Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle inhabitants, this may allow for continuous entry of immune cells into the castle and lead to the death of the castle inhabitants, and finally members of the royal family, the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner walls of the CNS castle moat and will highlight the importance of the CSF-drained castle moat in maintaining immune surveillance and in mounting immune responses in the CNS.

Distribution of intracellular and secreted surfactant during postnatal rat lung development

Pulmonary surfactant prevents alveolar collapse via reduction of surface tension. In contrast to human neonates, rats are born with saccular lungs. Therefore, rat lungs serve as a model for investigation of the surfactant system during postnatal alveolar formation. We hypothesized that this process is associated with characteristic structural and biochemical surfactant alterations. We aimed to discriminate changes related to alveolarization from those being either invariable or follow continuous patterns of postnatal changes. Secreted active (mainly tubular myelin (tm)) and inactive (unilamellar vesicles (ulv)) surfactant subtypes as well as intracellular surfactant (lamellar bodies (lb)) in type II pneumocytes (PNII) were quantified before (day (d) 1), during (d 7), at the end of alveolarization (d 14), and after completion of lung maturation (d 42) using electron microscopic methods supplemented by biochemical analyses (phospholipid quantification, immunoblotting for SP-A). Immunoelectron microscopy determined the localization of surfactant protein A (SP-A). (1) At d 1 secreted surfactant was increased relative to d 7-42 and then decreased significantly. (2) Air spaces of neonatal lungs comprised lower fractions of tm and increased ulv, which correlated with low SP-A concentrations in lung lavage fluid (LLF) and increased respiratory rates, respectively. (3) Alveolarization (d 7-14) was associated with decreasing PNII size although volume and sizes of Lb continuously increased. (4) The volume fractions of Lb correlated well with the pool sizes of phospholipids in lavaged lungs. Our study emphasizes differential patterns of developmental changes of the surfactant system relative to postnatal alveolarization.

Sheaf representations of MV-algebras and lattice-ordered abelian groups via duality

We study representations of MV-algebras -- equivalently, unital lattice-ordered abelian groups -- through the lens of Stone-Priestley duality, using canonical extensions as an essential tool. Specifically, the theory of canonical extensions implies that the (Stone-Priestley) dual spaces of MV-algebras carry the structure of topological partial commutative ordered semigroups. We use this structure to obtain two different decompositions of such spaces, one indexed over the prime MV-spectrum, the other over the maximal MV-spectrum. These decompositions yield sheaf representations of MV-algebras, using a new and purely duality-theoretic result that relates certain sheaf representations of distributive lattices to decompositions of their dual spaces. Importantly, the proofs of the MV-algebraic representation theorems that we obtain in this way are distinguished from the existing work on this topic by the following features: (1) we use only basic algebraic facts about MV-algebras; (2) we show that the two aforementioned sheaf representations are special cases of a common result, with potential for generalizations; and (3) we show that these results are strongly related to the structure of the Stone-Priestley duals of MV-algebras. In addition, using our analysis of these decompositions, we prove that MV-algebras with isomorphic underlying lattices have homeomorphic maximal MV-spectra. This result is an MV-algebraic generalization of a classical theorem by Kaplansky stating that two compact Hausdorff spaces are homeomorphic if, and only if, the lattices of continuous [0, 1]-valued functions on the spaces are isomorphic.

Self-esteem, narcissism, and stressful life events: Testing for selection and socialization

We examined whether self-esteem and narcissism predict the occurrence of stressful life events (i.e., selection) and whether stressful life events predict change in self-esteem and narcissism (i.e., socialization). The analyses were based on longitudinal data from 2 studies, including samples of 328 young adults (Study 1) and 371 adults (Study 2). The effects of self-esteem and narcissism were mutually controlled for each other and, moreover, controlled for effects of depression. After conducting the study-level analyses, we meta-analytically aggregated the findings. Self-esteem had a selection effect, suggesting that low self-esteem led to the occurrence of stressful life events; however, this effect became nonsignificant when depression was controlled for. Regardless of whether depression was controlled for or not, narcissism had a selection effect, suggesting that high narcissism led to the occurrence of stressful life events. Moreover, stressful life events had a socialization effect on self-esteem, but not on narcissism, suggesting that the occurrence of stressful life events decreased self-esteem. Analyses of trait–state models indicated that narcissism consisted almost exclusively of perfectly stable trait variance, providing a possible explanation for the absence of socialization effects on narcissism. The findings have significant implications because they suggest that a person’s level of narcissism influences whether stressful life events occur, and that self-esteem is shaped by the occurrence of stressful life events. Moreover, we discuss the possibility that depression mediates the selection effect of low self-esteem on stressful life events.

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.

Capture, crawl, cross: the T cell code to breach the blood-brain barriers

The central nervous system (CNS) is an immunologically privileged site to which access of circulating immune cells is tightly controlled by the endothelial blood-brain barrier (BBB; see Glossary) localized in CNS microvessels, and the epithelial blood-cerebrospinal fluid barrier (BCSFB) within the choroid plexus. As a result of the specialized structure of the CNS barriers, immune cell entry into the CNS parenchyma involves two differently regulated steps: migration of immune cells across the BBB or BCSFB into the cerebrospinal fluid (CSF)-drained spaces of the CNS, followed by progression across the glia limitans into the CNS parenchyma. With a focus on multiple sclerosis (MS) and its animal models, this review summarizes the distinct molecular mechanisms required for immune cell migration across the different CNS barriers.