Neutralizing antibodies against IFN‐β in multiple sclerosis: antagonization of IFN‐β mediated suppression of MMPs

Neutralizing antibodies (NAb) against interferon‐β (IFN‐β) develop in about a third of treated multiple sclerosis patients and are believed to reduce therapeutic efficacy of IFN‐β 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‐β 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‐β. 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‐β 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‐β. IFN‐β 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‐β therapy and the presence of NAb. While MxA is able to detect the biological action and reduced bioavailability of IFN‐β 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‐

Editorial: B cells in inflammatory and neurodegenerative diseases of the central nervous system

[no abstract available

X-ray spectral analysis of optically faint sources in the Chandra Deep Fields

We present the results of a detailed spectral analysis of optically faint hard X-ray sources in the Chandra deep fields selected on the basis of their high X-ray to optical flux ratio (X/O). The stacked spectra of high X/O sources in both Chandra deep fields, fitted with a single power-law model, are much harder than the spectrum of the X-ray background (XRB). The average slope is also insensitive to the 2-8 keV flux, being approximately constant around Gamma~1 over more than two decades, strongly indicating that high X/O sources represent the most obscured component of the XRB. For about half of the sample, a redshift estimate (in most of the cases a photometric redshift) is available from the literature. Individual fits of a few of the brightest objects and of stacked spectra in different redshift bins imply column densities in the range 10^{22-23.5} cm^{-2}. A trend of increasing absorption towards higher redshifts is suggested.Comment: 13 pages, 9 figures, 5 tables, accepted for pubblication in MNRA

The Chandra COSMOS Legacy Survey : Energy Spectrum of the Cosmic X-Ray Background and Constraints on Undetected Populations

Using Chandra observations in the 2.15 deg(2) COSMOS-legacy field, we present one of the most accurate measurements of the Cosmic X-ray Background (CXB) spectrum to date in the [0.3-7] keV energy band. The CXB has three distinct components: contributions from two Galactic collisional thermal plasmas at kT similar to 0.27 and 0.07 keV and an extragalactic power law with a photon spectral index Gamma = 1.45 +/- 0.02. The 1 keV normalization of the extragalactic component is 10.91 +/- 0.16 keV cm(-2) s(-1) sr(-1) keV(-1). Removing all X-ray-detected sources, the remaining unresolved CXB is best fit by a power law with normalization 4.18 +/- 0.26 keV cm(-2) s(-1) sr(-1) keV(-1) and photon spectral index Gamma = 1.57 +/- 0.10. Removing faint galaxies down to i(AB) similar to 27-28 leaves a hard spectrum with Gamma similar to 1.25 and a 1 keV normalization of similar to 1.37 keV cm(-2) s(-1) sr(-1) keV(-1). This means that similar to 91% of the observed CXB is resolved into detected X-ray sources and undetected galaxies. Unresolved sources that contribute similar to 8%-9% of the total CXB show marginal evidence of being harder and possibly more obscured than resolved sources. Another similar to 1% of the CXB can be attributed to still undetected star-forming galaxies and absorbed active galactic nuclei. According to these limits, we investigate a scenario where early black holes totally account for non-source CXB fraction and constrain some of their properties. In order to not exceed the remaining CXB and the z similar to 6 accreted mass density, such a population of black holes must grow in Compton-thick envelopes with N-H > 1.6 x 10(25) cm(-2) and form in extremely low-metallicity environments (Z(circle dot)) similar to 10(-3).Peer reviewe

Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future

Aggregated Recombinant Human Interferon Beta Induces Antibodies but No Memory in Immune-Tolerant Transgenic Mice

Purpose To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNβ) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory. Methods RhIFNβ-1b and three rhIFNβ-1a preparations with different aggregate levels were injected intraperitoneally in mice 15 × during 3 weeks, and the mice were rechallenged with rhIFNβ-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored. Results Bulk rhIFNβ-1a contained large, mainly non-covalent aggregates and stressed rhIFNβ-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFNβ-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFNβ-1b showed the highest and reformulated rhIFNβ-1a the lowest immunogenicity. In contrast with wild-type mice, transgenic mice did not show NABs, nor did they respond to the rechallenge

Learning from Nature: Pregnancy Changes the Expression of Inflammation-Related Genes in Patients with Multiple Sclerosis

Pregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood

Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex

We previously found that Mertk and its ligand Gas6, astrocytic genes involved in phagocytosis, are upregulated after acute sleep deprivation. These results suggested that astrocytes may engage in phagocytic activity during extended wake, but direct evidence was lacking. Studies in humans and rodents also found that sleep loss increases peripheral markers of inflammation, but whether these changes are associated with neuroinflammation and/or activation of microglia, the brain's resident innate immune cells, was unknown. Here we used serial block-face scanning electron microscopy to obtain 3D volume measurements of synapses and surrounding astrocytic processes in mouse frontal cortex after 6-8 h of sleep, spontaneous wake, or sleep deprivation (SD) and after chronic (∼5 d) sleep restriction (CSR). Astrocytic phagocytosis, mainly of presynaptic components of large synapses, increased after both acute and chronic sleep loss relative to sleep and wake. MERTK expression and lipid peroxidation in synaptoneurosomes also increased to a similar extent after short and long sleep loss, suggesting that astrocytic phagocytosis may represent the brain's response to the increase in synaptic activity associated with prolonged wake, clearing worn components of heavily used synapses. Using confocal microscopy, we then found that CSR but not SD mice show morphological signs of microglial activation and enhanced microglial phagocytosis of synaptic elements, without obvious signs of neuroinflammation in the CSF. Because low-level sustained microglia activation can lead to abnormal responses to a secondary insult, these results suggest that chronic sleep loss, through microglia priming, may predispose the brain to further damage.SIGNIFICANCE STATEMENT We find that astrocytic phagocytosis of synaptic elements, mostly of presynaptic origin and in large synapses, is upregulated already after a few hours of sleep deprivation and shows a further significant increase after prolonged and severe sleep loss, suggesting that it may promote the housekeeping of heavily used and strong synapses in response to the increased neuronal activity of extended wake. By contrast, chronic sleep restriction but not acute sleep loss activates microglia, promotes their phagocytic activity, and does so in the absence of overt signs of neuroinflammation, suggesting that like many other stressors, extended sleep disruption may lead to a state of sustained microglia activation, perhaps increasing the brain's susceptibility to other forms of damage

The X-ray properties of z>6z>6 quasars: no evident evolution of accretion physics in the first Gyr of the Universe

X-ray emission from QSOs has been used to assess SMBH accretion properties up to $z$~6. However, at $z>6$ only ~15 QSOs are covered by sensitive X-ray observations, preventing a statistically significant investigation of the X-ray properties of QSOs in the first Gyr of the Universe. We present new Chandra observations of 10 $z>6$ QSOs, selected to have virial black-hole mass estimates from Mg II line spectroscopy. Adding archival X-ray data for an additional 15 $z>6$ QSOs, we investigate the X-ray properties of the QSO population in the first Gyr of the Universe, focusing in particular on the $L_{UV}-L_{X}$ relation, which is traced by the $\alpha_{ox}$ parameter, and the shape of their X-ray spectra. We performed photometric analyses to derive estimates of the X-ray luminosities, and thus the $\alpha_{ox}$ values and bolometric corrections ($K_{bol}=L_{bol}/L_{X}$). We compared the resulting $\alpha_{ox}$ and $K_{bol}$ distributions with the results found for QSO samples at lower redshift. Finally, we performed a basic X-ray spectral analysis of the brightest $z>6$ QSOs to derive their individual photon indices, and joint spectral analysis of the whole sample to estimate the average photon index. We confirm a lack of significant evolution of $\alpha_{ox}$ with redshift, extending the results from previous works up to $z>6$, and the trend of an increasing bolometric correction with increasing luminosity found for QSOs at lower redshifts. The average power-law photon index of our sample ($\Gamma=2.20_{-0.34}^{+0.39}$ and $\Gamma=2.13_{-0.13}^{+0.13}$ for sources with $30$ net counts, respectively) is slightly steeper than, but still consistent with, typical QSOs at $z=1-6$. All these results point toward a lack of substantial evolution of the inner accretion-disk/hot-corona structure in QSOs from low redshift to $z>6$. Our data hint at generally high Eddington ratios at $z>6$.Comment: 15 pages. 10 figures. 7 tables. Accepted for publication in A&