Central nervous system (CNS) barriers predominantly mediate the immune-privileged status of the brain, and are also important regulators of neuroimmune communication. It is increasingly appreciated ...that communication between the brain and immune system contributes to physiologic processes, adaptive responses, and disease states. In this review, we discuss the highly specialized features of brain barriers that regulate neuroimmune communication in health and disease. In
, we discuss the concept of immune privilege, provide working definitions of brain barriers, and outline the historical work that contributed to the understanding of CNS barrier functions. In
, we discuss the unique anatomic, cellular, and molecular characteristics of the vascular blood-brain barrier (BBB), blood-cerebrospinal fluid barrier, and tanycytic barriers that confer their functions as neuroimmune interfaces. In
, we consider BBB-mediated neuroimmune functions and interactions categorized as five neuroimmune axes: disruption, responses to immune stimuli, uptake and transport of immunoactive substances, immune cell trafficking, and secretions of immunoactive substances. In
, we discuss neuroimmune functions of CNS barriers in physiologic and disease states, as well as pharmacological interventions for CNS diseases. Throughout this review, we highlight many recent advances that have contributed to the modern understanding of CNS barriers and their interface functions.
The blood–brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's ...disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-β (Aβ) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Aβ pathology.
Abstract Background The observation that mismatch negativity (MMN) is consistently impaired in schizophrenia has generated considerable interest in the use of this biomarker as an index of disease ...risk and progression. Despite such enthusiasm, a number of issues remain unresolved regarding the nature of MMN impairment. The present study expands upon an earlier meta-analysis of MMN impairment in schizophrenia by examining impairment across a range of clinical presentations, as well as across experimental parameters. Methods One hundred one samples of schizophrenia patients were included in the present study, including first-episode ( n = 13), chronic ( n = 13), and mixed-stage ( n = 75) samples. Additionally, MMN was examined in three related conditions: bipolar disorder ( n = 9), unaffected first-degree relatives ( n = 8), and clinical high risk ( n = 16). Results We found that MMN impairment 1) likely reflects a vulnerability to disease progression in clinical high-risk populations rather than a genetic risk for the condition; 2) is largely unrelated to duration of illness after the first few years of illness, indicating that impairment is not progressive throughout the life span; 3) is present in bipolar disorder, albeit to a lesser degree than in schizophrenia; and 4) is not modulated by experimental parameters such as magnitude of change between standard and deviant tones or frequency of deviant tones but may be modulated by attentional demands. Conclusions Such findings lay the foundation for a better understanding of the nature of MMN impairment in schizophrenia, as well as its potential as a clinically useful biomarker.
Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces for ...neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which the aging immune system alters central nervous system functions and neuroimmune responses, with a focus on brain barriers. Specific emphasis will be on recent works that have identified novel mechanisms by which BBB/BCSFB functions change with age, interactions of the BBB with age-associated immune factors, and contributions of the BBB to age-associated neurological disorders. Understanding how age alters BBB functions and responses to pathological insults could provide important insight on the role of the BBB in the progression of cognitive decline and neurodegenerative disease.
Papillary thyroid carcinomas are the most common endocrine cancer and are usually associated with good survival. However, some variants of papillary thyroid carcinomas may behave more aggressively ...than classic papillary thyroid carcinomas. The tall cell variant of papillary thyroid carcinoma is the most common aggressive variant of papillary thyroid carcinoma. The aggressive behavior has been ascribed to the histologic subtype and/or to the clinicopathologic features, an issue that remains controversial. The columnar variant of papillary thyroid carcinoma can be aggressive, particularly in older patients, with larger tumors showing a diffusely infiltrative growth pattern and extrathyroidal extension. A papillary thyroid carcinoma is designated as solid/trabecular variant when all or nearly all of a tumor not belonging to any of the other variants has a solid, trabecular, or nested (insular) appearance. This tumor must be distinguished from poorly differentiated thyroid carcinoma which has the same growth pattern but lacks nuclear features of papillary thyroid carcinoma and may show tumor necrosis and high mitotic activity. New to the fourth edition of the WHO Classification of Tumours of Endocrine Organs, the hobnail variant of papillary thyroid carcinoma is a moderately differentiated papillary thyroid carcinoma variant with aggressive clinical behavior and significant mortality. All of these variants are histologically unique and important to recognize due to their aggressive behavior.
Abstract The blood–brain barrier (BBB) is the monocellular interface that divides the peripheral circulation from direct contact with the central nervous system (CNS). This interface consists of ...several parallel barriers that include most notably the capillary bed of the CNS and the choroid plexus. These barriers at one level create the dichotomy between the circulating factors of the immune system and the components of the CNS only to regulate interactions between the immune and central nervous systems at other levels. The BBB is thus an integral part of the neuroimmune axis. Here, we will consider four aspects of BBB–neuroimmune interactions: BBB disruption as mediated by LPS and cytokines, cytokine transport across the BBB, immune cell trafficking, and effects of lipopolysaccharide (LPS) on various functions of the BBB.
It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via ...the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood-brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.
Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical ...interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.
Large quantities of immunoglobulin A (IgA) are constitutively secreted by intestinal plasma cells to coat and contain the commensal microbiota, yet the specificity of these antibodies remains ...elusive. Here we profiled the reactivities of single murine IgA plasma cells by cloning and characterizing large numbers of monoclonal antibodies. IgAs were not specific to individual bacterial taxa but rather polyreactive, with broad reactivity to a diverse, but defined, subset of microbiota. These antibodies arose at low frequencies among naïve B cells and were selected into the IgA repertoire upon recirculation in Peyer's patches. This selection process occurred independent of microbiota or dietary antigens. Furthermore, although some IgAs acquired somatic mutations, these did not substantially influence their reactivity. These findings reveal an endogenous mechanism driving homeostatic production of polyreactive IgAs with innate specificity to microbiota.
This paper reports the development of a ∼30 m resolution two‐dimensional hydrodynamic model of the conterminous U.S. using only publicly available data. The model employs a highly efficient numerical ...solution of the local inertial form of the shallow water equations which simulates fluvial flooding in catchments down to 50 km2 and pluvial flooding in all catchments. Importantly, we use the U.S. Geological Survey (USGS) National Elevation Dataset to determine topography; the U.S. Army Corps of Engineers National Levee Database to explicitly represent known flood defenses; and global regionalized flood frequency analysis to characterize return period flows and rainfalls. We validate these simulations against the complete catalogue of Federal Emergency Management Agency (FEMA) Special Flood Hazard Area (SFHA) maps and detailed local hydraulic models developed by the USGS. Where the FEMA SFHAs are based on high‐quality local models, the continental‐scale model attains a hit rate of 86%. This correspondence improves in temperate areas and for basins above 400 km2. Against the higher quality USGS data, the average hit rate reaches 92% for the 1 in 100 year flood, and 90% for all flood return periods. Given typical hydraulic modeling uncertainties in the FEMA maps and USGS model outputs (e.g., errors in estimating return period flows), it is probable that the continental‐scale model can replicate both to within error. The results show that continental‐scale models may now offer sufficient rigor to inform some decision‐making needs with dramatically lower cost and greater coverage than approaches based on a patchwork of local studies.
Key Points
A 30 m resolution flood hazard model of the entire conterminous United States is built using publicly available data
Delineations of flood hazard are comprehensively validated against United States government agency benchmarks
Model performance is largely comparable to quality local models, offering cheaper hazard information with complete spatial coverage
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