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"Klenerman, Paul"
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الجهاز المناعي
يعد الجهاز المناعي جهازا مركزيا لصحة الإنسان، ومحل اهتمام كثير من الأبحاث الطبية. ومع ازدياد فهمنا للجهاز المناعي، استطعنا تحقيق خطوات متقدمة للغاية في العلوم الطبية وبخاصة في مجال اللقاحات. ويشرح لنا مؤلف الكتاب الجهاز المناعي، وآلية عمله في أطوار الصحة والمرض. ويهتم خصوصا بالقواعد التي تحكم سلوكه، والمخاطر الصحية الرئيسة التي تحدق به. ويبين لنا أن الجهاز المناعي ما هو إلا مجموعة من الأعضاء والخلايا والرسائل الكيميائية تعمل جميعا لتوفر لنا الحماية من العدوى. ولا ينسى الكاتب يبين لنا ما يحدث إذا أخفقت المنظومات المناعية في عملها، وما يسببه ذلك من أشكال عدوى خطيرة.
Book
Hepatitis C
Hepatitis C virus (HCV) infection is a major health problem worldwide. The effects of chronic infection include cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As a result of shared routes of transmission, co-infection with HIV is a substantial problem, and individuals infected with both viruses have poorer outcomes than do peers infected with one virus. No effective vaccine exists, although persistent HCV infection is potentially curable. The standard of care has been subcutaneous interferon alfa and oral ribavirin for 24–72 weeks. This treatment results in a sustained virological response in around 50% of individuals, and is complicated by clinically significant adverse events. In the past 10 years, advances in HCV cell culture have enabled an improved understanding of HCV virology, which has led to development of many new direct-acting antiviral drugs that target key components of virus replication. These direct-acting drugs allow for simplified and shortened treatments for HCV that can be given as oral regimens with increased tolerability and efficacy than interferon and ribavirin. Remaining obstacles include access to appropriate care and treatment, and development of a vaccine.
Journal Article
The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses
Pre-existing cross-reactive immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in infection-naive subjects have been described by several studies. In particular, regions of high homology between SARS-CoV-2 and common cold coronaviruses have been highlighted as a likely source of this cross-reactivity. However, the role of such cross-reactive responses in the outcome of SARS-CoV-2 infection and vaccination is currently unclear. Here, we review evidence regarding the impact of pre-existing humoral and T cell immune responses to outcomes of SARS-CoV-2 infection and vaccination. Furthermore, we discuss the importance of conserved coronavirus epitopes for the rational design of pan-coronavirus vaccines and consider cross-reactivity of immune responses to ancestral SARS-CoV-2 and SARS-CoV-2 variants, as well as their impact on COVID-19 vaccination.This Review discusses the evidence for pre-existing cross-reactive immune responses to SARS-CoV-2, which are mainly due to infections with common cold coronaviruses, and how such cross-reactivity affects adaptive immune responses. Furthermore, it explores cross-reactivity in the context of SARS-CoV-2 variants of concern and its implications for vaccine development.
Journal Article
Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic in 2020. Testing is crucial for mitigating public health and economic effects. Serology is considered key to population-level surveillance and potentially individual-level risk assessment. However, immunoassay performance has not been compared on large, identical sample sets. We aimed to investigate the performance of four high-throughput commercial SARS-CoV-2 antibody immunoassays and a novel 384-well ELISA.
We did a head-to-head assessment of SARS-CoV-2 IgG assay (Abbott, Chicago, IL, USA), LIAISON SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Saluggia, Italy), Elecsys Anti-SARS-CoV-2 assay (Roche, Basel, Switzerland), SARS-CoV-2 Total assay (Siemens, Munich, Germany), and a novel 384-well ELISA (the Oxford immunoassay). We derived sensitivity and specificity from 976 pre-pandemic blood samples (collected between Sept 4, 2014, and Oct 4, 2016) and 536 blood samples from patients with laboratory-confirmed SARS-CoV-2 infection, collected at least 20 days post symptom onset (collected between Feb 1, 2020, and May 31, 2020). Receiver operating characteristic (ROC) curves were used to assess assay thresholds.
At the manufacturers' thresholds, for the Abbott assay sensitivity was 92·7% (95% CI 90·2–94·8) and specificity was 99·9% (99·4–100%); for the DiaSorin assay sensitivity was 96·2% (94·2–97·7) and specificity was 98·9% (98·0–99·4); for the Oxford immunoassay sensitivity was 99·1% (97·8–99·7) and specificity was 99·0% (98·1–99·5); for the Roche assay sensitivity was 97·2% (95·4–98·4) and specificity was 99·8% (99·3–100); and for the Siemens assay sensitivity was 98·1% (96·6–99·1) and specificity was 99·9% (99·4–100%). All assays achieved a sensitivity of at least 98% with thresholds optimised to achieve a specificity of at least 98% on samples taken 30 days or more post symptom onset.
Four commercial, widely available assays and a scalable 384-well ELISA can be used for SARS-CoV-2 serological testing to achieve sensitivity and specificity of at least 98%. The Siemens assay and Oxford immunoassay achieved these metrics without further optimisation. This benchmark study in immunoassay assessment should enable refinements of testing strategies and the best use of serological testing resource to benefit individuals and population health.
Public Health England and UK National Institute for Health Research.
Journal Article
MAIT cells and viruses
Mucosal associated invariant T cells (MAIT cells) bear a T cell receptor (TCR) that specifically targets microbially derived metabolites. Functionally, they respond to bacteria and yeasts, which possess the riboflavin pathway, essential for production of such metabolites and which are presented on MR1. Viruses cannot generate these ligands, so a priori, they should not be recognized by MAIT cells and indeed this is true when considering recognition through the TCR. However, MAIT cells are distinctive in another respect, since they respond quite sensitively to non‐TCR signals, especially in the form of inflammatory cytokines. Thus, a number of groups have shown that virus infection can be “sensed” by MAIT cells and a functional response invoked. Since MAIT cells are abundant in humans, especially in tissues such as the liver, the question has arisen as to whether this TCR‐independent MAIT cell triggering by viruses plays any role in vivo. In this review, we will discuss the evidence for this phenomenon and some common features which emerge across different recent studies in this area.
MAIT cells are abundant in humans and have been shown to respond to viruses. In this article, we explore the mechanisms behind this and what the implications are in vivo.
Journal Article
Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response
Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.
Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8
+
T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.
Journal Article
The Human Cell Atlas
The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
Journal Article
Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern
The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
Understanding the effect of vaccination on emerging SARS-CoV-2 variants of concern is of increasing importance. Here, James et al. report that two doses of vaccination with the Pfizer-BioNTech vaccine induce more robust immune responses to the B.1.1.7 and B.1.351 SARS-CoV-2 lineages than does natural infection.
Journal Article
Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report
The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.
Remdesivir is under evaluation for treatment of COVID-19 in clinical trials. Here, the authors report results of remdesivir treatment in a patient with COVID-19 and the genetic antibody deficiency XLA. They show a temporally correlated clinical and virological response, suggesting that remdesivir can reduce SARS-CoV-2 replication in patients.
Journal Article
T cell responses to cytomegalovirus
Key Points
Cytomegalovirus (CMV) induces large populations of CD8
+
T cells that retain effector functions, have an effector memory phenotype and home to peripheral organs. The phenomenon has been termed 'memory inflation' on the basis of longitudinal studies in mouse models.
The CMV-specific T cell populations that undergo memory inflation are a subset of those that are primed, and they are maintained owing to persistence of the antigen. The viral peptides that drive these responses seem to be presented by non-professional antigen-presenting cells and are immunoproteasome independent.
The expanded CD8
+
T cell populations that are observed in CMV infection have a transcriptional profile that is different to that seen in 'exhausted' CD8
+
T cells but is similar to that seen in T cells responding to other low-level persistent challenges, such as adenoviral vaccines, in both humans and mice. Using the adenoviral system, conventional T cell responses can acquire features of expanded CMV-specific T cell responses by modifying the peptide context.
The CMV-induced CD8
+
T cell responses are dependent on CD4
+
T cell help and co-stimulatory signals. Such signals are probably required to support the recruitment of effector memory T cells from a pool of central memory T cells, although the precise nature and niche of the non-professional antigen-presenting cells involved are still ill-defined.
In elderly populations, the marked expansion of CMV-specific T cells is associated with a failure to control the virus and increased levels of CMV-specific IgG, which are features that have been linked to adverse health outcomes in some large epidemiological studies. Although causal mechanisms have not been defined, local replication of CMV may influence vascular pathology through the activation of inflammatory pathways.
Infection with cytomegalovirus induces an unusually high level of long-lasting memory T cells that have potent effector functions. Understanding how and why this occurs might help to improve responses to vaccination.
Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8
+
T cells — a phenomenon termed memory inflation — and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits.
Journal Article