Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS; however, up to 30% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration

Genetic associations with brain cortical thickness in multiple sclerosis

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS. Common genetic variation is associated with cortical thickness in multiple sclerosis (MS) patients. Here we performed GWA on two independent cohorts of patients (n=675 in total). While no marker exceeded genome-wide significance, protein interaction based network analysis identified pathways involved in glutamate signaling, neural development and intracellular calcium concentration as significantly associated with cortical thickness in MS

Genetic associations with brain cortical thickness in multiple sclerosis

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS. Common genetic variation is associated with cortical thickness in multiple sclerosis (MS) patients. Here we performed GWA on two independent cohorts of patients (n=675 in total). While no marker exceeded genome-wide significance, protein interaction based network analysis identified pathways involved in glutamate signaling, neural development and intracellular calcium concentration as significantly associated with cortical thickness in MS

Genetic associations with brain cortical thickness in multiple sclerosis.

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome-wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome-wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network-based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS

Increased osteopontin plasma levels in multiple sclerosis patients correlate with bone-specific markers

The pro-inflammatory cytokine osteopontin has been found to be highly expressed in multiple sclerosis lesions and plasma levels are increased during relapses in relapse-onset multiple sclerosis patients. The objective was to determine the relationship between osteopontin plasma and cerebrospinal fluid levels in relation to the immunoglobulin G index. In addition, osteopontin plasma levels were compared with osteopontin mRNA levels in peripheral blood mononuclear cells and bone-specific markers to analyse whether osteopontin may be peripherally produced. Osteopontin and bone-specific markers were determined in paired plasma-cerebrospinal fluid samples and serum samples of relapse-onset multiple sclerosis patients (n = 36), respectively. Osteopontin mRNA levels were determined by quantitative polymerase chain reaction analysis. Compared to healthy controls (n = 20), plasma osteopontin levels were significantly increased in relapsing-remitting multiple sclerosis patients and correlated (r = 0.43, p = 0.013) with the immunoglobulin G index. In contrast, cerebrospinal fluid osteopontin levels correlated neither with plasma osteopontin in paired samples nor with the immunoglobulin G index. Since osteopontin mRNA levels in peripheral blood mononuclear cells of relapsing-remitting multiple sclerosis patients did not correlate with osteopontin plasma levels, peripheral blood mononuclear cells might not be the major source for the increased osteopontin plasma levels. Osteopontin plasma levels correlated (r = 0.42, p = 0.035) with the bone-specific degradation product C-telopeptide of type-1 collagen. In addition, another immunomodulatory molecule involved in bone metabolism, 25-OH vitamin D, correlated negatively (r = -0.359, p = 0.048) with the immunoglobulin G index. This study suggests that bone-related molecules like osteopontin and vitamin D with important immunomodulatory functions are related to the immunoglobulin G index in relapsing-remitting multiple sclerosis patients