Educating Britain? Political Literacy and the Construction of National History

Despite the reflexive nature of historical enquiry and the degree of national interconnectness now theorized by historians in the United Kingdom, education debates over history teaching in Britain often yield a comforting defence of Britain's 'island story'. The singular 'island story' is an economical narrative device favoured by politicians and further mediated through newspapers which profit from such national cryogenics. Maintenance of a currency, or crisis, of Britishness can also be contrasted with the relative absence of longitudinal or comparative enquiry into identity and school curricula. In addition, the teaching of states, connections and post-sovereign communities is largely under-theorized, potentially contributing to the sterility of future debates about citizenship, agency and Britain’s wider political reach. It is argued here that the public framing of history as nationhood and the underdevelopment of children’s political literacy are mutually reinforcing conditions by which the state has constructed a stabilizing, yet shifting presence of the ‘national’

Hepatitis B Virus Lacks Immune Activating Capacity, but Actively Inhibits Plasmacytoid Dendritic Cell Function

Chronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFNα production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFNα induction in animal models and patients and chronic HBV patients display impaired IFNα production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFNα gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNFα, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFNα production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV

Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV

In patients with chronic hepatitis B virus (HBV), 2 predominant precursor dendritic cell (DC) subtypes, the myeloid dendritic cell (mDC) and the plasmacytoid dendritic cell (pDC), were recently found to be functionally impaired. HBV DNA was found to be present in the DC subtypes, but no viral replication could be detected. The question remains whether simply the presence of the virus and viral proteins causes this dysfunction of DCs. To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment. Treatment resulted in a mean 5 log(10) decrease in the viral load and normalization of alanine aminotransferase within 3 months. The number of mDCs, but not of pDCs, increased significantly over 6 months of treatment to a level comparable to that of uninfected healthy controls. The allostimulatory capacity of isolated and in vitro matured mDCs increased significantly after 3 months of treatment. Accordingly, mDCs exhibited an increased capacity to produce tumor necrosis factor alpha and interleukin-12 after 3-6 months of treatment. There was no change in interferon alpha production by pDCs during treatment. In conclusion, adefovir treatment results in an improvement in the number and functionality of mDCs, but not of pDCs. Our findings provide clues for the reasons why current antiviral therapy does not lead to consistently sustained viral eradicatio

Restoration of TLR3-Activated Myeloid Dendritic Cell Activity Leads to Improved Natural Killer Cell Function in Chronic Hepatitis B Virus Infection

There is increasing evidence that the function of NK cells in patients with chronic hepatitis B (CHB) infection is impaired. The underlying mechanism for the impaired NK cell function is still unknown. Since myeloid dendritic cells (mDC) are potent inducers of NK cells, we investigated the functional interaction of mDC and NK cells in CHB and the influence of antiviral therapy. Blood BDCA1(+) mDC and NK cells were isolated from 16 healthy controls or 39 CHB patients at baseline and during 6 months of antiviral therapy. After activation of mDC with poly(I (.) C) and gamma interferon (IFN-gamma), mDC were cocultured with NK cells. Phenotype and function were analyzed in detail by flow cytometry and enzyme-linked immunosorbent assay. Our findings demonstrate that on poly(I (.) C)/IFN-gamma-stimulated mDC from CHB patients, the expression of costimulatory molecules was enhanced, while cytokine production was reduced. In cocultures of poly(I (.) C)/IFN-gamma-stimulated mDC and NK cells obtained from CHB patients, reduced mDC-induced NK cell activation (i.e., CD69 expression) and IFN-gamma production compared to those in healthy individuals was observed. Antiviral therapy normalized mDC activity, since decreased expression of CD80 and CD86 on DC and of HLA-E on NK cells was observed, while poly(I (.) C)/IFN-gamma-induced cytokine production by mDC was enhanced. In parallel, successful antiviral therapy resulted in improved mDC-induced NK cell activation and IFN-gamma production. These data demonstrate that CHB patients display a diminished functional interaction between poly(I (.) C)/IFN-gamma activated mDC and NK cells due to impaired mDC function, which can be partially restored by antiviral therapy. Enhancing this reciprocal interaction could reinforce the innate and thus the adaptive T cell response, and this may be an important step in achieving effective antiviral immunity

Hepatitis B Virus Lacks Immune Activating Capacity, but Actively Inhibits Plasmacytoid Dendritic Cell Function

Chronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFN alpha production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFN alpha induction in animal models and patients and chronic HBV patients display impaired IFN alpha production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFN alpha gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNF alpha, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFN alpha production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV

Restoration of TLR3-Activated Myeloid Dendritic Cell Activity Leads to Improved Natural Killer Cell Function in Chronic Hepatitis B Virus Infection

There is increasing evidence that the function of NK cells in patients with chronic hepatitis B (CHB) infection is impaired. The underlying mechanism for the impaired NK cell function is still unknown. Since myeloid dendritic cells (mDC) are potent inducers of NK cells, we investigated the functional interaction of mDC and NK cells in CHB and the influence of antiviral therapy. Blood BDCA1(+) mDC and NK cells were isolated from 16 healthy controls or 39 CHB patients at baseline and during 6 months of antiviral therapy. After activation of mDC with poly(I (.) C) and gamma interferon (IFN-gamma), mDC were cocultured with NK cells. Phenotype and function were analyzed in detail by flow cytometry and enzyme-linked immunosorbent assay. Our findings demonstrate that on poly(I (.) C)/IFN-gamma-stimulated mDC from CHB patients, the expression of costimulatory molecules was enhanced, while cytokine production was reduced. In cocultures of poly(I (.) C)/IFN-gamma-stimulated mDC and NK cells obtained from CHB patients, reduced mDC-induced NK cell activation (i.e., CD69 expression) and IFN-gamma production compared to those in healthy individuals was observed. Antiviral therapy normalized mDC activity, since decreased expression of CD80 and CD86 on DC and of HLA-E on NK cells was observed, while poly(I (.) C)/IFN-gamma-induced cytokine production by mDC was enhanced. In parallel, successful antiviral therapy resulted in improved mDC-induced NK cell activation and IFN-gamma production. These data demonstrate that CHB patients display a diminished functional interaction between poly(I (.) C)/IFN-gamma activated mDC and NK cells due to impaired mDC function, which can be partially restored by antiviral therapy. Enhancing this reciprocal interaction could reinforce the innate and thus the adaptive T cell response, and this may be an important step in achieving effective antiviral immunity

Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells

. Natural killer cells (NK) are one of the key players in the eradication and control of viral infections. Infections with the hepatitis B virus (HBV) may lead to persistence in a subgroup of patients, and impaired NK cell functions have been observed in these patients. Crosstalk with other immune cells has been shown to modulate the function of NK cells. We studied the functional crosstalk between NK cells and plasmacytoid dendritic cell (pDC) and its modulation by HBV. Healthy human peripheral bloodderived NK cells and pDC were purified and cocultured in the presence or absence of HepG2.2.15-derived HBV under various in vitro conditions. The functionality of NK cells was assessed by evaluation of activation markers, cytokine production and cytotoxicity of carboxyfluorescein succinimidyl ester-labelled K562 target cells by flow cytometry or immunoassays. Additionally, the crosstalk was examined using NK and pDC from patients with chronic HBV. The activation of NK cells in cocultures with pDC, as demonstrated by CD69, CD25 and HLA-DR, was not affected by the presence of HBV. Similarly, when cocultured with pDC, the cytotoxic potential of NK cells was not influenced by HBV. However, HBV significantly inhibited pDC-induced IFN-? production by NK cells both in the presence and in the absence of CpG. As HBV did not affect cytokine-induced IFN-? production by NK cells cultured alone, the suppressive effect of HBV on NK cell function was mediated via interference with pDCNK cell interaction. In contrast to other viruses, HBV does not activate pDCNK cell interaction but inhibits pDC-induced NK cell function. In parallel with NK cells of patients with chronic HBV, which show diminished cytokine production with normal cytotoxicity, HBV specifically suppressed pDC-induced IFN-? production by NK cells without affecting their cytolytic ability. These data demonstrate that HBV modulates pDCNK cell crosstalk, which may contribute to HBV persistence

Kupffer cells express a unique combination of phenotypic and functional characteristics compared with splenic and peritoneal macrophages

The immunostimulatory role of Kupffer cells in various inflammatory liver diseases is still not fully understood. In this study, phenotypic and functional aspects of Kupffer cells from healthy C57BL/6 mice were analyzed and compared with those of splenic and peritoneal macrophages to generate a blueprint of the cells under steady-state conditions. In the mouse liver, only one population of Kupffer cells was identified as F4/80(high)CD11b(low) cells. We observed that freshy isolated Kupffer cells are endocytic and show a relatively high basal ROS content. Interestingly, despite expression of TLR mRNA on Kupffer cells, ligation of TLR4, TLR7/8, and TLR9 resulted in a weak induction of IL-10, low or undetectable levels of IL-12p40 and TNF, and up-regulation of CD40 on the surface. Kupffer cells and splenic macrophages show functional similarities, in comparison with peritoneal macrophages, as reflected by comparable levels of TLR4, TLR7/8, and TLR9 mRNA and low or undetectable levels of TNF and IL-12p40 produced upon TLR ligation. The unique, functional characteristics of Kupffer cells, demonstrated in this study, suggest that Kupffer cells under steady-state conditions are specialized as phagocytes to clear and degrade particulates and only play a limited immunoregulatory role via the release of soluble mediators. J. Leukoc. Biol. 92: 723-733; 2012