Although activated murine NK cells can use the granule exocytosis pathway to kill target cells immediately upon recognition, resting murine NK cells are minimally cytotoxic for unknown reasons. Here, ...we showed that resting NK cells contained abundant granzyme A, but little granzyme B or perforin; in contrast, the mRNAs for all three genes were abundant. Cytokine-induced in vitro activation of NK cells resulted in potent cytotoxicity associated with a dramatic increase in granzyme B and perforin, but only minimal changes in mRNA abundance for these genes. The same pattern of regulation was found in vivo with murine cytomegalovirus infection as a physiologic model of NK cell activation. These data suggest that resting murine NK cells are minimally cytotoxic because of a block in perforin and granzyme B mRNA translation that is released by NK cell activation.
An unbridled host immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to underlie severe cases of the disease and has been labeled a ‘cytokine storm ...syndrome’ (CSS). Here, we emphasize that categorization of syndromes triggered by a completely novel pathogen based on other seemingly similar, but potentially distinct, known entities is an inherently risky endeavor.
An uncontrolled host immune response following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and a cytokine storm contribute to severe coronavirus disease 2019 (COVID-19).Among the myriad clinical syndromes identified in patients with COVID-19, multisystem inflammatory syndrome in children (MIS-C) is emerging as a severe complication in pediatric patients.Cohorts of pediatric patients with MIS-C reveal overlapping but distinct pictures from SARS-CoV-2-associated cytokine storm syndrome (CSS) with respect to their clinical and laboratory profile.While candidates for targeted therapies based on understanding of the pathogenesis of SARS-CoV-2-associated CSSs are emerging, and there may be overlap in the pathogenesis and therapy, it is clear that syndrome-specific approaches will be necessary.
We recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting ...pathways of the host. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wild type (BavPat1/2020) strain and four additional variant strains;
alpha
(B.1.1.7),
beta
(B.1.351),
delta
(B.1.617.2) and
gamma
(P.1)
in vitro
, with 50% effective concentration (EC
50
) estimates of 4.1 μM, 8.5 μM, 24.1 μM, 8.2 μM and 13.6 μM, respectively. A separate experiment focusing on a combination of 10 μM stenoparib and 0.5 μM remdesivir, an antiviral drug, resulted in over 80% inhibition of the
alpha
variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.
The dynamic life of natural killer cells Yokoyama, Wayne M; Kim, Sungjin; French, Anthony R
Annual review of immunology,
01/2004, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Natural killer (NK) cells play important roles in immunological processes, including early defense against viral infections. This review provides an overview of the dynamic in vivo life of NK cells ...from their development in the bone marrow to their mature peripheral responses and their ultimate demise, with particular emphasis on mouse NK cells and viral infections.
Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells ...modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases.
Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues ...and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells-licensed or unlicensed-and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.
During early viral infection, activation of natural killer (NK) cells elicits the effector functions of target cell lysis and cytokine production. However, the cellular and molecular mechanisms ...leading to NK cell activation during viral infections are incompletely understood. In this study, using a model of acute viral infection, we investigated the mechanisms controlling cytotoxic activity and cytokine production in response to influenza (flu) virus. Analysis of cytokine receptor deficient mice demonstrated that type I interferons (IFNs), but not IL-12 or IL-18, were critical for the NK cell expression of both IFN-γ and granzyme B in response to flu infection. Further, adoptive transfer experiments revealed that NK cell activation was mediated by type I IFNs acting directly on NK cells. Analysis of signal transduction molecules showed that during flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent. In addition, granzyme B induction in NK cells was mediated by signaling primarily through STAT1, but not STAT4, while IFN-γ production was mediated by signaling through STAT4, but not STAT1. Therefore, our findings demonstrate the importance of direct action of type I IFNs on NK cells to mount effective NK cell responses in the context of flu infection and delineate NK cell signaling pathways responsible for controlling cytotoxic activity and cytokine production.
Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function ...remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142−/− mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-β (TGF-β) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.
Display omitted
•miR-142 is induced by IL-15 and is required for type 1 ILC development and homeostasis•miR-142 targets Socs1 thereby promotes IL-15 receptor signaling in type 1 ILCs•αV integrin, a miR142-3p target, promotes IL-15-independent survival in type 1 ILCs•miR-142 is critical for cytokine production and NK-cell-mediated viral control
IL-15 and TGF-β support the homeostasis and molecular programs of distinct innate lymphoid cell (ILC) types. Berrien-Elliott and colleagues identify that microRNA-142 is required for IL-15 receptor signaling and NK cell survival, whereas loss of microRNA-142 results in distinct TGF-β- and/or integrin-supported type 1 ILCs.
The incidence and prevalence of granulomatosis with polyangiitis (GPA) in the US is not well characterized. Owing to its rarity, outcomes data in pediatric-onset GPA are also lacking. The aims of ...this study were to describe the epidemiology of GPA and outcomes in GPA patients in the US, and to compare outcomes between pediatric and working-age adult patients.
A retrospective cohort study using the 2006-2014 Truven Health Analytics MarketScan Commercial Claims and Encounters Database was conducted. The incidence and prevalence rates of pediatric and adult GPA (age <65 years) were calculated. Outcomes among the 2 age groups were analyzed.
A total of 5,562 cases of GPA were identified, of which 214 (3.8%) were pediatric onset and 5,348 (96.2%) were adult onset. The incidence rate of pediatric-onset GPA was 1.8 cases per 1 million person-years, compared to 12.8 cases per 1 million person-years in working-age adults. There was a slight female preponderance in both groups (63% and 53% among pediatric and adult GPA patients, respectively). Rates of hospitalization and severe infections were high in both children and working-age adults, but children had more frequent hospitalizations (rate ratio RR 1.3 95% confidence interval (95% CI) 1.1-1.4) and 2-3-times higher rates of leukopenia (RR 2.6 95% CI 1.5-4.3), neutropenia (RR 2.2 95% CI 1.2-4.0), and hypogammaglobulinemia (RR 3.7 95% CI 2.0-6.4). Time-to-event analyses showed no differences in the time to hospitalization, severe infection, major relapse, or end-stage renal disease.
This study represents the largest cohort of GPA reported to date. Pediatric GPA patients experienced more frequent hospitalizations and were more vulnerable to hematologic complications than non-elderly adult patients.
The host immune system functions constantly to maintain chronic commensal and pathogenic organisms in check. The consequences of these immune responses on host physiology are as yet unexplored, and ...may have long-term implications in health and disease. We show that chronic viral infection increases epithelial turnover in multiple tissues, and the antiviral cytokines type I interferons (IFNs) mediate this response. Using a murine model with persistently elevated type I IFNs in the absence of exogenous viral infection, the Irgm1−/− mouse, we demonstrate that type I IFNs act through nonepithelial cells, including macrophages, to promote increased epithelial turnover and wound repair. Downstream of type I IFN signaling, the highly related IFN-stimulated genes Apolipoprotein L9a and b activate epithelial proliferation through ERK activation. Our findings demonstrate that the host immune response to chronic viral infection has systemic effects on epithelial turnover through a myeloid-epithelial circuit.
Display omitted
•Chronic viral infection stimulates epithelial proliferation and turnover•The antiviral cytokines type I interferons promote enhanced wound repair•Type I interferon signaling in macrophages mediates increased epithelial turnover•The interferon-stimulated genes Apol9a/b promote proliferation through epithelial ERK activation
Type I interferons (IFNs) are integral antiviral cytokines. Sun et al. show that elevation of IFNs during chronic viral infection increases epithelial turnover and enhances wound repair. This effect of IFNs is driven indirectly through macrophages and mediated by the interferon-stimulated genes Apolipoprotein L9a/b through epithelial ERK activation.
PDF
