Can Gene Shape MS Treatment Outcomes? The Case of USP18 and Interferon-β Response
Multiple sclerosis (MS), a complex immune-mediated disease of the central nervous system, often feels like a genetic and immunological puzzle. While some patients respond well to immune-modulating therapies like interferon-β (IFN-β), others see little benefit. What if we could pinpoint a gene that not only contributes to MS susceptibility but also predicts treatment response?
A collaborative study from Barcelona, led by Malhotra and colleagues, dives into this very question, spotlighting a gene called USP18 — an interferon-stimulated gene and key regulator of immune signaling. Their work unravels how variations in USP18 may influence both MS risk and therapeutic efficacy of IFN-β, potentially reshaping how we approach personalized care in MS.
The Molecular Gatekeeper: What Is USP18?
USP18 (Ubiquitin-Specific Peptidase 18) is not just another gene in the interferon pathway. It's a gatekeeper. Induced by type I interferons, USP18 acts as a “brake,” damping down the IFN signaling cascade by preventing excessive activation of STAT1—a key player in immune activation. It also removes ISG15, a ubiquitin-like modifier, from proteins, fine-tuning inflammatory responses.
But here’s where it gets interesting: previous work by this group showed that USP18 is underexpressed in MS patients' blood cells compared to healthy individuals. This hinted at a dysfunctional interferon brake system in MS—a potentially critical clue.
Genetic Clues: Polymorphisms and Haplotypes
To dig deeper, the team examined two single nucleotide polymorphisms (SNPs) in the USP18 gene: one in the intronic region (rs2542109) and one in the promoter region (rs9618216). They genotyped over 690 MS patients and 1,000 healthy controls.
Two specific haplotypes — combinations of these SNPs — stood out:
TG haplotype: Associated with higher MS risk
CG haplotype: Surprisingly, less common in MS patients, suggesting a protective effect
But here's the twist: individuals carrying the CG haplotype showed lower expression of USP18 in their immune cells. That might seem counterintuitive, but remember: without this brake, immune signaling could spiral out of control—fueling the very inflammation that characterizes MS.
The Expression Connection: Disease Activity and USP18
The next logical step? See how these genetic patterns translate into clinical outcomes.
MS patients with the low-expression CG haplotype (CACG) had:
Higher relapse rates
Worse neurological disability scores (EDSS)
This aligns with the idea that reduced USP18 fails to restrain overactive immune responses, potentially worsening MS pathology. In contrast, those with the reference haplotype (CACA) fared better clinically.
Treatment Response: Predicting IFN-β Efficacy
Interferon-β has been a cornerstone of MS treatment for decades, but only some patients benefit. Could USP18 genetics provide predictive clues?
Indeed, the study found that patients homozygous for the A allele of SNP rs2542109 (i.e., AA genotype) were more likely to respond favorably to IFN-β therapy. However, when they examined how these genotypes affected USP18 expression after IFN-β stimulation, the differences were negligible. So, while the AA genotype may serve as a marker of response, it likely influences IFN-β pathways in more complex, indirect ways.
Promoter Puzzle: Where Are the Brakes Breaking?
To explain the lowered USP18 expression in CG haplotype carriers, researchers looked for transcription factor binding sites in the promoter region. They found potential docking sites for several immune-related regulators, especially STAT1 — a central interferon pathway effector. However, the exact mechanism by which the CG haplotype reduces expression remains unclear and is likely influenced by additional regulatory factors or epigenetic changes.
Implications: Toward Personalized MS Therapy
This study adds an important piece to the MS puzzle. By linking USP18 polymorphisms to disease risk, gene expression, and treatment response, it highlights a potential biomarker that could guide both diagnosis and therapeutic decisions. It also underscores the value of studying not just which genes are present — but how they're regulated and expressed in the immune battlefield of MS.
Final Thoughts
The immune system thrives on balance — too much activation, and we tip into autoimmunity; too little, and we fail to defend ourselves. USP18 is part of the balancing act in the interferon signaling orchestra. By better understanding its role in MS, we inch closer to therapies that are not just reactive, but predictive and personalized.
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:
Malhotra, S., Morcillo‐Suárez, C., Nurtdinov, R., Rio, J., Sarro, E., Moreno, M., ... & Comabella, M. (2013). Roles of the ubiquitin peptidase USP 18 in multiple sclerosis and the response to interferon‐β treatment. European Journal of Neurology, 20(10), 1390-1397.
