Epstein-Barr virus (EBV) is an enigma; on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy ...individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.
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AMPA receptors are tetrameric glutamate‐gated ion channels that mediate a majority of fast excitatory neurotransmission in the brain. They exist as calcium‐impermeable (CI‐) and calcium‐permeable ...(CP‐) subtypes, the latter of which lacks the GluA2 subunit. CP‐AMPARs display an array of distinctive biophysical and pharmacological properties that allow them to be functionally identified. This has revealed that they play crucial roles in diverse forms of central synaptic plasticity. Here we summarise the functional hallmarks of CP‐AMPARs and describe how these are modified by the presence of auxiliary subunits that have emerged as pivotal regulators of AMPARs. A lasting change in the prevalence of GluA2‐containing AMPARs, and hence in the fraction of CP‐AMPARs, is a feature in many maladaptive forms of synaptic plasticity and neurological disorders. These include modifications of glutamatergic transmission induced by inflammatory pain, fear conditioning, cocaine exposure, and anoxia‐induced damage in neurons and glia. Furthermore, defective RNA editing of GluA2 can cause altered expression of CP‐AMPARs and is implicated in motor neuron damage (amyotrophic lateral sclerosis) and the proliferation of cells in malignant gliomas. A number of the players involved in CP‐AMPAR regulation have been identified, providing useful insight into interventions that may prevent the aberrant CP‐AMPAR expression. Furthermore, recent molecular and pharmacological developments, particularly the discovery of TARP subtype‐selective drugs, offer the exciting potential to modify some of the harmful effects of increased CP‐AMPAR prevalence in a brain region‐specific manner.
figure legend AMPARs containing GluA2 (red subunits) are Ca2+‐impermeable (CI‐AMPARs). Those that lack GluA2 are Ca2+‐permeable (CP‐AMPARs) and are implicated in diverse forms of synaptic plasticity and disease. Both native CP‐ and CI‐AMPARs contain various auxiliary subunits (shown as yellow, green or turquoise) that affect AMPAR function and play a role in the regulation of relative CP‐/CI‐AMPAR prevalence. Image based on PDB model 6NJM.
Epstein–Barr virus (EBV) is a ubiquitous human pathogen, infecting > 90% of the adult population. In the vast majority of healthy individuals, infection with EBV runs a relatively benign course. ...However, EBV is by no means a benign pathogen. Indeed, apart from being associated with at least seven different types of malignancies, EBV infection can cause severe and often fatal diseases—hemophagocytic lymphohistiocytosis, lymphoproliferative disease, B-cell lymphoma—in rare individuals with specific monogenic inborn errors of immunity. The discovery and detailed investigation of inborn errors of immunity characterized by heightened susceptibility to, or increased frequency of, EBV-induced disease have elegantly revealed cell types and signaling pathways that play critical and non-redundant roles in host-defense against EBV. These analyses have revealed not only mechanisms underlying EBV-induced disease in rare genetic conditions, but also identified molecules and pathways that could be targeted to treat severe EBV infection and pathological consequences in immunodeficient hosts, or even potentially enhance the efficacy of an EBV-specific vaccine.
The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic ...effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain.
We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and "asymptomatic Alzheimer's disease" (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10-8, FC = 0.52, q = 1.03 x 10-6), linolenic acid (p = 2.5 x 10-4, FC = 0.84, q = 4.03 x 10-4), docosahexaenoic acid (p = 1.7 x 10-7, FC = 1.45, q = 1.24 x 10-6), eicosapentaenoic acid (p = 4.4 x 10-4, FC = 0.16, q = 6.48 x 10-4), oleic acid (p = 3.3 x 10-7, FC = 0.34, q = 1.46 x 10-6), and arachidonic acid (p = 2.98 x 10-5, FC = 0.75, q = 7.95 x 10-5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.
The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During our life, we are surrounded by continuous threats from a diverse range of invading pathogens. Our immune system has evolved multiple mechanisms to efficiently deal with these threats so as to ...prevent them from causing disease. Terminal differentiation of mature B cells into plasma cells (PC) - the antibody (Ab) secreting cells of the immune system - is critical for the generation of protective and long-lived humoral immune responses. Indeed, efficient production of antigen (Ag)-specific Ab by activated B cells underlies the success of most currently available vaccines. The mature B-cell pool is composed of several subsets, distinguished from one according to size, surface marker expression, location, and Ag exposure, and they all have the capacity to differentiate into PCs. For a B-cell to acquire the capacity to produce Abs, it must undergo an extensive differentiation process driven by changes in gene expression. Two broad categories of Ags exist that cause B-cell activation and differentiation: T cell dependent (TD) or T cell independent (TI). In addition to the B-cell subset and nature of the Ag, it is important to consider the cytokine environment that can also influence how B-cell differentiation is achieved. Thus, while many cytokines can induce Ab-secretion by B cells after activation with mimics of TD and TI stimuli in vitro, they can have different efficacies and specificities, and can often preferentially induce production of one particular Ig isotype over another. Here, we will provide an overview of in vitro studies (mouse and human origin) that evaluated the role of different cytokines in inducing the differentiation of distinct B-cell subsets to the PC lineage. We will place particular emphasis on IL-21, which has emerged as the most potent inducer of terminal B-cell differentiation in humans. We will also focus on the role of IL-21 and defects in B-cell function and how these contribute to human immunopathologies such as primary immunodeficiencies and B-cell mediated autoimmune conditions.
We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents ...the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which ...accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.
Human immunity against EBV-lessons from the clinic Tangye, Stuart G; Palendira, Umaimainthan; Edwards, Emily S J
The Journal of experimental medicine,
02/2017, Letnik:
214, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring ...sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell-mediated therapy to treat disorders associated with or induced by EBV infection.
Cytokines play critical roles in regulating the development, survival, differentiation, and function of immune cells. Cytokines exert their function by binding specific receptor complexes on the ...surface of immune cells and activating intracellular signaling pathways, thereby resulting in induction of specific transcription factors and regulated expression of target genes. While the function of cytokines is often fundamental for the generation of robust and effective immunity following infection or vaccination, aberrant production or function of cytokines can underpin immunopathology. IL-21 is a pleiotropic cytokine produced predominantly by CD4+ T cells. Gene-targeting studies in mice, in vitro analyses of human and murine lymphocytes, and the recent discoveries and analyses of humans with germline loss-of-function mutations in IL21 or IL21R have revealed diverse roles of IL-21 in immune regulation and effector function. This review will focus on recent advances in IL-21 biology that have highlighted its critical role in T cell-dependent B cell activation, germinal center reactions, and humoral immunity and how impaired responses to, or production of, IL-21 can lead to immune dysregulation.
In this issue of JEM, Çakan et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230944) explore a CXCL4-mediated mechanism by which TLRs cause autoimmunity in human B cells, breaching bone marrow ...tolerance.
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