Increased susceptibility to infections, particularly respiratory viral infections, is a hallmark of advancing age. The underlying mechanisms are not well understood, and there is a scarcity of information regarding the contribution of the innate immune system, which is the first line of defense against infections. In the present study, we have investigated the effect of advancing age on plasmacytoid dendritic cell (PDC) function because they are critical in generating a robust antiviral response via the secretion of interferons (IFN). Our results indicate that PDCs from the aged are impaired in their capacity to secrete IFN-I in response to influenza virus and CPG stimulation. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated impaired phosphorylation of transcription factor, IRF-7. Furthermore, aged PDCs were observed to be impaired in their capacity to induce perforin and granzyme in CD8 T cells. Comparison of the antigen-presenting capacity of aged PDC with young PDC revealed that PDCs from aged subjects display reduced capacity to induce proliferation and IFN-gamma secretion in CD4 and CD8 T cells as compared with PDCs from young subjects. In summary, our study demonstrates that advancing age has a profound effect on PDC function at multiple levels and may therefore, be responsible for the increased susceptibility to infections in the elderly.
Dengue virus (DENV) is the most significant human arboviral pathogen and causes ∼400 million infections in humans each year. In previous work, we observed that mast cells (MC) mediate vascular leakage during DENV infection in mice and that levels of MC activation are correlated with disease severity in human DENV patients (St John et al., 2013b). A major risk factor for developing severe dengue is secondary infection with a heterologous serotype. The dominant theory explaining increased severity during secondary DENV infection is that cross-reactive but non-neutralizing antibodies promote uptake of virus and allow enhanced replication. Here, we define another mechanism, dependent on FcγR-mediated enhanced degranulation responses by MCs. Antibody-dependent mast cell activation constitutes a novel mechanism to explain enhanced vascular leakage during secondary DENV infection.DOI: http://dx.doi.org/10.7554/eLife.05291.001
A characteristic clinical feature of dengue virus infection is thrombocytopenia, though its underlying mechanism is not definitively determined. By adoptive transfer of human CD34؉ fetal liver cells into immunodeficient mice, we have constructed humanized mice with significant levels of human platelets, monocytes/macrophages, and hepatocytes. Infection of these mice with both lab-adapted and clinical strains of dengue virus induces characteristic human hematological changes, including transient leukopenia and thrombocytopenia. We show that the specific depletion of human platelets is not mediated by antibodies in the periphery or reduced production of human thrombopoietin in the liver but reduction of human megakaryocytes and megakaryocyte progenitors in the bone marrow of the infected mice. These findings identify inhibition of platelet production in the bone marrow as a key mechanism underlying dengue-induced thrombocytopenia and suggest the utility of the improved humanized mouse model in studying dengue virus infection and pathogenesis in a human cell context. Dengue is an acute febrile illness caused by dengue virus (DENV), which is spread through mosquito vectors. Dengue manifests in a wide range of clinical symptoms and is usually accompanied by hematological changes, such as leukopenia and thrombocytopenia in mild cases and plasma leakage, hemorrhage, or organ impairment, such as liver damage, in severe cases (1). Even after decades of research, the cause of thrombocytopenia or platelet drop during dengue disease is still unclear.Platelets are small (2 to 3 m), anucleated cells which play a major role in homeostasis and coagulation. They are derived from megakaryocytes, which are large (30-to 100-m), nucleated, polyploid cells. Megakaryocytes differentiate from hematopoietic stem cells in the bone marrow (BM) (2, 3) through progenitor cells known as megakaryocytic CFU (CFU-MK) that express CD34 and CD41 (4). Thrombopoietin (TPO) is the principal cytokine that drives the expansion and differentiation of the progenitors to megakaryocytes (3, 5) and is produced mainly by hepatocytes in the liver (6).Two hypotheses have been proposed to explain thrombocytopenia during DENV infection: clearance of platelets from periphery and loss of platelet production in the BM. The peripheral mechanism is thought to involve antibody-mediated depletion where the antibody-opsonized DENV binds to platelets, which are then cleared by activated immune cells (7,8). Another possibility is that antibodies to the viral nonstructural protein (NS1) crossreact with autoantigens expressed on platelets, which binds and tags them for clearance (9, 10). Alternatively, platelet production in the BM could be suppressed, although the evidence supporting this hypothesis is lacking due to difficulties in obtaining BM biopsy specimens from acute dengue patients. One report shows that the BM was hypocellular early during dengue disease but later became hypercellular, as if recovered from acute suppression (11). There is also evidence that DENV i...
The immune system has evolved to mount immune responses against foreign pathogens and to remain silent against self-antigens. A balance between immunity and tolerance is required as any disturbance may result in chronic inflammation or autoimmunity. Dendritic cells (DCs) actively participate in maintaining this balance. Under steady-state conditions, DCs remain in an immature state and do not mount an immune response against circulating self-antigens in the periphery, which maintains a state of tolerance. By contrast, foreign antigens result in DC maturation and DC-induced T-cell activation. Inappropriate maturation of DCs due to infections or tissue injury may cause alterations in the balance between the tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases. This article provides an overview of the effects of advancing age on DC functions and their implications in autoimmunity.
Medical gases are pharmaceutical molecules which offer solutions to a wide array of medical needs. This can range from use in burn and stroke victims to hypoxia therapy in children. More specifically however, gases such as oxygen, helium, xenon, and hydrogen have recently come under increased exploration for their potential theraputic use with various brain disease states including hypoxia-ischemia, cerebral hemorrhages, and traumatic brain injuries. As a result, this article will review the various advances in medical gas research and discuss the potential therapeutic applications and mechanisms with regards to the field of neurobiology.
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