No proinflammatory signature in CD34+ hematopoietic progenitor cells in multiple sclerosis patients.

Autologous hematopoietic stem cell transplantation (aHSCT) has been used as a therapeutic approach in multiple sclerosis (MS). However, it is still unclear if the immune system that emerges from autologous CD34+ hematopoietic progenitor cells (HPC) of MS patients is pre-conditioned to re-develop the proinflammatory phenotype. The objective of this article is to compare the whole genome gene and microRNA expression signature in CD34+ HPC of MS patients and healthy donors (HD). CD34+ HPC were isolated from peripheral blood of eight MS patients and five HD and analyzed by whole genome gene expression and microRNA expression microarray. Among the differentially expressed genes (DEGs) only TNNT1 reached statistical significance (logFC=3.1, p<0.01). The microRNA expression was not significantly different between MS patients and HD. We did not find significant alterations of gene expression or microRNA profiles in CD34+ HPCs of MS patients. Our results support the use of aHSCT for treatment of MS.

Olfactory threshold is impaired in early, active multiple sclerosis.

BACKGROUND: Olfactory dysfunction has been reported in multiple sclerosis (MS). However, to date no data are available on different qualities of olfactory function, namely odour identification, odour discrimination and odour perception threshold. OBJECTIVE: To assess different qualities of olfactory function in patients with MS and correlate these with demographic data, clinical data, depression, quality of life and cognitive functions. METHODS: In this cross-sectional study, 50 patients with MS or clinically isolated syndrome and 30 healthy controls were included. Olfactory function was measured using the Sniffin' Sticks test. RESULTS: The scores for odour identification (p = 0.001), odour perception threshold (p = 0.037) and the combined score of odour identification, discrimination and perception threshold (TDI, p = 0.002) were significantly lower in MS. Hyposmia for identification (p = 0.0017), threshold (p = 0.017) and TDI score (p = 0.0014) was more frequent in MS. Olfactory threshold was impaired in patients who were clinically active in the previous year (p = 0.026) and in patients with a disease duration less than 2 years (p = 0.0093). Identification score was negatively correlated with disease duration (p = 0.0017). Olfactory function was not associated with disability, depression or quality of life. CONCLUSIONS: We report evidence for qualitatively distinct hyposmia in MS, with increased smell threshold in the early inflammatory phases of the disease and impaired identification with a more widespread chronic disease.

Interferon-beta antibodies have a higher affinity in patients with neutralizing antibodies compared to patients with non-neutralizing antibodies.

In this study, we investigated the affinity, determined by a relative affinity assay, using increasing concentrations of sodium-isothiocyanate to disrupt the antigen antibody binding of neutralizing and non-neutralizing antibodies against interferon-beta (IFNbeta)-1a and -1b in 73 serum samples of MS patients treated with IFNbeta-1a or -1b. Relative affinity values were significantly higher in NAB-positive compared to NAB-negative samples and in samples of IFNbeta-1a-treated patients compared to IFNbeta-1b. A significant positive correlation between relative affinity values and therapy duration indicates affinity maturation as another qualitative factor in IFNbeta neutralization.

Smoking is a risk factor for early conversion to clinically definite multiple sclerosis.

BACKGROUND: Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome. METHODS: We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients' smoking status was obtained at the time of the clinically isolated syndrome. RESULTS: During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2-2.8) for smokers compared with non-smokers (P = 0.008). CONCLUSIONS: Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.

Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients.

Interferon beta (IFNbeta) is a first-line therapy for multiple sclerosis (MS). However, some patients experience a decline in efficacy with continued therapy due to the development of anti-IFNbeta neutralizing antibodies (NAb). We investigated the frequency of NAb cross-sectionally in 846 MS patients who were receiving IFNbeta-1b, IFNbeta-1a im, or IFNbeta-1a sc. The frequency of NAb in patients receiving IFNbeta-1a im was lower (5%) than in patients treated with any other form of IFNbeta (22-35%) (P < 0.0001). Binding antibodies (BAb) were measured in 808 patients. The frequency differed significantly between treatment groups, ranging from 45% (IFNbeta-1a im) to 88% (IFNbeta-1b). The proportion of NAb-positive patients within the BAb-positive group differed significantly among treatment groups, ranging between 12% (IFNbeta-1a im) and 51% (IFNbeta-1a sc). The median NAb titer from all IFNbeta-1a-treated patients was higher than from IFNbeta-1b-treated patients (446 versus 171 NU/ mL, P = 0.04). Among NAb-positive patients, the frequency of NAb titers > 100 NU/mL was 71% for IFNbeta-1a compared with 58% for IFNbeta-1b (P = 0.04). Except for conflicting data regarding IFNbeta-1a sc, the results are generally consistent with the literature and together with the differing proportion of NAb-positive patients within the BAb-positive group, provide further insight into the immunogenicity of the IFNbeta preparations.

Increased frequencies of serum antibodies to neurofilament light in patients with primary chronic progressive multiple sclerosis.

We investigated whether serum and cerebrospinal fluid (CSF) antibodies to the light subunit of the NF protein (NF-L), a main component of the axonal cytoskeleton, may serve as biological markers for axonal pathology and/or disease progression in multiple sclerosis (MS). IgG to NF-L was measured in sera and CSF of MS patients, patients with inflammatory demyelinating diseases of the PNS, with acute inflammatory neurological diseases (including bacterial and viral meningitis), with neurodegenerative diseases, with acute noninflammatory neurological diseases (including stroke, headache and backache) and healthy controls by enzyme-linked immunosorbent assay. We found that serum anti-NF-L IgG antibodies were significantly elevated in MS patients with primary progressive disease course and we provide evidence for an intrathecal production of these antibodies. Our findings support the use of serum antibodies to NF-L as a marker for axonal destruction.

Mutations in the gene for toll-like receptor 4 and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with heterogeneous pathological features, disease courses and genetical backgrounds. In this study we determined whether genetic variants of toll-like receptor (TLR) 4, which confer substantial differences in the inflammation elicited by bacterial lipopolysaccharide, are related to the development of MS. We found no differences in the frequencies of the cosegregating TLR4 Asp299Gly and Thr399Ile polymorphisms between Austrian MS patients (11.6%) and age-matched controls (13.7%). Furthermore, we could not detect any influence of these mutations on clinical parameters and serum levels of soluble adhesion molecules of MS patients. Our data indicate that these TLR4 polymorphisms have no influence on the incidence, progression and inflammatory parameters of MS.

Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity.

BACKGROUND: It has been reported that in some patients with MS who develop neutralizing antibodies (NAbs) against interferon beta (IFNbeta), antibody levels can initially increase and then decrease thereafter even when treatment is continued. OBJECTIVE: To determine whether NAb titre correlates with time to reversion to NAb negativity in patients with multiple sclerosis (MS). METHODS: Twenty-eight patients with MS who were NAb-positive during treatment with one of the currently available IFNbetas were included in this retrospective study. NAb titres were determined by the myxovirus resistance protein A induction assay. Patients were considered NAb-positive if they had at least two consecutive samples with titres of > or = 20 neutralizing units (NU). Reversion to NAb-negative status was defined as two consecutive negative samples (NAb titre of < 20 NU) after NAb positivity. RESULTS: When measured two years after treatment initiation, a NAb titre of < 75 NU had a 91.7% sensitivity and a 87.5% specificity for reversion to NAb negativity in the following two years (after a total of four years of treatment). In addition, somewhat surprisingly, patients whose serum converted to NAb-negative generally developed peak NAb titres earlier than patients who remained NAb-positive (mean time of first detection was 21 versus 38 months, respectively). CONCLUSION: The NAb titre might support treatment decisions in patients with MS whose test results are positive for NAbs.

Genetic variants in the tumor necrosis factor receptor II gene in patients with multiple sclerosis.

Common genetic variants have been shown to influence disease susceptibility, disease course, or both in multiple sclerosis (MS). Several studies have suggested a role for tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of MS. Recently, it has been reported that the TNF receptor (TNFR) II plays an essential role in the pathology and progression of experimental autoimmune encephalomyelitis, an animal model of MS. To investigate whether TNFR II polymorphisms influence susceptibility and/or clinical progression of MS, genomic DNA of 321 samples of the Austrian Genetics in MS study group and DNA of 174 platelet donors, who served as healthy controls, were genotyped for five polymorphic sites in the TNFR II gene: exon 6 nucleotide (nt) 676*T-->G, exon 6 nt 783*G-->A (both are associated with non-conserved amino acid substitution), exon 10 nt 1663*G-->A, exon 10 nt 1668*T-->G, and exon 10 nt 1690*T-->C (all of which are located in the 3' non-coding region of the gene). We found a significant association between exon 10 nt 1668*T-->G polymorphism and susceptibility to MS. The other investigated nucleotide substitutions were not associated with susceptibility to or clinical parameters in MS.