Type 2 immunity in the skin and lungs Akdis, Cezmi A.; Arkwright, Peter D.; Brüggen, Marie-Charlotte ...
Allergy,
July 2020, Letnik:
75, Številka:
7
Journal Article
Recenzirano
Odprti dostop
There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. ...Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)‐25, IL‐33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL‐4, IL‐5, IL‐9, and IL‐13. IL‐4 and IL‐13 activate B cells to class‐switch to IgE and also play a role in T‐cell and eosinophil migration to allergic inflammatory tissues. IL‐13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL‐4 and IL‐13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL‐5 acts on activation, recruitment, and survival of eosinophils. IL‐9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL‐5 and its receptor, and IL‐4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T‐cell maturation, regulatory T‐cell development, and T‐cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD.
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced ...CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
Las artes decorativas experimentaron en España un importante desarrollo en los años centrales del pasado siglo. A este resurgimiento colaboró una institución singular, nacida en 1941 como fundación ...privada por la donación de cuatro millones de pesetas que hizo Francisco Franco, su fundador. La Fundación Generalísimo Franco - Industrias Artísticas Agrupadas (desde 1984 Fundación de Gremios y a partir de 1989 Nueva Fundación de Gremios) puso en marcha talleres de alfombras, tapices, reposteros, tejjidos de seda, bordados, fundición, talla, escultura, porcelana (horno y decoración), vidrieras, muebles, diseño de interiores, y restauración de relojes, de tapices y de alfombras, la mayoría de los cuales estuvieron activos durante los cincuenta y cuatro años de su existencia.
The “CTCF code” hypothesis posits that CTCF pleiotropic functions are driven by recognition of diverse sequences through combinatorial use of its 11 zinc fingers (ZFs). This model, however, is ...supported by in vitro binding studies of a limited number of sequences. To study CTCF multivalency in vivo, we define ZF binding requirements at ∼50,000 genomic sites in primary lymphocytes. We find that CTCF reads sequence diversity through ZF clustering. ZFs 4–7 anchor CTCF to ∼80% of targets containing the core motif. Nonconserved flanking sequences are recognized by ZFs 1–2 and ZFs 8–11 clusters, which also stabilize CTCF broadly. Alternatively, ZFs 9–11 associate with a second phylogenetically conserved upstream motif at ∼15% of its sites. Individually, ZFs increase overall binding and chromatin residence time. Unexpectedly, we also uncovered a conserved downstream DNA motif that destabilizes CTCF occupancy. Thus, CTCF associates with a wide array of DNA modules via combinatorial clustering of its 11 ZFs.
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•Genome-wide maps of 11 CTCF zinc finger mutants in B lymphocytes•Zinc finger mutations differentially affect CTCF binding and nuclear mobility•CTCF uses zinc finger clusters to recognize DNA sequence diversity•DNA sequences flanking the core motif modulate CTCF binding
CTCF is a nuclear architectural protein that binds to thousands of highly diverse sequences in eukaryotes. The current hypothesis, known as the “CTCF code,” proposes that CTCF binds DNA targets through combinatorial use of its 11 zinc fingers (ZFs). This model, however, is mostly supported by in vitro binding studies. By expressing ZF mutants in B lymphocytes, Resch, Casellas, and colleagues now present genome-wide maps of CTCF multivalency. They show that CTCF reads sequence diversity by relying on well-defined ZF clusters.
Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a posttranscriptional microRNA-223 (miR-223) target directing human hematopoietic ...progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin “bivalent domains,” hypermethylation, recruitment of polycomb (PcG)–RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.
Advances in the understanding of the epigenetic events underlying the regulation of developmental genes expression and cell lineage commitment are revealing novel regulatory networks. These also ...involve distinct components of the epigenetic pathways, including chromatin histone modification, DNA methylation, repression by polycomb complexes and microRNAs. Changes in chromatin structure, DNA methylation status and microRNA expression levels represent flexible, reversible and heritable mechanisms for the maintenance of stem cell states and cell fate decisions. We recently provided novel evidence showing that microRNAs, besides determining the post-transcriptional gene silencing of their targets, also bind to evolutionarily conserved complementary genomic seed-matches present on target gene promoters. At these sites, microRNAs can function as a critical interface between chromatin remodeling complexes and the genome for transcriptional gene silencing. Here, we discuss our novel findings supporting a role of the transcriptional chromatin targeting by polycomb-microRNA complexes in lineage fate determination of human hematopoietic cells.
BackgroundAutologous CAR-T therapy has revolutionized the treatment of multiple myeloma (MM), but many patients still face obstacles in accessing these therapies due to manufacturing limitations and ...the absence of allogeneic alternatives. A major obstacle faced by allogeneic cell therapies is allograft rejection. While elimination of class I HLA expression via deletion of the beta-2 microglobulin gene (b2m) abrogates graft-versus-host disease (GvHD), it renders the off-the-shelf CAR-T highly susceptible to the host NK cell killing due to the absence of ‘self’ signals.MethodsTo overcome this limitation, we investigated the use of an anti-CD38 IgG1 monoclonal antibody (CD38 mAb) to deplete NK cells. CD38 is highly expressed on NK cells as well as plasma cells. Clinical data suggests that treatment with CD38 mAb induces antibody dependent cellular cytotoxicity (ADCC), leading to significant depletion of NK cells in patients with MM who are in refractory or relapsed stages. Based on these findings, we hypothesized that CD38 mAb could protect allogeneic T cells from NK-mediated cytotoxicity.ResultsHere, we show that in vitro treatment with CD38 mAb effectively depletes 70% of NK cells from peripheral blood mononuclear cells (PBMC) obtained from healthy donors. Importantly, this treatment does not have a significant impact on other hematopoietic cells such as T, B cells and monocytes. Furthermore, we observed a 50% reduction in NK-mediated cytotoxicity against CD38 and b2m double knock-out (DKO) allogeneic T cells when treated with CD38 mAb, compared to the untreated control.Similarly, PBMC isolated from patients with MM and treated with the CD38 mAb regimen displayed a significant decrease in the NK cell population, resulting in impaired cytotoxicity against DKO allogeneic T cells. To further validate our findings, we utilized a mouse model in which human NK cells were engrafted and retained their ability to reject DKO T cells upon injection. In vivo administration of CD38 mAb in these mice showed a dose-dependent depletion of engrafted NK cells in the blood and peripheral tissues, leading to a median reduction of 60% in NK-mediated killing of DKO allogeneic T cells.ConclusionsCollectively, our in vitro and in vivo data strongly support the notion that pharmacological depletion of NK cells through CD38 mAb treatment represents a promising approach to avoid allorejection of CAR-T products. These findings provide valuable insights into the potential use of CD38 mAb as a strategy to enhance the safety and efficacy of allogeneic CAR-T cell therapies.Ethics ApprovalThe mouse study described in this abstract was approved by AstraZeneca’s Ethics Board and met with regards to the humane treatment of animals
Janus kinase (JAK) inhibitors are widely used in the treatment of multiple autoimmune and inflammatory diseases. Immunologic and transcriptomic profiling have revealed major alterations on natural ...killer (NK) cell homeostasis associated with JAK inhibitions, while information on other innate lymphoid cells (ILCs) is still lacking. Herein, we observed that, in mice, the homeostatic pool of liver ILC1 was less affected by JAK inhibitors compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance.
Estrogen receptors (ERs) are a recognized prognostic factor and therapeutic target in breast cancer. The loss of ER expression relates to poor prognosis, poor clinical outcome and impairs the use of ...anti-estrogenic treatment. Histone deacetylase inhibitors are candidate drugs for cancer therapy. Among them, valproic acid (VPA) is a long used and safe anti-epileptic drug. We studied the biological consequences of the chromatin remodeling action of VPA in a normal human mammary epithelial cell line and in ERα-positive and ERα-negative breast cancer cell lines. In these cells and regardless of their ER status, VPA-induced cell differentiation, as shown by increased milk lipids production, decreased expression of the CD44 antigen and growth arrest in the G
0–G
1 phase of the cell cycle. These effects were accompanied by decreased Rb phosphorylation, hyperacetylation of the p21
WAF1/CIP1 gene promoter and increased p21 protein expression. Only in breast cancer cells, cyclin B1 expression was decreased and the cells accumulated also in G
2. ERα expression decreased in ERα-positive, increased in ERα-negative and was unchanged in normal mammary epithelial cells, as did the expression of progesterone receptor, a physiological ERα target. VPA decreased the expression of the invasiveness marker pS2 in ERα-positive breast cancer cells, but did not cause its re-expression in ERα-negative cells. Overall, these data suggest that in both ERα-positive and -negative malignant mammary epithelial cells VPA reprograms the cells to a more differentiated and “physiologic” phenotype that may improve the sensitivity to endocrine therapy and/or chemotherapy in breast cancer patients.
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