The TCR Repertoire Reconstitution in Multiple Sclerosis: Comparing One-Shot and Continuous Immunosuppressive Therapies

Natalizumab (NTZ) and autologous hematopoietic stem cell transplantation (AHSCT) are two successful treatments for relapsing-remitting multiple sclerosis (RRMS), an autoimmune T-cell-driven disorder affecting the central nervous system that is characterized by relapses interspersed with periods of complete or partial recovery. Both RRMS treatments have been documented to impact T-cell subpopulations and the T-cell receptor (TCR) repertoire in terms of clone frequency, but, so far, the link between T-cell naive and memory populations, autoimmunity, and treatment outcome has not yet been established hindering insight into the post-treatment TCR landscape of MS patients. To address this important knowledge gap, we tracked peripheral T-cell subpopulations (naïve and memory CD4+ and CD8+) across 15 RRMS patients before and after two years of continuous treatment (NTZ) and a single treatment course (AHSCT) by high-throughput TCRß sequencing. We found that the two MS treatments left treatment-specific multidimensional traces in patient TCRß repertoire dynamics with respect to clonal expansion, clonal diversity and repertoire architecture. Comparing MS TCR sequences with published datasets suggested that the majority of public TCRs belonged to virus-associated sequences. In summary, applying multi-dimensional computational immunology to a TCRß dataset of treated MS patients, we show that qualitative changes of TCRß repertoires encode treatment-specific information that may be relevant for future clinical trials monitoring and personalized MS follow-up, diagnosis and treatment regimes. Natalizumab (NTZ) and autologous hematopoietic stem cell transplantation (AHSCT) are two successful treatments for relapsing–remitting multiple sclerosis (RRMS), an autoimmune T-cell–driven disorder affecting the central nervous system that is characterized by relapses interspersed with periods of complete or partial recovery. Both RRMS treatments have been documented to impact T-cell subpopulations and the T-cell receptor (TCR) repertoire in terms of clone frequency, but, so far, the link between T-cell naive and memory populations, autoimmunity, and treatment outcome has not yet been established hindering insight into the posttreatment TCR landscape of MS patients. To address this important knowledge gap, we tracked peripheral T-cell subpopulations (naive and memory CD4+ and CD8+) across 15 RRMS patients before and after 2 years of continuous treatment (NTZ) and a single treatment course (AHSCT) by high-throughput TCRβ sequencing. We found that the two MS treatments left treatment-specific multidimensional traces in patient TCRβ repertoire dynamics with respect to clonal expansion, clonal diversity, and repertoire architecture. Comparing MS TCR sequences with published datasets suggested that the majority of public TCRs belonged to virus-associated sequences. In summary, applying multidimensional computational immunology to a TCRβ dataset of treated MS patients, we show that qualitative changes of TCRβ repertoires encode treatment-specific information that may be relevant for future clinical trials monitoring and personalized MS follow-up, diagnosis, and treatment regimens

Investigating Serum sHLA-G Cooperation With MRI Activity and Disease-Modifying Treatment Outcome in Relapsing-Remitting Multiple Sclerosis

Relapsing-remitting multiple sclerosis (RRMS) is a demyelinating disease in which pathogenesis T cells have a major role. Despite the unknown etiology, several risk factors have been described, including a strong association with human leukocyte antigen (HLA) genes. Recent findings showed that HLA class I-G (HLA-G) may be tolerogenic in MS, but further insights are required. To deepen the HLA-G role in MS inflammation, we measured soluble HLA-G (sHLA-G) and cytokines serum level in 27 patients with RRMS at baseline and after 12 and 24 months of natalizumab (NTZ) treatment. Patients were divided into high (sHLA-G>20 ng/ml), medium (sHLA-G between 10 and 20 ng/ml), and low (sHLA-G <10 ng/ml) producers. Results showed a heterogeneous distribution of genotypes among producers, with no significant differences between groups. A significant decrease of sHLA-G was found after 24 months of NTZ in low producers carrying the +3142 C/G genotype. Finally, 83.3% of high and 100% of medium producers were MRI-activity free after 24 months of treatment, compared to 63.5% of low producers. Of note, we did not find any correlation of sHLA-G with peripheral cell counts or cytokines level. These findings suggest that serum sHLA-G level may partly depend on genotype rather than peripheral inflammation, and that may have impacted on MRI activity of patients over treatment

Unveiling the local structure of doubly doped CeO2: a synchrotron X-ray pair distribution function study

Rare earth-doped ceria systems form one of the most thoroughly studied materials classes to be employed as solid electrolytes in solid oxide cells. In order to unveil the structural details ruling the ionic conductivity properties, the (Ce1-xREx)O2-x/2 series with RE = (Nd0.63Dy0.37), (Nd0.74Tm0.26), and (Sm0.67Gd0.33), and x ranging between 0.05 and 0.60, has been synthesized and characterized by means of synchrotron X-ray powder diffraction and pair distribution function analyses. By coupling the mentioned techniques, the whole spectrum of structural order and disorder characterizing these compounds at different length scales was revealed and discussed in detail. With reference to the average scale, for x >= 0.40 or 0.50, depending on the system, the Fmm crystal structure of the CeO2-based solid solution is accompanied by defect aggregates with the Ia structure growing within the ceria matrix. The local structure (r < 10 & Aring;), in contrast, even at the lowest doping degree can be described as a disordered fluctuation between the average structures characterizing the Fmm and Ia phases, which explains the reduction in ionic conductivity observed even within the stability range of the CeO2-based solid solution

Thermal properties of the magnetic RuSr2GdCu2O8 superconductor

A thermal study was performed on the RuSr2GdCu2O8 (Ru-1212) magnetic superconductor phase to investigate the effect of the annealingtreatments in flowing O2 on the stability limit of the phase and on its structural, magnetic and transport properties. DTA-TG measurements were utilized to determine the decomposition process and the dependence of the decomposition temperatureon the annealing atmosphere. The decomposition of the Ru-1212 phase was found sensitive to the oxygen partial pressure and increases with PO2 and the annealingtime. The annealing treatments exert a depressing effect on the strength of the magnetic interaction, an enhancement on the superconductiveproperties and the vanishing of the magnetostriction.A decomposition reaction of Ru-1212 phase was proposed and discussed

Pyrolysis of grape marc before and after the recovery of polyphenol fraction

In this work, winery industry wastes were valorised through the extraction of high added value compounds (polyphenols), followed by thermal conversion of the exhausted solid residues. For this purpose, three different temperatures (623, 723 and 823 K) were tested. The increase of the heat treatment temperature resulted in a significant increment in gas production containing methane and other hydrocarbons. Lipophilic liquid product quantity in grape marc was limited both before and after the polyphenol extraction. The recovery of phenolic compounds before the thermal treatment notably decreases the chemical oxygen demand level of the resulting hydrophilic liquid fraction. The pyrolysis residue represents from 30 to 55% of the initial mass but corresponds to a relevant decrease of its volume, and can be considered a good source of graphitic carbon with higher calorific value with respect to the initial grape waste and applicable for energy production

Synthesis and thermal decomposition of mixed Gd \u2013 Nd oxalates

Several (Gd1\u2013xNdx)2[C2O4]3\ub7nH2O samples (0x1) were prepared by a coprecipitation method: the precipitation is quantitative and all the samples are homogeneous in stoichiometry. XRD analyses have shown that a complete solid solution is formed over the whole range of compositions. The dried Gd rich oxalates have initially a low water content which gradually increases with the Nd content. All the oxalates decompose in O2 around 700\ub0C either into a single mixed oxide or in a mixture of oxides through several steps, which can be ascribed to the loss of water and CO2

Synthesis, structure and magnetic properties in the Nd2O3\u2013Gd2O3 mixed system synthesized at 1200\ub0 C

Phase relation studies in the Gd2O3\u2013Nd2O3 system have been performed on (Gd1-xNdx)2O3 samples with the purpose of performing a systematic study of the composition effects on their structural and magnetic properties. All the samples were synthesized by calcination of the related oxalates at 1200 \ub0C in order to ensure the complete decomposition of the oxalates. Five phase regions, namely an A-type hexagonal, a B-type monoclinic, a C-type cubic solid solution and two biphasic mixtures of the former three phase fields were detected in this system.The magnetic susceptibility measurements showed the presence of antiferromagnetic interactions in all samples. TheCurie\u2013Weiss temperature shows a non-linear dependence on concentration. Deduced effective magnetic moments are close to the free ion values