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261.
OBJECTIVE
Natural killer (NK) cells from NOD mice have numeric and functional abnormalities, and restoration of NK cell function prevents autoimmune diabetes in NOD mice. However, little is known about the number and function of NK cells in humans affected by type 1 diabetes. Therefore, we evaluated the phenotype and function of NK cells in a large cohort of type 1 diabetic children.RESEARCH DESIGN AND METHODS
Peripheral blood mononuclear blood cells were obtained from subjects whose duration of disease was between 6 months and 2 years. NK cells were characterized by flow cytometry, enzyme-linked immunosorbent spot assays, and cytotoxicity assays. Signaling through the activating NK cell receptor, NKG2D, was assessed by immunoblotting and reverse-phase phosphoprotein lysate microarray.RESULTS
NK cells from type 1 diabetic subjects were present at reduced cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the cytokines interleukin (IL)-2 and IL-15. Analysis before and after IL-2 stimulation revealed that unlike NK cells from nondiabetic control subjects, NK cells from type 1 diabetic subjects failed to downregulate the NKG2D ligands, major histocompatibility complex class I–related chains A and B, upon activation. Moreover, type 1 diabetic NK cells also exhibited decreased NKG2D-dependent cytotoxicity and interferon-γ secretion. Finally, type 1 diabetic NK cells showed clear defects in NKG2D-mediated activation of the phosphoinositide 3-kinase–AKT pathway.CONCLUSIONS
These results are the first to demonstrate that type 1 diabetic subjects have aberrant signaling through the NKG2D receptor and suggest that NK cell dysfunction contributes to the autoimmune pathogenesis of type 1 diabetes.Type 1 diabetes is a multifactorial autoimmune disease characterized by T-cell destruction of insulin-producing β-cells and the eventual loss of glucose homeostasis (1). Although both genetic and environmental factors contribute to the breakdown of immunological self-tolerance, and many of the hallmarks of disease in humans are recapitulated in the NOD mouse (2), the precise mechanisms driving pathogenesis remain unclear. Current evidence suggests that natural killer (NK) cells may be both important regulators and inducers of autoimmune diseases (3–8), and several reports (9–13) have documented that NK cells in NOD mice are impaired compared with those in healthy mice. Although investigations of human subjects with type 1 diabetes have described NK cell alterations, these studies have been limited in size, and the mechanisms underlying the phenotype have not been identified (14–20).NK cells are well known to have critical roles against viral, bacterial, and parasitic pathogens through the direct killing of infected cells and the production of proinflammatory cytokines such as interferon (IFN)-γ and tumor necrosis factor-α (21). A balance of signals received through a diverse array of activating and inhibitory surface receptors determines whether NK cells evoke their potent effector functions toward a target (22). Some activating receptors are known to bind foreign viral proteins, whereas others recognize self-proteins that are induced upon cellular stress (23). A prominent activating receptor involved in the recognition of stressed, infected, or transformed cells is the C-type lectin NKG2D (24). Signaling by NKG2D is mediated through its association with the transmembrane adaptor protein DNAX-activating protein of 10 kDa (DAP10). Although the NKG2D-DAP10–signaling complex is unusual because it lacks an immunoreceptor tyrosine–based activation motif, DAP10 does contain a “YxxM” motif that functions to recruit the p85 subunit of phosphoinositide3-kinase (PI3K) upon tyrosine phosphorylation (25,26).Recent work (27) has shown that NOD NK cells exhibit decreased NKG2D-dependent functioning and that this deficit may contribute to disease in this murine model. Activated NOD NK cells, but not C57BL/6 NK cells, were found to maintain NKG2D ligand expression, resulting in the downmodulation of the NKG2D receptor through a mechanism dependent on the “YxxM” motif of DAP10 (27). Reduced NKG2D expression on NOD NK cells was mirrored by decreased cytotoxic and cytokine-secreting functions (27). Notably, we have previously shown that administration of complete Freund adjuvant (CFA) to NOD mice causes NK cells to downregulate NKG2D ligand expression and that the phenomenon is correlated with increased NKG2D receptor expression and heightened NK cell functions (28,29). In addition, NK cells rejuvenated by CFA treatment were able to protect NOD SCID (severe combined immune deficiency) mice from the development of autoimmune diabetes following the adoptive transfer of these hosts with diabetogenic splenocytes (28,29). Collectively, these findings suggest that the chronic exposure of NOD NK cells to NKG2D ligands results in their desensitization and also that augmentation of NK cell function protects NOD mice from disease.Given the important regulatory role of NK cells in diabetes of the NOD mouse, we sought to determine whether numeric or functional deficits also are present among human type 1 diabetic NK cells. Here, we report that NK cells from children with type 1 diabetes constitute a significantly reduced fraction of peripheral mononuclear cells relative to age-matched nondiabetic control subjects and that these NK cells are poorly responsive to interleukin (IL)-2/IL-15 stimulation. Analogous to findings in the NOD mouse (27–29), dysregulated expression of the NKG2D ligands on activated type 1 diabetic NK cells is present and associated with both impaired NKG2D-mediated effector function and signaling. These results suggest that NK cell dysfunction and aberrant NKG2D signaling may be a consequence of, or contribute to, the pathogenesis of type 1 diabetes. 相似文献262.
263.
Pogka V Kossivakis A Kalliaropoulos A Moutousi A Sgouras D Panagiotopoulos T Chrousos GP Theodoridou M Syriopoulou VP Mentis AF 《Journal of medical virology》2011,83(10):1841-1848
Viruses are the major cause of pediatric respiratory tract infection and yet many suspected cases of illness remain uncharacterized. This study aimed to determine the distribution of several respiratory viruses in children diagnosed as having influenza-like illness, over the winter period of 2005-2008. Molecular assays including conventional and real time PCR protocols, were employed to screen respiratory specimens, collected by clinicians of the Influenza sentinel system and of outpatient pediatric clinics, for identification of several respiratory viruses. Of 1,272 specimens tested, 814 (64%) were positive for at least one virus and included 387 influenza viruses, 160 rhinoviruses, 155 respiratory syncytial viruses, 95 adenoviruses, 81 bocaviruses, 47 parainfluenza viruses, 44 metapneumoviruses, and 30 coronaviruses. Simultaneous presence of two or three viruses was observed in 173 of the above positive cases, 21% of which included influenza virus and rhinovirus. The majority of positive cases occurred during January and February. Influenza virus predominated in children older than 1 year old, with type B being the dominant type for the first season and subtypes A/H3N2 and A/H1N1 the following two winter seasons, respectively. Respiratory syncytial virus prevailed in children younger than 2 years old, with subtypes A and B alternating from year to year. This is the most comprehensive study of the epidemiology of respiratory viruses in Greece, indicating influenza, rhinovirus and respiratory syncytial virus as major contributors to influenza-like illness in children. 相似文献
264.
265.
Localization of MMP‐9 in multinuclear giant cells in keloids after treatment with 5‐fluorouracil with or without combination of cryotherapy and cryotherapy alone 下载免费PDF全文