A Systems Medicine View of Multiple Sclerosis: Immune Dysregulation and Metabolic Reprogramming
Multiple sclerosis (MS) is a complex immune-mediated disease of the central nervous system characterized by demyelination, neurodegeneration, and highly heterogeneous clinical outcomes. Despite the availability of multiple disease-modifying therapies (DMTs), treatment responses vary widely, and disease progression is often not fully prevented. The study by Pazhouhandeh and colleagues applies a systems medicine framework to address this complexity by interrogating autoantibody repertoires in relapsing–remitting MS (RRMS) patients before and after initiation of DMT. This approach aims to move beyond single-pathway explanations and instead identify coordinated immune and metabolic disturbances that shape disease onset and therapeutic response.
Rationale for Autoantibody Repertoire Analysis
Although MS has long been considered a T-cell–driven disease, increasing evidence highlights a central role for B cells and autoantibodies in disease initiation and progression. Autoantibodies can exert diverse biological effects, ranging from complement activation and Fc-receptor signaling to modulation of receptor activity and disruption of axon–myelin interactions. Importantly, autoantibody targets may change during treatment, reflecting both immune suppression and compensatory biological responses. By comparing newly diagnosed, untreated patients (NDP) with patients receiving DMT (RP), the authors sought to capture dynamic immunological signatures associated with active disease versus treatment-modulated states.
Experimental Strategy and Systems-Level Integration
The study employed a random peptide phage display library to enrich peptides recognized by serum IgG from NDP and RP groups. Identified peptides were mapped to human proteins using sequence homology, generating two condition-specific protein datasets. These datasets were then integrated into protein–protein interaction networks using STRING and visualized with graph-theoretical tools. Functional interpretation relied on gene ontology and pathway enrichment analyses, allowing the authors to identify overrepresented biological processes and signaling cascades. This multilayered workflow exemplifies systems medicine by combining experimental immunology with network biology and bioinformatics.
Immune Dysregulation in Newly Diagnosed Patients
Network and pathway analyses revealed that untreated RRMS patients exhibit strong enrichment of immune-related pathways, including B-cell receptor signaling, T-cell receptor signaling, natural killer cell–mediated cytotoxicity, and TNF-α signaling. Additional enrichment of glutamatergic synapse and excitotoxicity-related pathways suggested a mechanistic link between immune activation and neurodegeneration. Proteins involved in leukocyte adhesion, complement activation, and sphingolipid signaling further underscored the convergence of inflammatory and neurotoxic processes during early disease stages. Collectively, these findings depict MS onset as a highly inflammatory, immune-driven state with direct consequences for neuronal integrity.
Metabolic and Lipid Pathway Remodeling During Therapy
In contrast, patients receiving DMT showed a marked shift toward pathways associated with cellular metabolism, lipid homeostasis, and energy sensing. The AMP-activated protein kinase (AMPK) pathway, peroxisome proliferator-activated receptor (PPAR) signaling, adipocytokine signaling, and fatty acid metabolism were prominently enriched. These pathways are central regulators of glucose and lipid utilization and are increasingly recognized as modulators of immune cell function. The emergence of metabolic signaling networks in treated patients suggests that DMT not only suppresses immune activation but also reprograms systemic and cellular metabolism in ways that may influence inflammation, remyelination, and neuroprotection.
Viral Infection, Endocrine Signaling, and Network Hubs
Beyond immune and metabolic pathways, the study identified viral infection–related signatures, particularly those associated with Epstein–Barr virus (EBV), in treated patients. This observation aligns with epidemiological and immunological evidence implicating EBV in MS susceptibility and disease activity. Additionally, androgen receptor signaling emerged as a notable pathway in the treatment group, consistent with experimental and clinical data supporting a neuroprotective and remyelinating role for androgens. Network analysis highlighted key hub proteins, such as MET in untreated patients and ADIPOQ in treated patients, whose immunoreactivity was experimentally validated, supporting their functional relevance within the identified networks.
Implications for Pathogenesis and Therapeutic Development
This study demonstrates that MS cannot be adequately explained by isolated immune abnormalities but instead reflects coordinated disturbances across immune, metabolic, and neurobiological systems. The transition from immune-dominant networks in untreated patients to metabolism- and lipid-centered networks during therapy suggests a dynamic rebalancing of disease mechanisms under pharmacological intervention. Importantly, the identification of pathway-level changes and central network hubs provides a rational framework for biomarker discovery and therapeutic targeting. By embracing a systems medicine approach, this work offers a more integrated understanding of MS pathophysiology and highlights new avenues for precision treatment strategies.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Pazhouhandeh, M., Sahraian, M. A., Siadat, S. D., Fateh, A., Vaziri, F., Tabrizi, F., ... & Rahimi Jamnani, F. (2018). A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients. Clinical & Experimental Immunology, 192(1), 18-32.
