29194580

Summary

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

Introduction

Multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system (CNS), is diagnosed predominantly in young adults with an average age of 30 years. This demyelinating disease has affected approximately 2·5 million people worldwide 1. Among MS medications, interferon (IFN)‐β, glatiramer acetate, teriflunomide and dimethyl fumarate are considered as first‐line therapies, whereas fingolimod, natalizumab, alemtuzumab and mitoxantrone are administered in unresponsive patients 2. Although different disease‐modifying therapies (DMTs) are available for the relapsing–remitting MS (RR‐MS), the most common clinical form of the disease (accounting for 85% of MS cases), they fail to prevent disease progression 1, 2. Furthermore, patient response to DMTs is highly variable, and new medications may result in adverse reactions despite their potent effects 3.

Although T lymphocyte‐driven autoimmunity and tissue damage are the central processes in MS, clonally expanded autoreactive B cells can also break anti‐neuronal tolerance and exacerbate neurodegeneration 4. Immunoglobulins which are produced in the CNS and cerebrospinal fluid (CSF) by activated B cells can target self‐antigens such as intracellular proteins which are released due to tissue damage and exposed to the immune system 4.

According to the literature, targets of autoantibodies in MS patients include proteins such as CNS myelin components (e.g. myelin basic protein, myelin‐associated glycoprotein, myelin oligodendrocyte glycoprotein and proteolipid protein), domain I of beta‐2 glycoprotein I, aquaporin‐4, neurofascin, contactin‐2 (CNTN2) and inward‐rectifying potassium channel (KIR4.1) 4, 5, 6, 7.

Immunoglobulin G oligoclonal bands are detected at the first clinical event in nearly 90% of patients who are eventually diagnosed with MS 4, 8. Long‐term stability of oligoclonal bands after aggressive therapy and the presence of antibodies targeting neuronal cell‐surface molecules during demyelination indicate the involvement of the same B cell and plasma cell clones in MS development 9.

In recent years, several studies have evaluated the autoantibody repertoires in MS patients and examined proteomic and transcriptomic alterations during DMT. Also, these studies have introduced biomarkers or drug targets through bioinformatics 10, 11, 12, 13. In this regard, Hecker et al. 10 investigated the autoantibody repertoires in serum and CSF samples of patients with RR‐MS or primary progressive MS (PP‐MS) via high density‐peptide microarray representing the protein sequences of 45 MS autoantigens. Their results revealed that one of the peptides belonged to a region of an Epstein–Barr virus nuclear antigen 1 (EBNA1) protein and was homologous to alpha‐crystallin B chain in humans 10. Furthermore, a combined pathway analysis was performed on genomewide association studies and expression data to identify new critical pathways in MS. In addition to three pathways reported in a previous study [Janus kinase/signal transducers and activators of transcription (JAK‐STAT) signalling pathway, acute myeloid leukaemia and T cell receptor signalling pathway] 14, several other pathways were also identified (e.g. antigen processing and presentation, focal adhesion and mechanistic target of rapamycin signalling pathway). Furthermore, two pathways related to infectious diseases, including toxoplasmosis and Staphylococcus aureus infection, were found 11.

Moreover, Cordiglieri et al. 12 investigated peripheral blood gene and protein expression profiles in RR‐MS patients on DMT. They found eight differentially expressed genes, including integrin alpha 2b (ITGA2B), integrin beta‐3 (ITGB3), CD177, immunoglobulin J chain (IGJ), IL‐5RA, matrix metalloproteinase‐8 (MMP8), purinergic receptor P2Y12 (P2RY12) and protein S100‐B (S100β) down‐regulated in response to the different therapies, except S100β, which was up‐regulated 12. Also, to identify genetic factors impacting on long‐term response to IFN‐β, Clarelli et al. 13 performed a pharmacogenetic study on IFN‐β‐treated MS patients and found significant pathways linked to inflammatory processes and presynaptic membrane (with involvement of glutamate receptor ionotropic, kainate 2 (GRIK2) and glutamate metabotropic receptor 3 (GRM3)]. Nevertheless, none of these studies were evaluated autoantibody‐related data to track changes in pathways before and after DMT.

In comparison with MS patients, risk of cancers such as lung cancer and non‐Hodgkin's lymphoma (NHL) is higher in patients with autoimmune diseases, e.g. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) 15, 16, 17, 18, 19. Accordingly, we have evaluated the autoantibody repertories in patients with non‐small‐cell lung cancer 20, NHL 21, SLE, RA (in press) and MS to find common events and indeed common targets. With this background in mind, in the present study we employed a systems medicine approach to compare the autoantibody repertoires of newly diagnosed patients with RR‐MS (NDP) and those receiving DMT (RP). The main objectives were to identify pathways involved in the physiopathology of MS, the amelioration of MS and cancer development or suppression in MS patients.

Materials and methods

Subjects

MS patients enrolled for the current study were confirmed by a neurologist, based on the McDonald diagnostic criteria. The patients were subjected to a comprehensive neurological examination every 3 months, including physical assessment of disease and estimation of expanded disability status scale (EDSS) score. The blood samples of 11 untreated newly diagnosed RR‐MS patients (NDP group; all women; age range, 17–57 years; mean age, 28·5 years) and 47 RR‐MS patients on DMT (RP group; 37 women and 10 men; age range, 16–51 years; mean age, 33·5 years) were collected from the MS clinic of Sina hospital in Tehran, Iran. The average duration of disease in the RP group was 6 years, and the patients had a history of IFN‐β, glatiramer acetate, azathioprine and glucocorticoids use. Based on the patient information, those with a history of malignancy or autoimmune diseases were excluded from the study.

The sample size included 92 healthy, age‐ and gender‐matched individuals, who were selected randomly (52 men and 40 women; age range, 11–80 years; mean age, 37·8 years). The blood level of C‐reactive protein (≤ 6 mg/dl), erythrocyte sedimentation rate (≤ 32 mm/h), rheumatoid factor (negative RF), complete blood cell count and chest X‐ray were examined in the patients. The healthy subjects discontinued anti‐inflammatory drugs for 3 days prior to sampling. The volunteers were interviewed to assess their demographic information and risk factors for autoimmune diseases and cancers (e.g. history of diseases in patients and their families) 20, 21.

The present study was performed in accordance with the Declaration of Helsinki and was approved by the local ethical committee of Multiple Sclerosis Research Center of Sina Hospital. In addition, written informed consents were obtained from the participants before enrolment. The characteristics of all three groups are demonstrated in Supporting information, Table S1.

IgG purification from the sera

The sera of healthy controls, NDP and RP groups were mixed separately and IgG was purified with the Melon™ Gel IgG Purification Kit (Pierce, Rockford, IL, USA), according to the manufacturer's instruction 21.

Biopanning on purified IgG

According to the manufacturer's instruction, the Ph.D.TM‐C7C phage display peptide library kit (New England Biolabs, Beverly, MA, USA) was used to perform three successive cycles of biopanning on purified IgG of the NDP and RP groups 21.

Polyclonal and monoclonal phage enzyme‐linked inmmunosorbent assay (ELISA)

Polyclonal phage ELISA was performed on the input and output phages of biopanning cycles in the NDP and RP groups. The specificity of 50 phage clones from biopanning on the NDP and RP IgG was evaluated separately by monoclonal phage ELISA, based on the Ph.D.TM‐C7C kit instruction (Supporting information) 21, 22.

DNA sequencing

In the NDP and RP groups, single‐stranded DNAs of 12 phages with the highest signal intensities in monoclonal phage ELISA were extracted according to the Ph.D.TM‐C7C kit manual. Following sequencing, DNA sequences were translated into amino acids by Gene Runner version 5.0. The selected peptides were evaluated in the Biopanning Data Bank (MimoDB) (http://immunet.cn/bdb/) to remove target‐unrelated peptides (if present) 23. Then, they were blasted for Homo sapiens proteins, using the BLASTp tool and Refseq protein database 21, 24.

Determination of significant protein complexes and MS‐linked proteins

The proteins predicted via blasting (score ≥ 18·5) were categorized into two NDP and RP groups and analysed in the ConsensusPathDB database (CPDB) (http://cpdb.molgen.mpg.de) to find significant protein complexes (P < 0·05) with two components in the NDP or RP protein data set. To determine which proteins had been reported as MS‐related proteins in the DisGeNET database, a full list of MS‐related genes was downloaded from DisGeNET (http://disgenet.org). The common genes in each NDP or RP data set were selected, sorted and ranked using a disease specificity index (DSI) and a DisGeNET score. The former shows the degree of gene specificity for the disease and the latter is a score displaying the robustness of the relation. The sum of the calculated DSI and the DisGeNET Score was measured as total rank (integrating specificity and robustness).

Network visualization, gene ontology (GO) and pathway enrichment analysis of predicted proteins

To show the molecular interaction networks, the NDP and RP protein data sets were introduced individually to STRING version 10.0 (http://string-db.org) 25 and protein–protein interactions (edges) were extracted. The proteins (nodes) and their edges were visualized using Gephi version 0.9.1. By running the modularity function, the nodes were coloured differently and laid out circularly based on their modules. GO terms and pathways in the top three NDP and RP modules were revealed using Metascape (http://metascape.org) 26 and Enrichr (http://amp.pharm.mssm.edu/Enrichr/) 27 web tools, respectively. Literature data‐mining was also performed to find out the contribution of pathways and hubs to MS, DMT and cancer 21.

NDP‐ and RP‐specific networks

NDP‐ and RP‐specific networks were made by highlighting significant pathways in the B cell receptor signalling pathway and the AMP‐dependent protein kinase (AMPK) signalling pathway as critical pathways in NDP and RP, respectively. Over‐represented terms and key proteins from the NDP and RP protein data sets were also added to the B cell receptor and AMPK signalling pathways taken from the KEGG database 28.

Evaluation of the immunoreactivity of hepatocyte growth factor receptor (MET) and adiponectin/acrp30 protein (ADIPOQ) by ELISA

In this study, reactivity of the selected hubs, MET (NovoPro Bioscience, Shanghai, China) and ADIPOQ (R&D Systems, Inc., Minneapolis, MN, USA) with the sera of NDP and RP groups were assessed by ELISA, respectively (Supporting information) 21, 22.

Statistical analysis

GraphPad Prism® was used to perform statistical analyses and the data were demonstrated as the mean ± standard deviation (s.d.). Statistical significance was determined by a two‐tailed Student's t‐test. A P‐value < 0·05 was considered statistically significant.

Results

Two NDP and RP protein data sets were generated by peptide library enrichment

In polyclonal phage ELISA, the phage pools from three panning cycles showed a steady increase in the intensity of binding to purified IgG of NDP and RP groups versus the negative control group (bovine serum albumin; BSA). Of phages from the third round of panning on the NDP and RP IgG, which showed significantly higher intensities compared to the control, 25 NDP‐ and RP‐specific phage clones were selected randomly and evaluated via monoclonal phage ELISA. Altogether, 12 of 25 NDP‐ and RP‐specific phage clones, which exhibited strong signals in comparison with the negative control (BSA), were selected for further analysis (Fig. 1a,b). After purification and DNA sequencing of the selected phage clones, 11 clones in the NDP group presented meaningful sequences, among which NM1, NM2, NM4, NM6, NM7 and NM12 (‐CGLRMALDC‐; 50%), as well as NM9–11 (‐CHDPSHQLC‐; 25%), showed similar sequences. In addition, among 12 RP‐specific phage clones, six clones showed correct sequences, three of which encoded the same peptide sequence (RM1, RM5 and RM9; ‐CNSLPPWSC‐; 25%). By evaluating the selected peptides in the MimoDB database, no target‐unrelated peptides were found. Two lists consisting of 188 and 295 proteins were retrieved via blasting NDP‐ and RP‐related peptides, respectively (Supporting information). The number of proteins predicted by each peptide is plotted in Fig. 1c. Among proteins, mucin 5B (MUC5B) in the NDP group and vacuolar protein sorting‐associated protein 29 (VPS29), RNA polymerase II‐associated factor 1 homologue (PAF1), CD6 and ephrin type‐A receptor 4 (EPHA4) in the RP group were predicted by two different peptides. Also, oxygen‐regulated protein 1 (RP1), inactive tyrosine–protein kinase transmembrane receptor ROR1 (ROR1), SP100, acid phosphatase 2, lysosomal (ACP2) and lysosomal‐trafficking regulator (LYST) were common between the NDP and RP protein data sets.

Figure 1.

Figure 1

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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]

Significant protein complexes and MS‐related genes in the NDP and RP groups

In order to find protein complexes, two protein data sets were assessed in CPDB which presented the most significant complexes: interleukin enhancer‐binding factor 3 (IL‐F3)–exportin‐5 (XPO5), delta‐like protein 1 (DLL1):neurogenic locus notch homologue protein 1c (NOTCH1), protein transport protein SEC131A (SEC31A):SEC13:SEC23IP, αM/β2‐integrin/low‐density lipoprotein‐related protein tissue plasminogen activator (LRP/TPA) and αM/β2‐integrin/talin complexes for the NDP group; and PID, SNF2h/cohesion, histone deacetylase 2 (HDAC2)‐c/Mi2/nucleosome remodelling and deacetylase (NuRD) and linker of nucleoskeleton and cytoskeleton (LINC) complexes for the RP group (Supporting information, Table S2). There were also complexes which correlated with the immune system and MS pathogenicity: DLL1:NOTCH1 complex inducing T lymphopoiesis 29; αM/β2‐integrin/talin complex modulating T cell adhesion 30; and HDAC2‐c/Mi2/NuRD complex of which its principal component, Mi2 protein, was identified initially as an autoantigen in dermatomyositis 31. Approximately 25% of patients with dermatomyositis reveal anti‐Mi2 antibodies, leading to the development of malignancies with an unclear mechanism 31. According to the DisGeNET database, 15 and 20 genes of NDP and RP protein data sets were associated with MS, respectively (Supporting information, Table S3). The top three genes included alpha‐N‐acetylneuraminide alpha‐2,8‐sialyltransferase (ST8SIA1), Xin actin‐binding repeat‐containing protein 2 (XIRP2) and BMP/retinoic acid‐inducible neural‐specific protein 1 (BRINP1) in the NDP protein data set and voltage‐dependent calcium channel gamma‐4 subunit (CACNG4), vasoactive intestinal polypeptide receptor 2 (VIPR2) and adenosine deaminase domain‐containing protein 1 (ADAD1) in the RP protein data set, classified based on the total rank. Also, a group of genes, including IFN‐AR2, IL‐12RB2, CD6, tumour necrosis factor alpha‐induced protein 3 (TNF‐AIP3), IL‐23R and disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), was identified in the RP group, which plays a key role in various disorders such as MS.

Leyva et al. 32 reported a correlation between particular IFN‐AR2 polymorphisms and susceptibility to MS. Furthermore, several studies have demonstrated IFN‐AR2 over‐expression in different carcinomas, such as lung cancer 33. In addition, Grossman et al. 34 exhibited an association between IL‐12RB2 polymorphism and response to glatiramer acetate in MS patients. One of the most important identified genes was CD6, which was predicted through two RP‐related peptides. The remarkable effect of CD6 on the survival, proliferation and infiltration of activated T cells has made it a promising therapeutic target in MS 35. Furthermore, a number of reports have indicated the high protein level of ADAMTS4, as well as TNF‐AIP3 and IL‐23R polymorphisms in MS patients, thereby highlighting the role of these genes in MS 36, 37, 38.

Clustering, GO and pathway analysis of NDP and RP protein data sets

The NDP network, visualized via Gephi, consisted of 79 nodes and 89 edges, whereas a larger network of 141 nodes and 183 edges was formed for RP (Fig. 2a,b).

Figure 2.

Figure 2

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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]

Based on Metascape, significant GO terms for the top three modules of NDP were blood vessel endothelial cell differentiation (GO:0060837), coupled to transmembrane movement of substances (GO:0042626), transmembrane receptor protein tyrosine kinase activity (GO:0004714), regulation of canonical wingless‐related integration site (Wnt) signalling pathway (GO:0060828), leucocyte activation (GO:0045321), glutamate receptor signalling pathway (GO:0007215), platelet degranulation (GO:0002576) and immune response‐regulating cell surface receptor signalling pathway (GO:0002768). Over‐represented GO terms related to RP were histone acetyltransferase activity (GO:0004402), cellular response to light stimulus (GO:0071482), response to glucose (GO:0009749), nucleotide metabolic process (GO:0009117), Wnt signalling pathway (GO:0016055), positive regulation of Jun amino‐terminal kinases (JNK) cascade (GO:0046330), axonogenesis (GO:0007409), protein tyrosine kinase activity (GO:0004713), central nervous system development (GO:0007417), positive regulation of immune system process (GO:0002684) and regulation of cytokine production (GO:0001817).

Pathway analysis of NDP‐related modules with Enrichr led to the identification of a group of remarkable pathways: B and T cell‐receptor signalling pathways, natural killer cell (NK)‐mediated cytotoxicity, ATP‐binding cassette (ABC) transporters, glutamatergic synapse, TNF‐α signalling pathway, IL‐3 signalling pathway, sphingolipid signalling pathway, microRNAs in cancer, colorectal cancer, pathways in cancer, leptin signalling pathway, platelet‐derived growth factor (PDGF) pathway, epidermal growth factor receptor (EGFR) signalling pathway, as well as complement and coagulation cascades. As anticipated, B and T cell‐receptor signalling pathways were the main pathways over‐represented in NDP. The role of these pathways in the initiation of MS has been verified in many studies 39, 40. As shown in Fig. 3, NDP‐specific proteins, including NF‐kappa‐B inhibitor alpha (NFKBIA), nuclear factor of activated T cells cytoplasmic 3 (NFATC3), RAF proto‐oncogene serine/threonine–protein kinase (RAF1) and proto‐oncogene vav (VAV1), were involved in these pathways. Among highly ranked pathways, we identified ABC transporters in the NDP group. In this regard, Kooij et al. 41 have shown recently that the high expression of ABC transporters on the blood–brain barrier (BBB) is linked to neuroinflammatory processes involved in MS pathogenesis. They showed that ABC transporters could mediate the secretion of inflammatory molecules such as CCL2, resulting in immune cell migration 41. One of the notable pathways in this data set was glutamate excitotoxicity with the involvement of GRIK2 and GRIN2B, causing axonal damage through increasing intracellular calcium levels 42. Importantly, this event is linked to oligodendrocyte depletion and demyelinating processes 42. Glutamate overactivity may also contribute to the activation of T cells and infiltration of immune cells through the BBB 43. Another over‐represented pathway in the NDP group was the TNF‐α signalling pathway. Despite the primary data on the correlation of TNF with MS and promising animal studies on TNF inhibition, clinical evaluation of the TNF inhibitor, lenercept, was halted due to increased disease severity 44. This observation might be attributed to the stimulation of remyelination through TNF receptor 2, neuroprotective effects of TNF‐α‐induced NF‐κB activation and reduced glutamate excitotoxicity 44, 45. The IL‐3 signalling pathway, which is another significant pathway in the NDP group, may be also related to MS. Renner et al. 46 exhibited that IL‐3 expression in T cells was increased substantially during relapse in RR‐MS patients, and an anti‐IL‐3 monoclonal antibody reduced disease severity in experimental autoimmune encephalomyelitis (EAE). One of the most widely studied pathways associated with MS is the sphingolipid signalling pathway, also found in NDP. As well as the up‐regulation of sphingosine‐1‐phosphate receptors 1 and 3 in active MS lesions, the emergence of antibodies against sphingolipids in the sera and CSF of MS patients highlights the critical effects of these molecules and their pathways on MS pathogenesis 47. Apart from pathways such as B cell and T cell‐receptor signalling pathways as well as NK cell‐mediated cytotoxicity, which were directly related to cell‐mediated immunity; tumour‐related events, including microRNAs in cancer, pathways in cancer and colorectal cancer were also enriched in the NDP group. A set of critical proteins, including MET, ATP binding cassette subfamily c member 1 (ABCC1), NOTCH1, apoptosis regulator BAX (BAX), and RAF1, was observed in these pathways. Other significant pathways in the NDP group were the leptin signalling pathway and pathways related to growth factors such as PDGF and EGFR. It has been demonstrated that leptin stimulates proinflammatory immune responses in EAE and its blockade may result in the amelioration of MS disease activity 48. With respect to growth factors, Mori et al. 49 found that PDGF was related to long‐term synaptic potentiation and the clinical compensation of new lesions in MS. Additionally, their results revealed that the CFS level of PDGF was decreased in patients with PP‐MS 49. PDGF receptor, a marker of oligodendrocyte precursor cells (OPCs), stimulates OPC proliferation 50. In this way, Maeda et al. 51 showed that the PDGF‐α receptor was over‐expressed in proliferating oligodendroglia in the brains of MS patients, which provided a source of cells recovering the MS lesion. It has been reported that EGFR over‐expression leads to remyelination and increased oligodendrocytes generation 52. Furthermore, Tuller et al. 53 exhibited increased expression of EGFR during relapse in comparison with remission.

Figure 3.

Figure 3

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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]

AMPK signalling pathway, peroxisome proliferator‐activated receptor (PPAR) signalling pathway, adipocytokine signalling pathway, EBV infection, Wnt signalling pathway, androgen receptor signalling pathway and fatty acid‐related pathways were the major pathways in the RP group (Fig. 4). Also, cell adhesion molecules (CAMs), axon guidance, Notch signalling pathway, human T cell leukaemia virus type 1 (HTLV‐1) infection, adipose‐related pathways and the integrated pancreatic cancer pathway were the common pathways between the groups.

Figure 4.

Figure 4

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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]

The occurrence of a set of proteins, including ADIPOQ, hepatocyte nuclear factor 4 alpha (HNF4A) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) in the RP protein data set, signified a group of pathways, namely AMPK, PPAR, adipocytokine and adipogenesis signalling pathways (Fig. 4). The correlation between MS and decreased activity or loss of AMPK function has been demonstrated in several studies 54, 55. AMPK acts as a central metabolic switch, which directs glucose and lipid metabolism 56. Furthermore, AMPK is related to the regulation of inflammatory signalling pathways, and its enzyme activity is controlled by proteins such as ADIPOQ and leptin 56. ADIPOQ secreted by adipocytes functions through ADIPOQ receptor 1 (AdipoR1), which mediates the stimulation of AMPK phosphorylation and AdipoR2 which mediates PPAR‐α activity 57. This abundant circulating adipokine can modulate different immune‐related events, e.g. production, and enhancement of regulatory T cell count and IL‐10 secretion 57, 58. PPAR‐γ signalling is also related to ADIPOQ, and its agonists can control EAE by preventing IL‐1β, IL‐6, nitric oxide (NO) and TNF‐α production (by astrocytes and microglia) and inhibiting T helper type 1 (Th1) differentiation and IL‐12 generation/signalling 59.

Fatty acid biosynthesis and fatty acid degradation were enriched in this group due to the presence of RP‐specific proteins such as acetyl‐CoA carboxylase beta (ACACB) and fatty‐acid‐coenzyme A ligase, long‐chain 3 (ACSL3) (in biosynthesis), in addition to acetyl‐CoA acetyltransferase 2 (ACAT2) and ACSL3 (in degradation). Some studies have reported that acetyl‐CoA carboxylase (ACC), a downstream target of AMPK, contributes to the biosynthesis of fatty acid and inhibits fatty acid uptake 60. In addition, AMPK activation in the liver could directly increase fatty acid uptake and enhance fatty acid oxidation via inhibitory phosphorylation of ACC2 61. The role of disordered lipid metabolism in the development of MS has been suggested recently by several researchers 62, 63, 64, 65. Under various stress conditions, such as local hypoxia, which can change normal glucose metabolism to lipid metabolism, lipid levels are decreased, leading to the prevention of myelin sheath lipidation; therefore, the myelin sheath becomes susceptible to inflammatory attack 65.

Identification of RP‐specific proteins, chromodomain‐helicase‐‐DNA‐binding protein 8 (CHD8) and EP300, as negative and positive regulators of the Wnt signalling pathway, respectively, highlights the role of this pathway in RP. It has been proposed that the dysregulated Wnt/β‐catenin signalling pathway is correlated with lack of remyelination mostly observed in MS patients. Also, its restimulation in CNS vessels can partially restore the functional integrity of the BBB and restrict the infiltration of immune cells into the CNS 66, 67.

EBV infection is considered as a major environmental risk factor for MS 68, 69. By blasting RP‐specific peptides for EBV, one peptide (‐CNSLPPWSC‐) resembled EBNA1 protein. In this regard, Petersen et al. 70 found that the presence of anti‐EBNA‐1 IgG in the sera of MS patients was associated with disease activity; also, IFN‐β non‐responders showed higher levels of this antibody than the responders.

The notable finding of this study was the emergence of androgen receptor in the RP group. Testosterone, acting on the neural androgen receptor, can promote remyelination in severely demyelinated brain lesions, and lack of androgen receptor or testosterone can impair spontaneous remyelination by oligodendrocytes 71. In a pilot clinical trial, testosterone therapy in male RR‐MS patients led to reduced neurodegeneration 72.

Among common pathways, adhesion molecules were majorly involved in cell migration and MS‐related processes. These events can occur due to interactions of NDP‐related [reelin (RELN), integrin alpha M (ITGAM), ITGB8 and talin‐1 (TLN1)] and RP‐related [netrin‐G2 (NTNG2), CD6, L‐selectin (SELL), CNTN1, intercellular adhesion molecule 3 (ICAM3), programmed cell death protein 1 (PDCD1) and neogenin 1 (NEO1)] adhesion molecules with other central molecules involved in neurodegeneration 47.

In some studies, the association of axon guidance with a group of proteins such as MET, plexin C1 (PLXNC1) and neuropilin‐1 (NRP1) in NDP and semaphorin 5A (SEMA5A), EPHA4 and NTNG2 in RP has been reported 67, 73, 74, 75, showing active axons‐related events in RP. Notch and HTLV‐1 infection signalling pathways were two important pathways observed in both NDP and RP groups. Canonical activation of Notch by DLL1 or Jagged leads to the blockade of oligodendroglial differentiation, whereas nuclear translocation of the Notch intracellular domain (following stimulation with the non‐canonical ligand, contactin) causes remyelination processes 76, 77. Although we did not find any HTLV‐1‐related proteins in the data sets, the HTLV‐1 infection signalling pathway was identified in both groups. Furthermore, several studies have evaluated the correlation between MS and HTLV‐1 infection as a probable aetiological factor 78, 79.

Detection of a set of proteins with remarkable roles in MS

Overall, 17 and 19 nodes with the highest betweenness centrality and degree were specified as the hubs of NDP and RP networks, respectively. Table 1 presents these hubs, along with the data gathered through literature data‐mining to assess their relationship with MS.

Table 1.

Relations between multiple sclerosis (MS) and newly diagnosed relapsing–remitting MS patients (NDP)‐ and MS patients receiving disease‐modifying therapy (RP)‐specific hubs

Hub Role in MS
NOTCH1 Delta and Jagged as canonical Notch ligands block oligodendroglial differentiation whereas contactin, a non‐canonical Notch receptor ligand, enhances remyelination 76, 77. Autoantibodies against contactin 1 and 2 have been found in MS patients 106, 107
ITGAM Based on genome‐wide association studies, ITGAM is associated with SLE and MS and downregulated by glatiramer acetate 108, 109
DLL1 Anti‐DLL1 monoclonal antibody can prevent the development of TMEV‐IDD disease by reducing and enhancing CD+4 cells which produce IFN‐γ and IL‐10, respectively 110, 111
VAV1 VAV1 expression was enhanced in MS patients and associated with TNF and IFN‐γ expression in CSF and peripheral blood cells 112
CTNND2 CTNND2 has been found in the critical region related to the MS susceptibility 113
MET HGF exerts neuroprotective and immunomodulatory effects in EAE model 114. IFN‐β can induce HGF in monocytes of patients with MS 115
ERBB4 Neuregulin 1/ERBB4 contributes to early migration of oligodendrocyte precursors 116
RELN RELN expression in inactive demyelinated lesions is higher than normal tissues while its expression is lower in activated lesions 117.
NRP1 The blockade of Sema3A/NRP1/plexin‐A1 decreases the invasion of immune system and enhances remyelination 74
LRP1 LRP1 plays a key role in the clearance of degraded myelin and is over‐expressed in the CNS in EAE model 118
EP300 A proteomic study showed that EP300 is increased in MS patients’ CSF 119. Its acetyltransferase activity seems to be necessary for maintenance of self‐tolerance of B cells and suppression of autoimmune diseases 120
ACACB The activity of acetyl‐CoA carboxylases is correlated with the fatty acids metabolism and myelination. High doses of biotin, their cofactor, also enhances remyelination 121
PCK2 The emergence of a specific allele of PCK1, related to Alzheimer's disease susceptibility, in MS patients is associated with the severity of brain atrophy 122. DNA hypomethylation of PCK2 in CD4+ T cells is connected to the autoimmune diseases 123
NCOR2 The expression of BCL‐6 and NCOR2 decreased via miR‐10a leads to the limitation of inducible regulatory T cell conversion to T follicular helper cells 124
DNMT3B It has been demonstrated that DNMT3B over‐expression promotes neurodegeneration 125
RELB Th1 differentiation and production of IFN‐γ are severely reduced in RELB‐deficient T cells 126. RELB is a member of NF‐κB family 126. Although IFN‐β increases the activity of NF‐κB pathway, corticosteroids and glatiramer acetate repress this pathway in PBMCs and astrocytes, respectively 127
NF1 Among 20 cases of co‐occurrence of neurofibromatosis type 1 and MS, seven cases have been reported from Iran. Some patients with NF1 and MS have a mutation in OMgp, involved in myelination and embedded in the intron of NF1 128, 129
EPHA4 Several studies have demonstrated that EPHA4 plays a key role during neuroinflammation, causing axonapathy 130
HNF4A It has been shown that has‐miR‐197 can target HNF4A interacting with CYP3A4. In addition, CYP3A4 is involved in MS by the regulation of vitamin D metabolism 131
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Blue rows: RP‐specific hubs. BCL‐6 = B cell lymphoma 6 protein; CTNND2 = catenin delta‐2; CSF = cerebrospinal fluid; CYP3A4 = cytochrome P450 3A4; DNMT3B = DNA (cytosine‐5)‐methyltransferase 3B; EAE = experimental autoimmune encephalomyelitis; EP300 = histone acetyltransferase p300; EPHA4 = ephrin type‐A receptor 4; ERBB4 = receptor tyrosine‐protein kinase erbB‐4; HGF = hepatocyte growth factor; HNF4A = hepatocyte nuclear factor 4‐alpha; IFN = interferon; ITGAM = integrin alpha M; LRP1 = low‐density lipoprotein‐related protein 1; MET = hepatocyte growth factor receptor; NF1 = neurofibromin; NRP1 = neuropilin‐1; NCOR2 = nuclear receptor corepressor 2; NF1 = neurofibromin; OMgp = oligodendrocyte‐myelin glycoprotein; PBMCs = peripheral blood mononuclear cells; PCK1 = phosphoenolpyruvate carboxykinase 1; RELB = transcription factor RelB; RELN = reelin; SLE = systemic lupus erythematosus; Sema3A = semaphorin 3A; TMEV‐IDD = Theiler's murine encephalomyelitis virus‐induced demyelinating disease; VAV = proto‐oncogene vav. [Colour figure can be viewed at wileyonlinelibrary.com]

Apart from NDP‐ and RP‐specific hubs there was a group of proteins which was not ranked highly, but its roles in MS could not be ignored. Factor VIII and ITGAM in the NDP group and C6 and complement factor H (CFH) in the RP group were found in complement and coagulation cascades associated with the demyelination process 80. Low‐density lipoprotein receptor related protein 1 (LRP1), low‐density lipoprotein‐related protein 2 (LRP2) and low‐density lipoprotein receptor (LDLR) in the NDP protein data set are involved in the clearance of degenerated myelin and cellular debris around the demyelinating region in MS 81. Other NDP‐specific proteins which need to be considered are as follows: gamma‐aminobutyric acid type B receptor subunit 1 (GABBR1) (target of baclofen) which produces slow and prolonged inhibitory signals by inhibitory neurotransmitter gamma‐aminobutyric acid (GABA) 82, GABA transporter 2 (GAT‐2), which mediates GABA transportation through cell membrane 82, as well as a group of proteins, including alpha‐fetoprotein 83, plexin‐C1 84 and nuclear autoantigen Sp‐100 85 associated with inflammation. Although anoctamin 2 is known as an autoimmune target in MS 86, in this study we found only anoctamin 6, which influences the functions of macrophages against bacteria 87.

In the RP protein data set, there were different proteins correlated with MS or drugs used by MS patients. Hydroxycarboxylic acid receptor 2 (HCAR2) in RP acts as a high‐affinity receptor for niacin which, at higher doses, results in enhanced ADIPOQ secretion, decreased lipolysis and apoptosis induction in mature neutrophils 88, 89. Three receptors were found in the RP protein data set, which are all major contributors to MS: the first, GABARA1, interacts with GABA to reduce the detrimental effects of glutamate and modulates cytotoxicity of immune cells expressing GABARA 82, 90; the second receptor, IL‐12RB2, is involved in IFN‐γ production by activated T cells and its over‐expression has been reported in MS patients 91; and the third receptor, plexin‐A4, negatively regulates T cell‐mediated immunity 92.

The reactivity of NDP and RP sera with the selected hubs

Based on characteristics such as betweenness centrality and degree, MET and ADIPOQ, as NDP‐and RP‐specific hubs, were selected, respectively, to evaluate their reactivity with the sera of MS patients. The data exhibited specific binding of two hubs to their related NDP and RP sera (P < 0·001). In contrast, the selected hubs showed poor binding to the sera of age‐matched healthy subjects (Fig. 5).

Figure 5.

Figure 5

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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]

Discussion

In the present study, we show how evaluation of the autoantibody repertoires of RR‐MS patients before and during treatment helps unravel the mystery of MS. The NDP and RP protein data sets were investigated to find proteins playing key roles in pathways involved in MS pathogenesis. Initially, a set of notable proteins was found in this study, while previous studies have reported autoantibodies against some of these proteins 93.

It has been demonstrated that autoantibodies can show different modes of action, owing to their nature and affinity to autoantigens. Besides the shielding effect of autoantibodies in blocking potentially harmful proteins, these antibodies can trigger complement activation and cause cytotoxicity, initiate Fc receptor‐related pathways, disrupt axon–myelin interactions, prevent axonal conduction, interrupt the BBB and change the function of oligodendrocytes 4.

Some autoantibodies are protective, as detrimental effects of proteins (e.g. CD6, IL‐12R, glutamate receptors, ABC transporters and integrins) can be inhibited by binding of autoantibodies to these proteins, particularly when over‐expressed in MS. In this regard, Yan Li and colleagues 35, by employing an anti‐CD6 monoclonal antibody, treated an established EAE in mice expressing human CD6. Conversely, proteins with neuroprotective effects are enhanced in MS due to a negative feedback or in response to drugs. Therefore, autoantibodies targeting these proteins can be divided into several panels. Some antibodies are non‐functional and block proteins such as LRP1, GABAR and ADIPOQ which, in turn, disrupts their functions and deteriorates MS outcomes. In this regard, anti‐ADIPOQ antibody might be generated due to the elevated level of ADIPOQ in the CSF of MS patients on DMT 59. As we did not find ADIPOQ in NDP, it seems that DMT activates pathways in RP, augmenting ADIPOQ production. Some antibodies are functional, bind to receptors (e.g. niacin‐induced HCAR2, ERBB4 and MET) and function as agonists, thereby augmenting signalling pathways which can improve the clinical symptoms of MS. Instead, some antibodies can bind proteins such as CD6, IL‐12R and GRIN2B, and thus activate pathways leading to disease progression. Antibodies targeting glutamate receptors may act as agonists and cause excitotoxicity and complement‐mediated cell death 4. Anti‐glutamate receptor antibodies are associated with inflammatory and neurodegenerative disorders, and their clearance is often correlated with clinical improvement 4. According to the literature, anti‐GRIN2B (NMDAR2B) antibodies, at low concentration, enhance receptor function and increase excitatory postsynaptic potentials mediated through the NMDA receptor 94. However, at high concentration, these antibodies can be pathogenic, leading to excitotoxicity 94. Therefore, the administration of NMDA receptor antagonists such as amantadine, memantine and MK‐801 can be a promising approach to combat disease 4. Furthermore, a high number of autoantibodies are produced against intracellular proteins which are released due to apoptosis and suboptimal clearance of cell debris, exposing hidden proteins such as TNF‐AIP3, RAF1, HNF4A and PCK2 to immune cells. These observations demonstrate that autoantibodies can function as a double‐edged sword, stimulating neurorehabilitation or neural injury.

A chain of events was observed in the NDP group, including penetration of T cells into the BBB through adhesion molecules, over‐activity of NK, B and T cells, antibody activity through Fc receptor which led to phagocytosis, apoptosis, and myelin destruction, complement and coagulation cascades, sphingolipid pathway, axon guidance, NMDAR activity and glutamate excitotoxicity in glutamatergic synapse, resulting in MS in these patients.

Intriguingly, well‐known MS‐related pathways such as the B cell receptor (BCR), T cell receptor (TCR), chemokine signalling pathways and NK cell‐mediated cytotoxicity in the NDP group, were not found in the RP group. One reason can be the effects of DMT on the immune system, including the reduction of NK cells, the elicitation of suboptimal TCR signalling and decreased chemokine secretion following the administration of IFN‐β and glatiramer acetate, as established in several studies 95, 96, 97.

In the present study, apart from common pathways such as adhesion molecules and the Notch signalling pathway observed in the two groups, different pathways were activated in patients on DMT (RP). Indeed, viral infections and lipid metabolism disorder were the major events in this group. Alsaggar et al. 98 found that IFN‐β over‐expression suppresses adipose inflammation induced by a high‐fat diet, inhibits the infiltration of immune cells into adipose tissues and reduces proinflammatory cytokine production in mice on a high‐fat diet. Croze et al. 99 described that IFN‐β regulates metabolic processes which control the balance of fatty acids and derived biomolecules. Fatty acids and lipids, as the building blocks of lipids and CNS, respectively, are involved in inflammation triggering diseases such as MS 62, 63, 64, 65. Up‐regulation of lipid metabolism, mitochondrial dysfunction and inflammatory responses have been reported in MS, Alzheimer's disease, Parkinson's disease and some cancers 62, 63, 64. In this regard, by disrupting fatty acid metabolism, CNS inflammation may be down‐regulated 62, 63, 64.

Considering the emergence of ADIPOQ and pathways such as the AMPK and PPAR signalling pathways and fatty acid metabolism in the RP group, it seems that lipid‐ and immune system‐related pathways are linked in patients on DMT. ADIPOQ has anti‐inflammatory activities in the immune system cells, and its low serum level is associated with disease severity 59. Although there are discrepancies about ADIPOQ serum level in patients with MS, ADIPOQ increases in patients in remission or on metformin, pioglithazone, disease‐modifying anti‐rheumatic drugs or TNF‐α inhibitor therapy and results in disease alleviation 56, 58, 59, 100, 101. As mentioned earlier in the Results section, ADIPOQ can activate AMPK and PPAR signalling pathways through AdipoR1 and AdipoR2, respectively 58. In this way, AdipoRon, as an AdipoR agonist, has been proposed as a promising therapeutic agent for obesity‐related diseases 102. Activation of AMPK causes decreased lipid synthesis and enhanced fatty acid oxidation in the liver 61. Furthermore, AMPK activation leads to suppression of some cytokines induced by IFN‐γ in the cells, such as astrocytes and microglia playing critical roles in the demyelination 103. Meares et al. 103 showed that during the onset and peak of EAE, AMPK signalling is down‐regulated in the brain. Chief enzymes involved in lipid metabolism and immune system responses are regulated by PPARs. Therefore, metformin and pioglitazone promoting PPAR‐γ and AMPK signalling pathways may be promising in MS 58. In contrast to full agonists such as pioglitazone (an adipogenic agent causing edema and fluid retention), CHS‐131, as a selective PPAR‐γ modulator, showed reduced side effects and decreased the incidence of contrast‐enhancing lesions by approximately 50% in RR‐MS patients enrolled in a phase IIb trial 104 (http://www.intekrin.com/programs.html).

A number of studies have reported the lower risk of cancer in MS patients compared to patients with other autoimmune diseases 18, 19. In line with these studies NK cells, in addition to BCR and TCR signalling pathways as representatives of innate and adoptive immune systems, respectively, were enriched significantly in the NDP group. Nonetheless, we found cancer‐related proteins such as MET, NOTCH1, RAF1 and ABCC1 in pathways such as microRNAs in cancer and pathways in cancer. Involvement of these proteins in pathways correlated with the immunity and cancer development may infer their chief contributions to events in MS patients. Among over‐represented terms in the RP group, lipid metabolism was the most important event, which might also be related to cancer. It has been shown that the low expression level of ADIPOQ is connected to the enhanced risk of endometrial, breast, prostate and colorectal cancers 105. The occurrence of an ADIPOQ‐specific antibody in RP might be due to ADIPOQ over‐expression in this group. ADIPOQ can function as a tumour suppressor through activating the AMPK signalling pathway in MS patients. By inhibiting acetyl‐CoA carboxylase involved in fatty acid homeostasis, AMPK can suppress tumour cell proliferation and promote apoptosis 60.

In conclusion, assessment of the autoantibody repertoires of RR‐MS patients by employing a systems medicine approach provides a considerable opportunity to discover altered or dysregulated pathways. We not only found critical pathways related to B cells, T cells and viral infections demonstrated in previous studies, but also identified some new pathways correlated with cancer, glutamatergic synapse and disordered lipid metabolism, which may play remarkable roles in events emerging in patients with MS.

Disclosure

The authors declare that they have no conflict of interest.

Author contributions

F. R. J. conceived and designed the experiments. M. A. S and F. M. helped to design the study. M. P. helped the data analysis and interpretation. F. R. J., F. T., E. F., A. K. A., S. P. G. and F. A. performed the experiments. F. R. J. wrote the paper. S. D. S., F. V., A. F. and M. P. were involved in the manuscript preparation. All authors reviewed the manuscript.

Supporting information

Additional Supporting Information may be found in the online version of this article at the publisher's website:

Table S1. Baseline characteristic of newly diagnosed relapsing–remitting MS patients (NDP), MS patients receiving disease‐modifying therapy (RP) and healthy volunteers

Table S2. The top significant protein complexes. The ConsensusPathDB database (CPDB) was used to assess the newly diagnosed relapsing–remitting MS patients (NDP) and MS patients receiving disease‐modifying therapy (RP) data sets for detection of protein complexes. The criteria were a P‐value of less than 0·05 and the presence of at least two components

Table S3. Multiple sclerosis (MS)‐related genes based on the DisGeNET database

Click here for additional data file. (891KB, doc)

Acknowledgements

The authors would like to thank the personnel of Sina hospital (Tehran, Iran) for their assistance with sample collections. This work was supported by a grant from the Iran national science foundation (grant number 92002095).

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Associated Data

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Supplementary Materials

Additional Supporting Information may be found in the online version of this article at the publisher's website:

Table S1. Baseline characteristic of newly diagnosed relapsing–remitting MS patients (NDP), MS patients receiving disease‐modifying therapy (RP) and healthy volunteers

Table S2. The top significant protein complexes. The ConsensusPathDB database (CPDB) was used to assess the newly diagnosed relapsing–remitting MS patients (NDP) and MS patients receiving disease‐modifying therapy (RP) data sets for detection of protein complexes. The criteria were a P‐value of less than 0·05 and the presence of at least two components

Table S3. Multiple sclerosis (MS)‐related genes based on the DisGeNET database

Click here for additional data file. (891KB, doc)

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