Cytomegalovirus (CMV) seropositivity is associated with increased risk for atherosclerotic disease in patients with end-stage renal disease. This association is due to a unique peripheral blood CD4(+) T cell population which lack CD28 (CD4(+)CD28(-) T cells). Here we found that this patient population has a significant age-dependent increase of CD4(+)CD28(-) T cells that comprise over half of the circulating CD4 T cells in some. Patients over 50 years of age have a 50-fold higher percentage of CD4(+)CD28(-) T cells compared to seronegative patients and a 5-fold higher percentage when compared to seropositive healthy controls. Stimulation by CMV-antigen or by polyclonal stimulation using PMA and ionomycin showed that CD4(+)CD28(-) cells in patients with end stage renal disease degranulated and secreted interferon gamma thus indicating that they are cytolytic. The average anti-CMV IgG titer displayed a remarkable age-dependent increase only in patients with end stage renal disease. These findings are highly suggestive of repetitive antigenic stimulation of the immune system in patients with end stage disease by subclinical CMV reactivation which might contribute to increased atherosclerotic risk.
Serologic responses to T cell-dependent vaccinations are severely attenuated in patients with ESRD, but the reasons for this is unknown. In this study, a detailed analysis of antigen-specific T cell responses was performed. Patients on hemodialysis and age-and gender-matched healthy control subjects were vaccinated with hepatitis B surface antigen (HBsAg), antigen-specific CD4 ϩ T cells were monitored at regular intervals with intracellular cytokine staining and proliferation assays. IL-2-and IFN-␥-producing CD4 ϩ T cells were identified as either central or effector memory CD4 ϩ T cells using antibodies directed against CD45RO and the chemokine receptor CCR7. Control subjects mounted a memory T cell response comprising both central and effector memory CD4 ϩ T cells, with the central memory response occurring 1 wk before the effector memory response. IL-2 ϩ HBsAg-specific memory CD4 ϩ T cells were primarily detected within the effector population. Patients with ESRD showed a delayed response of IL-2-and IFN-␥-producing central memory CD4 ϩ T cells, but their maximal responses were similar to those of control subjects. In contrast, patients with ESRD produced only 6.3% of the IL-2 ϩ HBsAgspecific effector memory CD4 ϩ T cells produced by control subjects (0.5 Ϯ 0.2 ϫ 10 4 /L versus 8 Ϯ 3.5 ϫ 10 4 /L; P Ͻ 0.001), and this impaired response correlated with antigen-specific T cell proliferation and anti-HBsAg IgG titers. In conclusion, the production of antigen-specific effector memory CD4 ϩ T cells after vaccination, which is critical to achieve an adequate humoral response, is severely impaired in patients with ESRD. 19: 148319: -149019: , 200819: . doi: 10.1681 Patients with ESRD show clinical signs of an immune defect characterized by an increased susceptibility for infections and a decreased immune response to T cell-dependent antigens (e.g., hepatitis B vaccination). The precise mechanisms responsible for this immune defect are unknown; however, changes in T cell subsets and/or function may contribute substantially to the impaired cellular immune response, because ESRD is associated with lymphopenia occurring in the B and T lymphocyte compartment. [1][2][3] The available data on B cell function of patients with ESRD do not indicate an impaired function. 4 The functional data on peripheral T cells in patients with ESRD are conflicting and obtained by using the unfractionated bulk of circulating T cells. 1,3,5,6 Developments in T cell research and availability of various chemokine receptors, such as CCR7, have enabled a dissection of the T lymphocytes in different subsets. 7,8 The major T cell compartments that can be distinguished are the naive T cells (Tnaive; antigen inexperienced) and the antigen ex- J Am Soc Nephrol
We previously found that low shear stress (LSS) induces atherosclerotic plaques in mice with increased lipid and matrix metalloproteinase content and decreased vascular smooth muscle and collagen content. Here, we evaluated the role of chemokines in this process, using an extravascular device inducing regions of LSS, high shear stress, and oscillatory shear stress (OSS) in the carotid artery. One week of shear stress alterations induced expression of IFN-γ-inducible protein-10 (IP-10) exclusively in the LSS region, whereas monocyte chemoattractant protein-1 (MCP-1) and the mouse homolog of growth-regulated oncogene α (GRO-α) were equally upregulated in both LSS and OSS regions. After 3 weeks, GRO-α and IP-10 were specifically upregulated in LSS regions. After 9 weeks, lesions with thinner fibrous caps and larger necrotic cores were found in the LSS region compared with the OSS region. Equal levels of MCP-1 expression were observed in both regions, while expression of fractalkine was found in the LSS region only. Blockage of fractalkine inhibited plaque growth and resulted in striking differences in plaque composition in the LSS region. We conclude that LSS or OSS triggers expression of chemokines involved in atherogenesis. Fractalkine upregulation is critically important for the composition of LSS-induced atherosclerotic lesions.
BackgroundThere is increasing evidence that unacylated ghrelin (UAG) improves insulin sensitivity and glucose homeostasis; however, the mechanism for this activity is not fully understood since a UAG receptor has not been discovered.Methodology/Principal FindingsTo assess potential mechanisms of UAG action in vivo, we examined rapid effects of UAG on genome-wide expression patterns in fat, muscle and liver of growth hormone secretagogue receptor (GHSR)-ablated mice using microarrays. Expression data were analyzed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Regulation of subsets of these genes was verified by quantitative PCR in an independent experiment. UAG acutely regulated clusters of genes involved in glucose and lipid metabolism in all three tissues, consistent with enhancement of insulin sensitivity.Conclusions/SignificanceFat, muscle and liver are central to the control of lipid and glucose homeostasis. UAG rapidly modulates the expression of metabolically important genes in these tissues in GHSR-deleted mice indicating a direct, GHSR-independent, action of UAG to improve insulin sensitivity and metabolic profile.
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