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A series of controlled clinical trials have shown that exogenous interferon-beta (IFN-β) benefits patients with relapsing–remitting multiple sclerosis (RRMS) by reducing relapse rate, disability progression, and the formation of new brain and spinal cord lesions on magnetic resonance imaging (MRI) scans. Unfortunately, however, the effectiveness of IFN-β is limited in this setting by the occurrence of treatment non-responsiveness in nearly 25% of patients. Furthermore, clinicians who care for RRMS patients remain unable to accurately identify IFN-β non-responders prior to the initiation of therapy, causing delays in the use of alternative treatments and sometimes requiring that patients turn to medications with more significant side effects to control their disease. Progress has been made toward understanding how both endogenous and exogenous IFN-β act to slow RRMS as well as the related mouse model, experimental autoimmune encephalomyelitis (EAE). Most studies point to its inhibitory actions on circulating immune cells as being important for suppressing both disorders, but multiple potential target cells and inflammatory pathways have been implicated and those essential to confer its benefits remain undefined. This review focuses on the role of both endogenous and exogenous IFN-β in RRMS, paying particular attention to the issue of why certain individuals appear refractory to its disease-modifying effects. A continued goal in this field remains the identification of a convenient biomarker that accurately predicts IFN-β treatment non-responsiveness in individual RRMS patients. Development of such an assay will allow clinicians to customize therapy for patients with this complex disorder.

Human type I interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and immunomodulatory activities. They signal through the same cell surface receptors IFNAR1 and IFNAR2 yet evoking markedly different physiological effects. One differentiating factor of interferon-beta (IFN-β) from other type I interferons is the presence of theAsn-Gly-Arg (NGR) sequence motif, which, upon deamidation, converts to Asp-Gly-Arg (DGR) and iso-Asp-Gly-Arg (iso-DGR) motifs. In other proteins, the NGR and iso-DGR motifs are reported as CD13- and αvβ3, αvβ5, αvβ6, αvβ8 and α5β1 integrin-binding motifs, respectively. The scope of this study was to perform exploratory surface plasmon resonance (SPR) experiments to assess the binding properties of a deamidated IFN-β variant to integrins. For this purpose, integrin αvβ3 was selected as a reference model within the iso-DGR- integrin binding members. The obtained results show that deamidated IFN-β binds integrin αvβ3 with nanomolar affinity and that the response was dependent on the deamidation extent. Based on these results, it can be expected that deamidated IFN-β also binds to other integrin family members that are able to bind to the iso-DGR binding motif. The novel binding properties could help elucidate specific IFN-β attributes that under physiological conditions may be modulated by the deamidation.

The cytomegalovirus (CMV), a member of the beta-herpesvirus family, is widely spread among the world population and causes lifelong latent infections, which can lead to severe diseases in immunocompromised patients. Therefore, it is important to understand the interplay between different immune mechanisms that are essential for the control of CMV infection. To dissect the role of different recognition platforms, MyD88Trif−/− and Cardif−/− mice devoid of TLR- or RLH-dependent signaling, respectively, or MyD88TrifCardif−/− mice and STING−/− mice were i.v. infected with mouse adapted MCMV Δ m157. 75% of MyD88TrifCardif−/− mice succumbed to CMV infection within 7 days, whereas basically all MyD88Trif−/−, Cardif−/−, and STING−/− mice survived without signs of severe disease. Nevertheless, analysis of IFN- β reporter mice with the described recognition receptor deficiencies revealed that during the early phase of infection within the liver CMV induced IFN- β in a STING-dependent manner. In contrast, in MyD88TrifCardif−/− IFN- β reporter mice an enhanced reporter induction was detected during early and late phase of infection. In lymph nodes only the second wave of IFN- β production was detectable. This lymph node-specific IFN- β induction was reduced in MyD88TrifCardif−/− mice, whereas its magnitude was comparable in STING−/− and C57BL/6 mice. In conclusion, the obtained results indicated an important, but not exclusive role of TLR- and RLH-signaling in protection against MCMV Δ m157 infection. While STING-dependent signaling was not necessary to protect against CMV infection, it seemed to be crucial for the induction of early IFN- β within the liver.

In order to predict the clinical benefit of interferon-beta (IFN-beta) to patients with multiple sclerosis (MS), the following markers were investigated; (1) chronological change of cytokines (IFN-gamma, TNF-alpha, IL-6, IL-10, and TGF-beta) after administration of IFN-beta, (2) untoward effects of IFN-beta such as headache and arthralgia, (3) backgrounds of the patients such as age and relapse rate, (4) efficacy of IFN-beta therapy assessed by the change of relapse rate and progression of disability. Chronological blood sampling was performed 0, 10, and 24 h after injection of IFN-beta. The increase of serum IL-6 level in response to IFN-beta administration was associated with headache, arthralgia, relapse rate before treatment, and disability score at the initiation of the therapy. Significant association of change of serum TNF-alpha with age and headache was also observed. The important finding in this study was that patients with a transient increase in IL-6 in response to IFN-beta showed a slow disease progression. This result suggests that this transient increase in the serum IL-6 predicts favorable response to IFN-beta treatment.