Autoimmune neurological conditions associated with Zika virus infection

Zika virus (ZIKV) is an emerging flavivirus rapidly spreading throughout the tropical Americas. mosquitoes is the principal way of transmission of the virus to humans. ZIKV can be spread by transplacental, perinatal, and body fluids. ZIKV infection is often asymptomatic and those with symptoms present minor illness after 3 to 12 days of incubation, characterized by a mild and self-limiting disease with low-grade fever, conjunctivitis, widespread pruritic maculopapular rash, arthralgia and myalgia. ZIKV has been linked to a number of central and peripheral nervous system injuries such as Guillain-Barré syndrome (GBS), transverse myelitis (TM), meningoencephalitis, ophthalmological manifestations, and other neurological complications. Nevertheless, mechanisms of host-pathogen neuro-immune interactions remain incompletely elucidated. This review provides a critical discussion about the possible mechanisms underlying the development of autoimmune neurological conditions associated with Zika virus infection

La pérdida específica de células T de la subunidad catalítica p110? de PI-3-linasa da como resultado una producción mejorada de citocinas y una respuesta antitumoral

Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110? and p110? are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110? PI3K in normal or pathological immune responses is well established, yet the importance of p110? subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110? conditionally deleted in CD4+ and CD8+ T lymphocytes (p110??/??T) were used. p110??/??T mice show normal development of T cell subsets, but slightly reduced numbers of CD4+ T cells in the spleen. “In vitro,” TCR/CD3 plus CD28 activation of naive CD4+ and CD8+ p110??/??T T cells showed enhanced effector function, particularly IFN-? secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110??/??T cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110??/??T CD8+ T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110??/??T iTreg cells was diminished. Also, p110??/??T mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-?, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110??/??T mice inoculated with B16.F10 melanoma showed delayed tumor progression. The percentage of CD8+ T lymphocytes was higher and the percentage of Treg cells lower in the spleen of tumor-bearing p110??/??T mice. Also, IFN-? production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110? plays a significant role in antigen activation and differentiation of CD4+ and CD8+ T lymphocytes modulating antitumor immunity

Endothelial Damage in Sepsis: The Importance of Systems Biology

The early diagnosis and appropriate stratification of sepsis continues to be one of the most important challenges in modern medicine. Single isolated biomarkers have not been enough to improve diagnostic and prognostic strategies and to progress toward therapeutic goals. The information generated by the human genome project has allowed a more holistic approach to the problem. The integration of genomics, transcriptomics, proteomics and metabolomics in sepsis has allowed us to progress in the knowledge of new pathways which are pathophysiologically involved in this disease. Thus, we have understood the importance of and complex interaction between the inflammatory response and the endothelium. Understanding the role of important parts of the microcirculation, such as the endothelial glycocalyx and its interaction with the inflammatory response, has provided early recognition elements for clinical practice that allow the rational use of traditional medical interventions in sepsis. This comprehensive approach, which differs from the classical mechanistic approach, uses systems biology to increase the diagnostic and prognostic spectrum of endothelial damage biomarkers in sepsis, and to provide information on new pathways involved in the pathophysiology of the disease. This, in turn, provides tools for perfecting traditional medical interventions, using them at the appropriate times according to the disease's pathophysiological context, while at the same time discovering new and improved therapeutic alternatives. We have the challenge of transferring this ideal scenario to our daily clinical practice to improve our patients' care. The purpose of this article is to provide a general description of the importance of systems biology in integrating the complex interaction between the endothelium and the inflammatory response in sepsis

Cytokines and Inflammatory Mediators in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by a breakdown in immune tolerance that induces an attack on normal tissues by the immune system. The dysfunction within both the innate and adaptive immune systems increases cytokine production, B lymphocytic overproduction of autoantibodies, and T lymphocyte activity. Cytokines and inflammatory mediators have been associated with several clinical endpoints, including the activity of disease and outcomes. In fact, some of them have been associated with different clinical subphenotypes (e.g., lupus nephritis), suggesting their role as biomarkers, and, in some cases, therapeutic targets. Thus, knowledge of the pathophysiological processes associated with the development of SLE could aid in setting up better diagnostic and therapeutic approaches to reduce the high burden of disease, and thus improve quality of life and outcomes. Herein, the authors have compiled a concise review of the clinically relevant cytokines and inflammatory mediators associated with SLE and its manifestations

Cytokine and autoantibody clusters interaction in systemic lupus erythematosus

Background: Evidence supports the existence of different subphenotypes in systemic lupus erythematosus (SLE) and the pivotal role of cytokines and autoantibodies, which interact in a highly complex network. Thus, understanding how these complex nonlinear processes are connected and observed in real-life settings is a major challenge. Cluster approaches may assist in the identification of these subphenotypes, which represent such a phenomenon, and may contribute to the development of personalized medicine. Therefore, the relationship between autoantibody and cytokine clusters in SLE was analyzed. Methods: This was an exploratory study in which 67 consecutive women with established SLE were assessed. Clinical characteristics including disease activity, a 14-autoantibody profile, and a panel of 15 serum cytokines were measured simultaneously. Mixed-cluster methodology and bivariate analyses were used to define autoantibody and cytokine clusters and to identify associations between them and related variables. Results: First, three clusters of autoantibodies were defined: (1) neutral, (2) antiphospholipid antibodies (APLA)-dominant, and (3) anti-dsDNA/ENA-dominant. Second, eight cytokines showed levels above the threshold thus making possible to find 4 clusters: (1) neutral, (2) chemotactic, (3) G-CSF dominant, and (4) IFN?/Pro-inflammatory. Furthermore, the disease activity was associated with cytokine clusters, which, in turn, were associated with autoantibody clusters. Finally, when all biomarkers were included, three clusters were found: (1) neutral, (2) chemotactic/APLA, and (3) IFN/dsDNA, which were also associated with disease activity. Conclusion: These results support the existence of three SLE cytokine-autoantibody driven subphenotypes. They encourage the practice of personalized medicine, and support proof-of-concept studies. © 2017 The Author(s)

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Identificar a los culpables de las enfermedades neurológicas autoinmunes

El órgano diana de las enfermedades neurológicas autoinmunes (NAD) es el sistema nervioso central o periférico. La esclerosis múltiple (MS) es la NAD más común, mientras que el síndrome de Guillain-Barr e (GBS), la miastenia gravis (MG) y la neuromielitis óptica ( NMO) son NAD menos comunes, pero la incidencia de estas enfermedades ha aumentado de manera exponencial en los últimos años. La identificación de un culpable específico en los NAD es un desafío, ya que una miríada de factores desencadenantes interactúan entre sí para causar una respuesta autoinmune. Entre los factores que se han asociado con los NAD se encuentran la susceptibilidad genética, los mecanismos epigenéticos y los factores ambientales como la infección, la microbiota, las vitaminas, etc. Esta revisión se centra en los culpables más estudiados, así como en los mecanismos utilizados por estos para desencadenar el NAD.The target organ of neurological autoimmune diseases (NADs) is the central or peripheral nervous system.Multiple sclerosis (MS) is the most common NAD, whereas Guillain-Barre syndrome (GBS), myasthenia gravis(MG), and neuromyelitis optica (NMO) are less common NADs, but the incidence of these diseases has increasedexponentially in the last few years. The identification of a specific culprit in NADs is challenging since a myriad oftriggering factors interplay with each other to cause an autoimmune response. Among the factors that have beenassociated with NADs are genetic susceptibility, epigenetic mechanisms, and environmental factors such asinfection, microbiota, vitamins, etc. This review focuses on the most studied culprits as well as the mechanismsused by these to trigger NAD