New Therapies for Emerging Endotypes of Asthma

2020 ◽  
Vol 71 (1) ◽  
pp. 289-302 ◽  
Author(s):  
Geoffrey Lowell Chupp ◽  
Ravdeep Kaur ◽  
Anne Mainardi
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Allergic Inflammation ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Successful Development ◽  
Adaptive Immune ◽  
Immune Phenotypes ◽  
Personalized Approach

The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease. Advances in the detection of these subgroups using clinical characteristics and biomarkers have led to the successful development of targeted biologics. This has moved us to a more personalized approach to managing asthma. Here we review the emerging endotypes of asthma and the biologics that have been developed to treat them.

scholarly journals SARS-CoV-2 Serology Status Detected by Commercialized Platforms Distinguishes Previous Infection and Vaccination Adaptive Immune Responses

2021 ◽  
Author(s):  
Raymond T. Suhandynata ◽  
Nicholas J. Bevins ◽  
Jenny T. Tran ◽  
Deli Huang ◽  
Melissa A. Hoffman ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Adaptive Immune Response ◽  
Antibody Assay ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Previous Infection ◽  
A Cell

AbstractBackgroundThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 110 million individuals and led to 2.5 million deaths worldwide. As more individuals are vaccinated, the clinical performance and utility of SARS-CoV-2 serology platforms needs to be evaluated.MethodsThe ability of four commercial SARS-CoV-2 serology platforms to detect previous infection or vaccination were evaluated using a cohort of 53 SARS-CoV-2 PCR-positive patients, 89 SARS-CoV-2-vaccinated healthcare workers (Pfizer or Moderna), and 127 SARS-CoV-2 negative patients. Serology results were compared to a cell based SARS-CoV-2 pseudovirus (PSV) neutralizing antibodies assay.ResultsThe Roche S-(spike) antibody and Diazyme neutralizing antibodies (NAbs) assays detected adaptive immune response in 100.0% and 90.1% of vaccinated individuals who received two-doses of vaccine (initial and booster), respectively. The Roche N-(nucleocapsid) antibody assay and Diazyme IgG assay did not detect adaptive immune response in vaccinated individuals. The Diazyme Nabs assay correlated with the PSV SARS-CoV-2 ID50 neutralization titers (R2= 0.70), while correlation of the Roche S-antibody assay was weaker (R2= 0.39). Median PSV SARS-CoV-2 ID50 titers more than doubled in vaccinated individuals who received two-doses of the Moderna vaccine (ID50: 597) compared to individuals that received a single dose (ID50: 284).ConclusionsThe Roche S-antibody and Diazyme NAbs assays robustly detected adaptive immune responses in SARS-CoV-2 vaccinated individuals and SARS-CoV-2 infected individuals. The Diazyme NAbs assay strongly correlates with the PSV SARS-CoV-2 NAbs in vaccinated individuals. Understanding the reactivity of commercially available serology platforms is important when distinguishing vaccination response versus natural infection.SummaryThe Roche S (spike protein)-antibody and Diazyme neutralizing-antibodies (NAbs) assays were evaluated for their clinical utility in the detection of SARS-CoV-2 related adaptive immune responses by testing SARS-CoV-2 PCR-confirmed patients, SARS-CoV-2-vaccinated individuals, and SARS-CoV-2-negative individuals. Commercial serology results were compared to results generated using a cell-based SARS-CoV-2 pseudovirus (PSV) NAbs assay and previously validated SARS-CoV-2 commercial serology assays (Roche N (nucleocapsid protein) antibody and Diazyme IgG). We demonstrate that the Roche S-antibody and Diazyme NAbs assays detected adaptive immune response in SARS-CoV-2 vaccinated individuals and the presence of SARS-CoV-2 PSV NAbs. The Roche S-antibody assay had an observed positive percent agreement (PPA) of 100% for individuals who received two doses of the Pfizer or Moderna vaccine. By contrast, the Roche N assay and Diazyme IgG assay did not detect vaccine adaptive immune responses. Our findings also indicate that the Diazyme NAbs assay correlates strongly with the levels of SARS-CoV-2 ID50 neutralization titers using the PSV Nab assay in vaccinated individuals.

Adaptive immunity

2020 ◽  
pp. 325-336
Author(s):  
Paul Klenerman
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immunity ◽  
Innate Immune Response ◽  
Molecular Basis ◽  
Adaptive Immune Response ◽  
Antigenic Specificity ◽  
Adaptive Immune Responses ◽  
Research Attention ◽  
Adaptive Immune

The adaptive immune response is distinguished from the innate immune response by two main features: its capacity to respond flexibly to new, previously unencountered antigens (antigenic specificity), and its enhanced capacity to respond to previously encountered antigens (immunological memory). These two features have provided the focus for much research attention, from the time of Jenner, through Pasteur onwards. Historically, innate and adaptive immune responses have often been treated as separate, with the latter being considered more ‘advanced’ because of its flexibility. It is now clear this not the case, and in recent years the molecular basis for these phenomena has become much better understood.

scholarly journals Mutations in a Highly Conserved Motif of nsp1β Protein Attenuate the Innate Immune Suppression Function of Porcine Reproductive and Respiratory Syndrome Virus

2016 ◽  
Vol 90 (7) ◽  
pp. 3584-3599 ◽  
Author(s):  
Yanhua Li ◽  
Duan-Liang Shyu ◽  
Pengcheng Shang ◽  
Jianfa Bai ◽  
Kang Ouyang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune ◽  
Respiratory Syndrome Virus ◽  
Adaptive Immune Responses ◽  
Virus Growth ◽  
Conserved Motif ◽  
Adaptive Immune ◽  
Infected Cells ◽  
Growth Ability

ABSTRACTPorcine reproductive and respiratory syndrome virus (PRRSV) nonstructural protein 1β (nsp1β) is a multifunctional viral protein, which is involved in suppressing the host innate immune response and activating a unique −2/−1 programmed ribosomal frameshifting (PRF) signal for the expression of frameshifting products. In this study, site-directed mutagenesis analysis showed that the R128A or R129A mutation introduced into a highly conserved motif (123GKYLQRRLQ131) reduced the ability of nsp1β to suppress interferon beta (IFN-β) activation and also impaired nsp1β's function as a PRF transactivator. Three recombinant viruses, vR128A, vR129A, and vRR129AA, carrying single or double mutations in the GKYLQRRLQ motif were characterized. In comparison to the wild-type (WT) virus, vR128A and vR129A showed slightly reduced growth abilities, while the vRR129AA mutant had a significantly reduced growth ability in infected cells. Consistent with the attenuated growth phenotypein vitro, pigs infected with nsp1β mutants had lower levels of viremia than did WT virus-infected pigs. Compared to the WT virus in infected cells, all three mutated viruses stimulated high levels of IFN-α expression and exhibited a reduced ability to suppress the mRNA expression of selected interferon-stimulated genes (ISGs). In pigs infected with nsp1β mutants, IFN-α production was increased in the lungs at early time points postinfection, which was correlated with increased innate NK cell function. Furthermore, the augmented innate response was consistent with the increased production of IFN-γ in pigs infected with mutated viruses. These data demonstrate that residues R128 and R129 are critical for nsp1β function and that modifying these key residues in the GKYLQRRLQ motif attenuates virus growth ability and improves the innate and adaptive immune responses in infected animals.IMPORTANCEPRRSV infection induces poor antiviral innate IFN and cytokine responses, which results in weak adaptive immunity. One of the strategies in next-generation vaccine construction is to manipulate viral proteins/genetic elements involved in antagonizing the host immune response. PRRSV nsp1β was identified to be a strong innate immune antagonist. In this study, two basic amino acids, R128 and R129, in a highly conserved GKYLQRRLQ motif were determined to be critical for nsp1β function. Mutations introduced into these two residues attenuated virus growth and improved the innate and adaptive immune responses of infected animals. Technologies developed in this study could be broadly applied to current commercial PRRSV modified live-virus (MLV) vaccines and other candidate vaccines.

scholarly journals Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 323 ◽  
Author(s):  
Guoying Wang ◽  
Xianghui Li ◽  
Lei Zhang ◽  
Abualgasim Elgaili Abdalla ◽  
Tieshan Teng ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Th2 Responses ◽  
Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

Changes in immune responses to oxidized LDL epitopes during aging in hypercholesterolemic apoE(−/−) mice

2006 ◽  
Vol 291 (6) ◽  
pp. R1644-R1650 ◽  
Author(s):  
Paul C. Dimayuga ◽  
Xiaoning Zhao ◽  
Juliana Yano ◽  
Kuang-Yuh Chyu
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Time Course ◽  
Oxidized Ldl ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Collagen Content ◽  
Aortic Sinus ◽  
Adaptive Immune

Atherosclerosis is a disease associated with aging and is subject to modulation by both the innate and adaptive immune system. The time course of age-dependent changes in immune regulation in the context of atherosclerosis has not been characterized. This study aims to describe alteration of the immune responses to oxidized LDL (oxLDL) during aging that is associated with changes in plaque size and phenotype in apoE(−/−) mice. Mice fed a Western diet were euthanized at 15–17, 36, or >52 wk of age. The descending aortas were stained for assessment of extent of atherosclerosis. Plaque lipid, macrophage, and collagen content were evaluated in aortic sinus lesions. The adaptive immune response to oxLDL was assessed using anti-malondialdehyde-oxidized LDL (MDA-LDL) and copper-oxidized LDL (Cu-oxLDL) IgG, and the innate immune response was assessed using anti-Cu-oxLDL and phosphorylcholine (PC) IgM. Aging was associated with a significant increase in plaque area and collagen content and a decrease in plaque macrophage and lipid content. MDA-LDL IgG significantly increased at 36 wk but was reduced in mice >52 wk. Cu-oxLDL IgG increased with age and IgG-apoB immune complexes were increased in the >52 wk group. Cu-oxLDL and PC IgM significantly increased with age. The expression of splenic cytokines such as IFN-γ, IL-4, and IL-10 increased with age. Our study shows a generalized increase in innate immune responses associated with progression of atherosclerosis and a less inflammatory and less lipid-containing plaque phenotype during aging. The adaptive immune response appeared to be less generalized, with a specific reduction in MDA-LDL IgG.

scholarly journals The Neutrophil’s Role During Health and Disease

2019 ◽  
Vol 99 (2) ◽  
pp. 1223-1248 ◽  
Author(s):  
Pei Xiong Liew ◽  
Paul Kubes
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Acute Injury ◽  
Complex Cells ◽  
Adaptive Immune ◽  
Inflammatory Processes ◽  
Health And Disease ◽  
Injury And Repair

Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the role of the neutrophil has been undergoing a rejuvenation of sorts. Neutrophils are now considered complex cells capable of a significant array of specialized functions, and as an effector of the innate immune response, they are able to regulate many processes such as acute injury and repair, cancer, autoimmunity, and chronic inflammatory processes. Furthermore, evidence exists to indicate that neutrophils also contribute to adaptive immunity by aiding the development of specific adaptive immune responses or guiding the subsequent adaptive immune response. With this revived interest in neutrophils and their many novel functions, it is prudent to review what is currently known about neutrophils and, even more importantly, understand what information is lacking. We discuss the essential features of the neutrophil, from its origins, lifespan, subsets, margination and sequestration of the neutrophil to the death of the neutrophil. We highlight neutrophil recruitment to both infected and injured tissues and outline differences in recruitment of neutrophils between different tissues. Finally, we examine how neutrophils use different mechanisms to either bolster protective immune responses or negatively cause pathological outcomes at different locations.

SLPI and elafin: one glove, many fingers

2005 ◽  
Vol 110 (1) ◽  
pp. 21-35 ◽  
Author(s):  
Steven E. Williams ◽  
Thomas I. Brown ◽  
Ali Roghanian ◽  
Jean-Michel Sallenave
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune ◽  
Pathological Conditions ◽  
Related Proteins

Elafin and SLPI (secretory leucocyte protease inhibitor) have multiple important roles both in normal homoeostasis and at sites of inflammation. These include antiprotease and antimicrobial activity as well as modulation of the response to LPS (lipopolysaccharide) stimulation. Elafin and SLPI are members of larger families of proteins secreted predominantly at mucosal sites, and have been shown to be modulated in multiple pathological conditions. We believe that elafin and SLPI are important molecules in the controlled functioning of the innate immune system, and may have further importance in the integration of this system with the adaptive immune response. Recent interest has focused on the influence of inflamed tissues on the recruitment and phenotypic modulation of cells of the adaptive immune system and, indeed, the local production of elafin and SLPI indicate that they are ideally placed in this regard. Functionally related proteins, such as the defensins and cathelicidins, have been shown to have direct effects upon dendritic cells with potential alteration of their phenotype towards type I or II immune responses. This review addresses the multiple functions of elafin and SLPI in the inflammatory response and discusses further their roles in the development of the adaptive immune response.

scholarly journals Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Loïc Vivien Bocard ◽  
Andrew Robert Kick ◽  
Corinne Hug ◽  
Heidi Erika Lisa Lischer ◽  
Tobias Käser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.

SARS-CoV-2 elicits robust adaptive immune responses regardless of disease severity

2020 ◽  
Author(s):  
Stine SF Nielsen ◽  
Line K Vibholm ◽  
Ida Monrad ◽  
Rikke Olesen ◽  
Giacomo S Frattari ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Disease Severity ◽  
Adaptive Immune Response ◽  
T Cell Responses ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Robust Adaptive

AbstractThe SARS-CoV-2 pandemic currently prevails worldwide. To understand the immunological signature of SARS-CoV-2 infections and aid the search for treatments and vaccines, comprehensive characterization of adaptive immune responses towards SARS-CoV-2 is needed. We investigated the breadth and potency of antibody-, and T-cell immune responses, in 203 recovered SARS-CoV-2 infected patients who presented with asymptomatic to severe infections. We report very broad serological profiles with cross-reactivity to other human coronaviruses. Further, >99% had SARS-CoV-2 epitope specific antibodies, with SARS-CoV-2 neutralization and spike-ACE2 receptor interaction blocking observed in 95% of individuals. A significant positive correlation between spike-ACE2 blocking antibody titers and neutralization potency was observed. SARS-CoV-2 specific CD8+ T-cell responses were clear and quantifiable in 90% of HLA-A2+ individuals. The viral surface spike protein was identified as the dominant target for both neutralizing antibodies and CD8+ T cell responses. Overall, the majority of patients had robust adaptive immune responses, regardless of disease severity.Author summarySARS-CoV-2 can cause severe and deadly infections. However, the immunological understanding of this viral infection is limited. Currently, several vaccines are being developed to help limit transmission and prevent the current pandemic. However, basic understanding of the adaptive immune response developed during SARS-CoV-2 infections is needed to inform further vaccine development and to understand the protective properties of the developed immune response. We investigated, the adaptive immune response developed during SARS-CoV-2 infections in recovered patients experiencing a full spectrum of disease severity, from asymptomatic infections to severe cases requiring hospitalization. We used a novel multiplex serological platform, cell-based neutralization assays and dextramer flow cytometry assays to characterize a broad and robust humoral and cellular immune response towards SARS-CoV-2. We found that the vast majority of recovered individuals have clear detectable and functional SARS-CoV-2 spike specific adaptive immune responses, despite diverse disease severities. The detection of both a humoral and cellular functional spike specific immune response in the vast majority of the individuals, irrespective of asymptomatic manifestations, supports vaccine designs currently underway, and encourages further exploration of whether primary infections provide protection to reinfection.

Immune system physiology in anaesthetic practice

2017 ◽  
Author(s):  
Helen F. Galley ◽  
Heather M. Wilson
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Immune Systems ◽  
Adaptive Immune ◽  
System Physiology ◽  
Adaptive Immune Systems ◽  
Immune System Physiology

The immune system provides protection against invading pathogens, foreign cells including tumour cells, and macromolecules. It comprises an early, non-specific, innate immune response and a later, specific, adaptive immune response that helps prevent disease or recurrence of disease. Innate and adaptive immune systems work together with mutual interactivity distinguishing ‘self’ from ‘non-self components’ to provide effective immune responses and prevent infection. This chapter describes the basic processes involved in immune responses and illustrates the particular relevance for some disease processes as well as highlighting stresses associated with anaesthesia and surgery that can modulate responses.

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