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Neutralizing antibodies against IFN-beta in multiple sclerosis: antagonization of IFN-beta mediated suppression of
Francesca Gilli1, Antonio Bertolotto, Arianna Sala
1Centro Riferimento Regionale Sclerosi Multipa and Neurobiologia Clinica, Ospedale Universitario S. Luigi Gonzaga, Torino, Italy.
Abstract:
Neutralizing antibodies (NAb) against interferon-beta (IFN-beta) develop in about a third of treated multiple sclerosis patients and are believed to reduce therapeutic efficacy of IFN-beta on clinical and MRI measures. The expression of the interferon acute-response protein, myxovirus resistance protein A (MxA) is a sensitive measure of the biological activity of therapeutically applied IFN-beta and of its reduced bioavailability due to NAb. However, MxA may not be operative in the pathogenesis of multiple sclerosis or the therapeutic effect of IFN-beta. Instead, matrix metalloproteinases (MMPs) are increased in brain tissue, CSF and blood circulation of multiple sclerosis patients and function as effector molecules in several steps of multiple sclerosis pathogenesis. One of the molecular mechanisms by which IFN-beta exerts its beneficial effect in multiple sclerosis is reduction of MMP-9 expression and increase of its endogenous tissue inhibitor, TIMP-1. Quantitative PCR measurements of MMP-2 and MMP-9, TIMP-1 and TIMP-2, and MxA were performed in peripheral mononuclear cells from clinically stable multiple sclerosis patients with relapsing remitting disease course after short-term and long-term treatment with IFN-beta. IFN-beta therapy down-regulated the expression of MMP-9 and abolished that of MMP-2 in long-term, but not short-term treated multiple sclerosis, while levels of MxA were increased in both instances. The presence of NAb reversed these effects, i.e. led to reduced MxA and increased MMP-2/MMP-9 expression levels compared with NAb- patients. In contrast, expression of TIMPs in peripheral blood mononuclear cells remained unaffected by IFN-beta therapy and the presence of NAb. While MxA is able to detect the biological action and reduced bioavailability of IFN-beta on the basis of single injections, only MMP-9 shows quantitative correlation with the NAb titre. Together with evidence that an imbalance between MMP and TIMP expression is a crucial pathogenetic feature in multiple sclerosis, these findings support the concept of a significant role of NAb in reducing the therapeutic efficacy of IFN-beta.
Insights
Neutralizing antibodies (NAb) against interferon-beta (IFN-beta) can reduce treatment effectiveness in multiple sclerosis (MS). While MxA indicates IFN-beta activity, MMP-9 levels correlate with NAb titres, suggesting a key role in treatment efficacy.
Area of Science:
- Neuroimmunology
- Biochemistry
- Pharmacology
Background:
- Neutralizing antibodies (NAb) against interferon-beta (IFN-beta) are present in approximately one-third of multiple sclerosis (MS) patients, potentially reducing treatment efficacy.
- Matrix metalloproteinases (MMPs) are implicated in MS pathogenesis, and IFN-beta's therapeutic effects may involve modulating MMPs and their inhibitors (TIMPs).
Purpose of the Study:
- To investigate the impact of IFN-beta treatment and NAb presence on the expression of MxA, MMPs, and TIMPs in MS patients.
- To determine the correlation between NAb titres and the expression of these biomarkers.
Main Methods:
- Quantitative PCR was used to measure the expression of MMP-2, MMP-9, TIMP-1, TIMP-2, and MxA in peripheral mononuclear cells of MS patients.
- Patients were categorized based on short-term and long-term IFN-beta treatment and the presence or absence of NAb.
Main Results:
- IFN-beta treatment down-regulated MMP-9 and abolished MMP-2 expression in long-term treated patients, while MxA levels increased.
- The presence of NAb reversed these effects, leading to reduced MxA and increased MMP-2/MMP-9 expression.
- TIMP expression remained unaffected by IFN-beta therapy or NAb presence. MMP-9 expression correlated quantitatively with NAb titre.
Conclusions:
- MxA effectively indicates IFN-beta's biological activity and bioavailability, but MMP-9 expression shows a significant correlation with NAb titres.
- These findings support the role of NAb in diminishing IFN-beta's therapeutic efficacy in MS, highlighting the importance of MMP modulation.
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