Subject(s)
Altitude , Avicennia/physiology , Forests , Rhizophoraceae/physiology , Seawater/analysis , WetlandsSubject(s)
Advisory Committees/organization & administration , Disaster Planning , Federal Government , Policy Making , Science , Advisory Committees/history , Disaster Planning/history , Germany/epidemiology , Gulf of Mexico , Hemolytic-Uremic Syndrome/diagnosis , Hemolytic-Uremic Syndrome/epidemiology , Hemolytic-Uremic Syndrome/microbiology , Hemolytic-Uremic Syndrome/prevention & control , History, 21st Century , Humans , Iceland , Petroleum Pollution/history , Public Policy/history , Science/history , United Kingdom , United States , Volcanic Eruptions/history , WorkforceABSTRACT
MicroRNAs (miRNAs) are an important class of cellular regulators that modulate gene expression and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentiation, they modulate effector cell function, and they are implicated in the maintenance of homeostasis. Dendritic cells (DCs), the professional APCs involved in the coordination of adaptive immune responses, are also regulated by miRNAs. Some DC-relevant miRNAs, including miR-155 and miR-146a, are shared with other immune cells, whereas others have been newly identified. In this review, we summarize the current understanding of where miRNAs are active during DC development from myeloid precursors and differentiation into specialized subsets, and which miRNAs play roles in DC function.
Subject(s)
Cell Differentiation/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Gene Expression Regulation/immunology , MicroRNAs/immunology , Animals , HumansSubject(s)
Disease Outbreaks/prevention & control , Escherichia coli Infections/epidemiology , Escherichia coli Infections/prevention & control , Population Surveillance/methods , Escherichia coli/isolation & purification , Escherichia coli/pathogenicity , Escherichia coli Infections/diagnosis , Escherichia coli Infections/microbiology , European Union , Food Microbiology/methods , Germany/epidemiology , Humans , Politics , Vegetables/microbiologyABSTRACT
A hallmark of T cell-dependent immune responses is the progressive increase in the ability of serum antibodies to bind antigen and provide immune protection. Affinity maturation of the antibody response is thought to be connected with the preferential survival of germinal centre (GC) B cells that have acquired increased affinity for antigen via somatic hypermutation of their immunoglobulin genes. However, the mechanisms that drive affinity maturation remain obscure because of the difficulty in tracking the affinity-based selection of GC B cells and their differentiation into plasma cells. We describe a powerful new model that allows these processes to be followed as they occur in vivo. In contrast to evidence from in vitro systems, responding GC B cells do not undergo plasma cell differentiation stochastically. Rather, only GC B cells that have acquired high affinity for the immunizing antigen form plasma cells. Affinity maturation is therefore driven by a tightly controlled mechanism that ensures only antibodies with the greatest possibility of neutralizing foreign antigen are produced. Because the body can sustain only limited numbers of plasma cells, this "quality control" over plasma cell differentiation is likely critical for establishing effective humoral immunity.
Subject(s)
B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , Cell Differentiation/immunology , Germinal Center/cytology , Germinal Center/immunology , Plasma Cells/immunology , Amino Acid Substitution/genetics , Animals , Genes, Immunoglobulin , Immunoglobulin Heavy Chains/genetics , Mice , Mice, Transgenic , Plasma Cells/cytologyABSTRACT
Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eµ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eµ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.
Subject(s)
Cell Transformation, Neoplastic/genetics , Drug Resistance, Neoplasm , Hematopoietic Stem Cells/pathology , Lymphoma/drug therapy , Lymphopoiesis , Proto-Oncogene Proteins c-bcl-2/genetics , Up-Regulation , Animals , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/therapeutic use , Apoptosis Regulatory Proteins/metabolism , Autoimmunity , Bcl-2-Like Protein 11 , Cell Survival , Cyclophosphamide/pharmacology , Cyclophosphamide/therapeutic use , Hematopoiesis , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Lymphocytes/cytology , Lymphocytes/metabolism , Lymphocytes/pathology , Lymphoma/genetics , Lymphoma/pathology , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myeloid Cell Leukemia Sequence 1 Protein , Myeloid Cells/cytology , Myeloid Cells/metabolism , Myeloid Cells/pathology , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-myc/metabolismABSTRACT
The selection of an appropriate Ig isotype is critical for an effective immune response against pathogens. Isotype regulation is sensitive to external signals, particularly cytokines secreted by Th cells. For example, IL-4 induces isotype switching to IgG1 via a STAT6-dependent signaling pathway. In this study, we show that BCR ligation also induces IgG1 switching in mouse B cells. The extent of switch induction by Ag is affinity-dependent, and high-affinity Ag binding leads to IgG1 switching levels comparable to those induced by saturating IL-4. However, the Ag-induced IgG1 switch does not require additional cytokine signals and occurs in a STAT6-independent manner. Thus, BCR ligation represents a novel pathway for direct isotype switching leading to IgG1 secretion.
Subject(s)
Antibody Formation/immunology , Immunoglobulin Class Switching/immunology , Lymphocyte Activation/immunology , Receptors, Antigen, B-Cell/immunology , Animals , Antibody Affinity/immunology , Antigens/immunology , Cell Separation , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Mice , Mice, Inbred C57BL , Muramidase/immunology , Reverse Transcriptase Polymerase Chain ReactionSubject(s)
Animal Testing Alternatives , Toxicity Tests/methods , Toxicology/methods , Animal Testing Alternatives/methods , Animal Testing Alternatives/standards , Animal Testing Alternatives/trends , Animals , Dogs , Drug Industry/methods , Toxicity Tests/economics , Toxicity Tests/trends , Toxicology/trendsSubject(s)
Enteropathogenic Escherichia coli/isolation & purification , Escherichia coli Infections/epidemiology , Escherichia coli Infections/microbiology , Berlin/epidemiology , Disease Notification/statistics & numerical data , Disease Outbreaks/prevention & control , Enteropathogenic Escherichia coli/genetics , Enteropathogenic Escherichia coli/pathogenicity , Escherichia coli Infections/complications , Escherichia coli Infections/diagnosis , Europe/epidemiology , Food Contamination , Humans , Time FactorsSubject(s)
Museums , Natural History , Animals , Dinosaurs , Humans , Hungary , Military Personnel/education , Mummies , Natural History/organization & administration , Universities , WorkforceABSTRACT
Murine dendritic cells (DC) and macrophages respond to bacterial CpG DNA through toll-like receptor 9 (TLR9). Although it is frequently assumed that bacterial DNA is a direct stimulus for B cells, published work does not reliably show responses of purified B cells. Here we show that purified splenic B cells did not respond to Escherichia coli DNA with induction of CD86, despite readily responding to single-stranded (ss) phosphodiester CpG oligodeoxynucleotides (ODN). This was due to a combination of weak responses to both long and double-stranded (ds) DNA. B-cell DNA uptake was greatly reduced with increasing DNA length. This contrasts with macrophages where DNA uptake and subsequent responses were enhanced with increasing DNA length. However, when DNA was physically linked to hen egg lysozyme (HEL), HEL-specific B cells showed efficient uptake of DNA, and limited proliferation in response to the HEL-DNA complex. We propose that, in the absence of other signals, B cells have poor uptake and responses to long dsDNA to prevent polyclonal activation. Conversely, when DNA is physically linked to a B-cell receptor (BCR) ligand, its uptake is increased, allowing TLR9-dependent B-cell activation in an antigen-specific manner. We could not generate fragments of E. coli DNA by limited DNaseI digestion that could mimic the stimulatory effect of ss CpG ODN on naïve B cells. We suggest that the frequently studied polyclonal B-cell responses to CpG ODN are relevant to therapeutic applications of phosphorothioate-modified CpG-containing ODN, but not to natural responses to foreign or host dsDNA.
Subject(s)
Antigens/immunology , B-Lymphocytes/immunology , B-Lymphocytes/microbiology , DNA, Bacterial/immunology , Toll-Like Receptor 9/immunology , Animals , Cell Line , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligodeoxyribonucleotides/chemical synthesis , Oligodeoxyribonucleotides/immunology , Spleen/cytology , Spleen/immunologyABSTRACT
Translation of research advances into clinical practice for at-risk communities is important to eliminate disease disparities. Adult type 2 diabetes prevalence in the US territory of American Samoa is 21.5%, but little intervention research has been carried out there. We discuss our experience with cultural translation, drawing on an emerging implementation science, which aims to build a knowledge base on adapting interventions to real-world settings. We offer examples from our behavioral intervention study, Diabetes Care in American Samoa, which was adapted from Project Sugar 2, a nurse and community health worker intervention to support diabetes self-management among urban African Americans. The challenges we experienced and solutions we used may inform adaptations of interventions in other settings.