CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet β cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 105 polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens

Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice.

Clinicians often hesitate prescribing corticosteroids to treat corticosteroid-responsive conditions in sickle cell disease (SCD) patients because their use can be associated with complications (increased hospital readmission, rebound pain, strokes, avascular necrosis, acute chest syndrome). Consequently, SCD patients may receive suboptimal treatment for corticosteroid-responsive conditions. We conducted a preclinical trial of dissociative (vamorolone) and conventional (prednisolone) corticosteroid compounds to evaluate their effects on nociception phenotype, inflammation, and organ dysfunction in SCD mice. Prednisolone and vamorolone had no significant effects on nociception phenotype or anemia in homozygous mice. Conversely, prednisolone and vamorolone significantly decreased white blood cell counts and hepatic inflammation. Interestingly, the effects of vamorolone were milder than those of prednisolone, as vamorolone yielded less attenuation of hepatic inflammation compared to prednisolone. Compared to controls and heterozygotes, homozygotes had significant liver necrosis, which was significantly exacerbated by prednisolone and vamorolone despite decreased hepatic inflammation. These hepatic histopathologic changes were associated with increases in transaminases and alkaline phosphatase. Together, these results suggest that, even in the setting of decreasing hepatic inflammation, prednisolone and vamorolone were associated with significant hepatic toxicity in SCD mice. These findings raise the possibility that hepatic function deterioration could occur with the use of corticosteroids (conventional and dissociative) in SCD

Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer’s disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7–18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243–406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau

PRMT7 Can Prevent Neurovascular Uncoupling, Blood-Brain Barrier Permeability, and Mitochondrial Dysfunction in Repetitive and Mild Traumatic Brain Injury

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI

Natural distribution of bone remains in the intertidal zone from the south of Tierra del Fuego: taphonomic observations and archaeological implications

Se analiza el patrón de la distribución natural de huesos actuales en los distintos sectores de la franja costera de bahía Moat. Con este fin se busca evaluar los espacios donde existen mayores posibilidades de acumulación y dispersión de restos óseos y de generar expectativas sobre la integridad de los sitios arqueológicos. Asimismo, se evalúan las modificaciones naturales que se producen en la superficie cortical de los huesos. Los resultados muestran que la dinámica del intermareal actúa de manera disímil en la formación de los conjuntos óseos y que dichos procesos impactan en diferentes grados según la ubicación y la geoforma costera. Además, se identificaron distintas trayectorias tafonómicas para las aves y los mamíferos. Los resultados permiten predecir el grado de integridad de los sitios ubicados en los contextos ambientales aquí estudiados y constituyen herramientas valiosas para tomar decisiones en el marco de proyectos arqueológicos regionales.In this paper, the natural distribution pattern of modern bone remains in different parts of the Moat Bay coastal area is analyzed. The purpose of this analysis is to assess the areas with a higher probability of bone remains accumulation and dispersion, and to generate expectations about the integrity of archaeological sites. Additionally, the natural modifications that occur on the cortical surface of bones are evaluated. Results show that intertidal zone dynamics has a dissimilar effect in bone assemblage formation, and that these processes have different impact level depending on location and coastal landform type. Furthermore, different taphonomic trajectories for birds and mammals were identified. Results allow predicting the integrity level of the sites located in the environmental contexts under study and provide valuable decision-making tools for archaeological projects in this region.Sociedad Argentina de Antropologí

Distribución natural de restos óseos en la franja intermareal del sur de Tierra del Fuego: observaciones tafonómicas e implicancias arqueológicas

In this paper, the natural distribution pattern of modern bone remains in different parts of the Moat Bay coastal area is analyzed. The purpose of this analysis is to assess the areas with a higher probability of bone remains accumulation and dispersion, and to generate expectations about the integrity of archaeological sites. Additionally, the natural modifications that occur on the cortical surface of taphonomic bones are evaluated. Results show that intertidal zone dynamics has a dissimilar effect in bone assemblage formation, and that these processes have different impact level depending on location and coastal landform type. Furthermore, different taphonomic trajectories for birds and mammals were identified. Results allow predicting the integrity level of the sites located in the environmental contexts under study and provide valuable decision-making tools for archaeological projects in this region.Se analiza el patrón de la distribución natural de huesos actuales en los distintos sectores de la franja costera de bahía Moat. Con este fin se busca evaluar los espacios donde existen mayores posibilidades de acumulación y dispersión de restos óseos y de generar expectativas sobre la integridad de los sitios arqueológicos. Asimismo, se evalúan las modificaciones naturales que se producen en la superficie cortical de los huesos tafonómicos. Los resultados muestran que la dinámica del intermareal actúa de manera disímil en la formación de los conjuntos óseos y que dichos procesos impactan en diferentes grados según la ubicación y la geoforma costera. Además, se identificaron distintas trayectorias tafonómicas para las aves y los mamíferos. Los resultados permiten predecir el grado de integridad de los sitios ubicados en los contextos ambientales aquí estudiados y constituyen herramientas valiosas para tomar decisiones en el marco de proyectos arqueológicos regionales