B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS

Photochemistry of the PAH pyrene in water ice: the case for ion-mediated solid-state astrochemistry

Context. Icy dust grains play an important role in the formation of complex inter- and circumstellar molecules. Observational studies show that polycyclic aromatic hydrocarbons (PAHs) are abundantly present in the ISM in the gas phase. It is likely that these non-volatile species freeze out onto dust grains as well and participate in the astrochemical solid-state network, but experimental PAH ice studies are largely lacking. Methods. Near UV/VIS spectroscopy is used to track the in situ VUV driven photochemistry of pyrene containing ices at temperatures ranging from 10 to 125 K. Results. The main photoproducts of VUV photolyzed pyrene ices are spectroscopically identified and their band positions are listed for two host ices, \water and CO. Pyrene ionisation is found to be most efficient in \water ices at low temperatures. The reaction products, triplet pyrene and the 1-hydro-1-pyrenyl radical are most efficiently formed in higher temperature water ices and in low temperature CO ice. Formation routes and band strength information of the identified species are discussed. Additionally, the oscillator strengths of Py, Py^+ and PyH are derived and a quantitative kinetic analysis is performed by fitting a chemical reaction network to the experimental data. Conclusions. Pyrene is efficiently ionised in water ice at temperatures below 50 K. Hydrogenation reactions dominate the chemistry in low temperature CO ice with trace amounts of water. The results are put in an astrophysical context by determining the importance of PAH ionisation in a molecular cloud. The photoprocessing of a sample PAH in ice described in this manuscript indicates that PAH photoprocessing in the solid state should also be taken into account in astrochemical models.Comment: 11 pages, 8 figures, accepted for publication in A&

Ab initio study of step formation and self-diffusion on Ag(100)

Using the plane wave pseudopotential method we performed density functional theory calculations on the stability of steps and self-diffusion processes on Ag(100). Our calculated step formation energies show that the {111}-faceted step is more stable than the {110}-faceted step. In accordance with experimental observations we find that the equilibrium island shape should be octagonal very close to a square with predominately {111}-faceted steps. For the (100) surface of fcc metals atomic migration proceeds by a hopping or an exchange process. For Ag(100) we find that adatoms diffuse across flat surfaces preferentially by hopping. Adatoms approaching the close-packed {111}-faceted step edges descend from the upper terrace to the lower level by an atomic exchange with an energy barrier almost identical to the diffusion barrier on flat surface regions. Thus, within our numerical accuracy (approx +- 0.05 eV) there is no additional step-edge barrier to descent. This provides a natural explanation for the experimental observations of the smooth two-dimensional growth in homoepitaxy of Ag(100). Inspection of experimental results of other fcc crystal surfaces indicates that our result holds quite generally.Comment: 10 pages, 9 figures. Submitted to Phys. Rev B (October 31, 1996

The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies

Epstein–Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass-switched and class-switched memory B cells were reduced at 3–7 months, while only class-switched B cells returned back to baseline at 24–36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+

Prioritizing Emerging Zoonoses in The Netherlands

Background: To support the development of early warning and surveillance systems of emerging zoonoses, we present a general method to prioritize pathogens using a quantitative, stochastic multi-criteria model, parameterized for the Netherlands. Methodology/Principal Findings: A risk score was based on seven criteria, reflecting assessments of the epidemiology and impact of these pathogens on society. Criteria were weighed, based on the preferences of a panel of judges with a background in infectious disease control. Conclusions/Significance: Pathogens with the highest risk for the Netherlands included pathogens in the livestock reservoir with a high actual human disease burden (e.g. Campylobacter spp., Toxoplasma gondii, Coxiella burnetii) or a low current but higher historic burden (e.g. Mycobacterium bovis), rare zoonotic pathogens in domestic animals with severe disease manifestations in humans (e.g. BSE prion, Capnocytophaga canimorsus) as well as arthropod-borne and wildlife associated pathogens which may pose a severe risk in future (e.g. Japanese encephalitis virus and West-Nile virus). These agents are key targets for development of early warning and surveillance.Infrastructures, Systems and ServicesTechnology, Policy and Managemen

Rebalancing of mitochondrial homeostasis through an NAD+-SIRT1 pathway preserves intestinal barrier function in severe malnutrition.

BACKGROUND: The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health. METHODS: SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD +-precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities. FINDINGS: LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction. INTERPRETATION: Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials. FUNDING: This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen

Induction of brain-infiltrating T-bet–expressing B cells in multiple sclerosis

Objective: Results from anti-CD20 therapies demonstrate that B- and T-cell interaction is a major driver of multiple sclerosis (MS). The local presence of B-cell follicle-like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS-infiltrating B cells is not fully understood. Methods: Ex vivo flow cytometry was used to assess chemokine receptor profiles of B cells in blood, cerebrospinal fluid, meningeal, and brain tissues of MS patients (n = 10). Similar analyses were performed for distinct memory subsets in the blood of untreated and natalizumab-treated MS patients (n = 38). To assess T-bet(CXCR3)+ B-cell differentiation, we cultured B cells from MS patients (n = 21) and healthy individuals (n = 34) under T helper 1- and TLR9-inducing conditions. Their CNS transmigration capacity was confirmed using brain endothelial monolayers. Results: CXC chemokine receptor 3 (CXCR3)-expressing B cells were enriched in different CNS compartments of MS patients. Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3high IgG1+ subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of interferon-γ (IFNγ) reduced the transmigration potential and antigen-presenting function of these cells. IFNγ-induced B cells from MS patients showed increased T-bet expression and plasmablast development. Additional TLR9 triggering further upregulated T-bet and CXCR3, and was essential for IgG1 switching. Interpretation: This study demonstrates that T-bethigh IgG1+ B cells are triggered by IFNγ and TLR9 signals, likely contributing to enhanced CXCR3-mediated recruitment and local reactivity in the CNS of MS patients. ANN NEUROL 2019