Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy

Neoangiogenesis and Blood-brain Barrier Dysfunction in Human TSC Brain Lesions

Introduction: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of multiple benign tumors throughout the body and brain. Patients with TSC experience severe cognitive dysfunction and therapy-resistant seizures, which can be associated with refractory epilepsy and poor developmental outcomes. We hypothesize that neoangiogenesis, disruption of the blood-brain barrier, and leakage of serum proteins into the brain parenchyma play vital roles in the pathogenesis of TSC. Methods: In order to assess blood-brain barrier integrity, cortical tissue samples from TSC patients with intractable seizures, non-TSC patients with therapy-resistant epilepsy, and control subjects were immunolabeled for the serum protein fibrinogen, the adherens junction protein V-cadherin, and the tight junction protein occludin. Lectin was used to visualize blood vessels. Quantification was performed to assess average blood vessel segment length and branching. The fraction of membrane-associated V-cadherin and occludin, relative to the blood vessel surface area represented by lectin, was also analyzed. Results: The average length of blood vessel segments and the average number of branch nodes were significantly increased in TSC compared to epilepsy and control. The average surface area fraction of V-cadherin and occludin was significantly decreased in TSC compared to control. In addition, fibrinogen staining outside of the blood vessels was extensive in both TSC and epilepsy. These results confirm our hypothesis, suggesting blood-brain barrier dysfunction in TSC, with disease-specific neoangiogenic mechanisms in TSC. Discussion: Our results show increased blood-brain barrier permeability and increased vascular proliferation in TSC. These findings are likely due to decreased expression of tight junctions and adherens junctions in TSC cortical tissue. These results suggest that antiangiogenic therapies targeting the blood-brain barrier may offer a novel approach to preventing epileptogenesis in patients with TSC

Civil Liberties and Volunteering in Six Former Soviet Union Countries

To contribute to the debate as to whether volunteering is an outcome of democratization rather than a driver of it, we analyze how divergent democratization pathways in six countries of the former Soviet Union have led to varied levels of volunteering. Using data from the European Values Study, we find that Latvia, Lithuania, and Estonia—which followed a Europeanization path—have high and increasing levels of civil liberties and volunteering. In Russia and Belarus, following a pre-emption path, civil liberties have remained low and volunteering has declined. Surprisingly, despite the Orange Revolution and increased civil liberties, volunteering rates in Ukraine have also declined. The case of Ukraine indicates that the freedom to participate is not always taken up by citizens. Our findings suggest it is not volunteering that brings civil liberties, but rather that increased civil liberties lead to higher levels of volunteerin

The AGN contribution to the UV-FIR luminosities of interacting galaxies and its role in identifying the Main Sequence

Emission from active galactic nuclei (AGNs) is known to play an important role in the evolution of many galaxies including luminous and ultraluminous systems (U/LIRGs), as well as merging systems. However, the extent, duration, and exact effects of its influence are still imperfectly understood. To assess the impact of AGNs on interacting systems, we present a Spectral Energy Distribution (SED) analysis of a sample of 189 nearby galaxies. We gather and systematically re-reduce archival broad-band imaging mosaics from the ultraviolet to the far-infrared using data from GALEX, SDSS, 2MASS, IRAS, WISE, Spitzer and Herschel. We use spectroscopy from Spitzer/IRS to obtain fluxes from fine-structure lines that trace star formation and AGN activity. Utilizing the SED modelling and fitting tool CIGALE, we derive the physical conditions of the ISM, both in star-forming regions and in nuclear regions dominated by the AGN in these galaxies. We investigate how the star formation rates (SFRs) and the fractional AGN contributions ($f_{\rm{AGN}}$) depend on stellar mass, galaxy type, and merger stage. We find that luminous galaxies more massive than about $10^{10} \rm{M}_{*}$ are likely to deviate significantly from the conventional galaxy main-sequence relation. Interestingly, infrared AGN luminosity and stellar mass in this set of objects are much tighter than SFR and stellar mass. We find that buried AGNs may occupy a locus between bright starbursts and pure AGNs in the $f_{\rm{AGN}}$-[Ne V]/[Ne II] plane. We identify a modest correlation between $f_{\rm{AGN}}$ and mergers in their later stages.Comment: Accepted for publication in MNRAS; 24 pages, 15 figures, 3 tables (plus appendix

The Apache Point Observatory Galactic Evolution Experiment: First Detection of High Velocity Milky Way Bar Stars

Commissioning observations with the Apache Point Observatory Galactic Evolution Experiment (APOGEE), part of the Sloan Digital Sky Survey III, have produced radial velocities (RVs) for ~4700 K/M-giant stars in the Milky Way bulge. These high-resolution (R \sim 22,500), high-S/N (>100 per resolution element), near-infrared (1.51-1.70 um; NIR) spectra provide accurate RVs (epsilon_v~0.2 km/s) for the sample of stars in 18 Galactic bulge fields spanning -1-32 deg. This represents the largest NIR high-resolution spectroscopic sample of giant stars ever assembled in this region of the Galaxy. A cold (sigma_v~30 km/s), high-velocity peak (V_GSR \sim +200 km/s) is found to comprise a significant fraction (~10%) of stars in many of these fields. These high RVs have not been detected in previous MW surveys and are not expected for a simple, circularly rotating disk. Preliminary distance estimates rule out an origin from the background Sagittarius tidal stream or a new stream in the MW disk. Comparison to various Galactic models suggests that these high RVs are best explained by stars in orbits of the Galactic bar potential, although some observational features remain unexplained.Comment: 7 pages, 4 figures, accepted for publication in ApJ Letter

An expanded composite scale of MRI-defined disease severity in multiple sclerosis: MRDSS2

The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI–Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=−0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI–disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status

Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease

Teacher unionism in changing times: is this the real “new unionism”?

This article provides a case study of union change in an environment in which radical school restructuring is taking place, and active strategies to weaken and marginalize organized teachers are being pursued by the state. The case study union is the National Union of Teachers in England. The article explores a number of different strategies open to teacher unions, utilizing a framework provided by Turner (2004). Drawing on data collected at a national level, and in three local authority areas, I argue that the National Union of Teachers’ response to the erosion of collective bargaining is best presented as an amalgam of strategies focused on workplace organizing, political campaigning, and coalition building. The data demonstrate considerable congruence between national and local strategies, although local data reveal considerable challenges in implementation and consequently considerable unevenness in local experiences