Update on treatment in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT.     

Molecular imaging reveals time course of matrix metalloproteinase activity in acute cutaneous vasculitis in vivo

Matrix metalloproteinases (MMPs) play a critical role in various pathological conditions including cutaneous inflammation. Thus far, serial assessment of MMP activity in ongoing inflammation is hampered due to technical limitations. Here, we present an innovative method for longitudinal detection of MMP activity by in vivo imaging. First, we analysed skin sections from patients suffering from leucocytoclastic vasculitis (LcV) and detected a significant MMP signal via immunofluorescence staining. Then, we mimicked LcV in mice in a well‐studied model of immune complex‐mediated vasculitis (ICV). This acute inflammatory process was serially visualized in vivo using the fluorescence‐labelled MMP tracer Cy5.5‐AF443. The deposition of fluorescence‐labelled immune complexes and MMP tracer distribution was visualized repeatedly and non‐invasively by fluorescence reflectance imaging. In correlation with the presence of MMP‐2 and MMP‐9 in immunofluorescence stainings, Cy5.5‐AF443 accumulated in ICV spots in the skin of C57BL/6 mice. This tracer accumulation could also be observed in mice equipped with a dorsal skinfold chamber, where microscopic observations revealed an increased recruitment of fluorescence‐labelled leucocytes during ICV. The specificity of the MMP tracer was supported by (i) analysis of mice deficient in functional β₂‐integrins (CD18^?/?) and (ii) subsequent MMP immunofluorescence staining. These findings let us conclude that MMP accumulation in the acute phase of ICV depends on β₂‐mediated leucocyte recruitment. In summary, we show that MMPs are involved in ICV as determined by Cy5.5‐AF443, a new optical marker to longitudinally and non‐invasively follow MMP activity in acute skin inflammation in vivo.     

Chaperone domains convert prolyl isomerases into generic catalysts of protein folding

The cis/trans isomerization of peptide bonds before proline (prolyl bonds) is a rate-limiting step in many protein folding reactions, and it is used to switch between alternate functional states of folded proteins. Several prolyl isomerases of the FK506-binding protein family, such as trigger factor, SlyD, and FkpA, contain chaperone domains and are assumed to assist protein folding in vivo. The prolyl isomerase activity of FK506-binding proteins strongly depends on the nature of residue Xaa of the Xaa-Pro bond. We confirmed this in assays with a library of tetrapeptides in which position Xaa was occupied by all 20 aa. A high sequence specificity seems inconsistent with a generic function of prolyl isomerases in protein folding. Accordingly, we constructed a library of protein variants with all 20 aa at position Xaa before a rate-limiting cis proline and used it to investigate the performance of trigger factor and SlyD as catalysts of proline-limited folding. The efficiencies of both prolyl isomerases were higher than in the tetrapeptide assays, and, intriguingly, this high activity was almost independent of the nature of the residue before the proline. Apparently, the almost indiscriminate binding of the chaperone domain to the refolding protein chain overrides the inherently high sequence specificity of the prolyl isomerase site. The catalytic performance of these folding enzymes is thus determined by generic substrate recognition at the chaperone domain and efficient transfer to the active site in the prolyl isomerase domain.