Associations between HLA and autoimmune neurological diseases with autoantibodies

Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings

Galactic runaway O and Be stars found using Gaia DR3

A relevant fraction of massive stars are runaway stars. These stars move with a significant peculiar velocity with respect to their environment. We aim to discover and characterize the population of massive and early-type runaway stars in the GOSC and BeSS catalogs using Gaia DR3 astrometric data. We present a 2-dimensional method in the velocity space to discover runaway stars as those that deviate significantly from the velocity distribution of field stars, which are considered to follow the Galactic rotation curve. We found 106 O runaway stars, 42 of which were not previously identified as runaways. We found 69 Be runaway stars, 47 of which were not previously identified as runaways. The dispersion of runaway stars is a few times higher in Z and b than that of field stars. This is explained by the ejections they underwent when they became runaways. The percentage of runaways is 25.4% for O-type stars, and it is 5.2% for Be-type stars. In addition, we conducted simulations in 3 dimensions for our catalogs. They revealed that these percentages could increase to ~30% and ~6.7%, respectively. Our runaway stars include seven X-ray binaries and one gamma-ray binary. Moreover, we obtain velocity dispersions of ~5 km/s perpendicular to the Galactic plane for O- and Be-type field stars. These values increase in the Galactic plane to ~7 km/s for O-type stars due to uncertainties and to ~9 km/s for Be-type stars due to Galactic velocity diffusion. The excellent Gaia DR3 astrometric data have allowed us to identify a significant number of O-type and Be-type runaways in the GOSC and BeSS catalogs. The higher percentages and higher velocities found for O-type compared to Be-type runaways underline that the dynamical ejection scenario is more likely than the binary supernova scenario. Our results open the door to identifying new high-energy systems among our runaways by conducting detailed studies.Comment: 20 pages, 20 figures. Accepted for publication in A&

La huella de Lope de Vega en "Cómo se vengan los nobles", de Moreto: continuidades y disidencias

Ruth Lee Kennedy, in her The Dramatic Art of Moreto (1932), pointed out eleven comedies by Moreto that were based on previous plays by Lope. However, not all of those cases stick to the authentic authorship of Lope and the corresponding version of Moreto. This research, after present some theoretical questions about concepts like rewriting/ recasting/intertextuality, aims to address one of these rewriting pairs: El testimonio vengado, by Lope, and Cómo se vengan los nobles, attributed to Moreto, deepening, among other aspects, in the similarities and divergences present between both works in regards to the plot, the characters or the space and the time where the action takes place.Ruth Lee Kennedy, en The Dramatic Art of Moreto (1932), señaló once comedias de Moreto escritas a partir de obras de Lope. Sin embargo, no todos estos casos parecen ceñirse a la auténtica autoría de Lope y a la correspondiente versión de Moreto. Esta investigación, después de exponer una serie de cuestiones teóricas acerca de los conceptos de reescritura/refundición/intertextualidad, pretende abordar uno de estos pares de reescritura: El testimonio vengado, de Lope, y Cómo se vengan los nobles, atribuida a Moreto, ahondando, entre otros aspectos, en las similitudes y divergencias existentes entre ambas obras en lo que concierne al argumento, a los personajes o al espacio y al tiempo donde se desarrolla la acción

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors

Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors [e.g., human leukocyte antigen (HLA)] was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis

Protein Kinase Cε Is Required for Macrophage Activation and Defense Against Bacterial Infection

To assess directly the role of protein kinase C (PKC)ε in the immune system, we generated mice that carried a homozygous disruption of the PKCε locus. PKCε−/− animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCε−/− animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)γ, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Further analysis revealed that LPS-stimulated macrophages from PKCε−/− mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IκB kinase, a reduction in IκB degradation, and a decrease in nuclear factor (NF)κB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCε−/− mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCε is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCε, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality