Interleukin‐6 limits influenza‐induced inflammation and protects against fatal lung pathology

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza‐induced inflammation. Based on the capacity of interleukin‐6 (IL‐6) to govern both optimal T‐cell responses and inflammatory resolution, we hypothesised that IL‐6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza‐infected wild‐type control and IL‐6‐deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL?6 displayed a profound defect in their ability to mount an anti‐viral T‐cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro‐inflammatory cytokines, IFN‐α and TNF‐α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL‐6 in orchestrating anti‐viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.     

Immune tolerance to hepatitis C virus acquired during engraftment of bone marrow transplant

The CD4+ T-cell response appears to be important for clearance of hepatitis C virus (HCV) in the majority of individuals. We have recently described a series of human leucocyte antigen (HLA)-DR11-restricted T-cell epitopes derived from HCV proteins which enables distinct populations of memory CD4+ T cells to be detected and counted in all nonviraemic HCV subjects. We examined the case of an HLA-DR11+ recipient of a haematopoietic stem-cell transplant who was concurrently infected with HCV from an HLA-DR11+ donor sibling. An acute HCV hepatitis developed and was treated with type I interferon. After successful viral clearance, the recipient demonstrated a selective lack of HCV epitope-specific CD4+ T cells and absence of serological responses compared with the treated donor. The recipient had no evidence of any nonspecific immunosuppression. The subsequent effects of concurrent infection during immune reconstitution are not known in adult humans, but data from murine models suggest this can lead to a skewing of the T-cell repertoire because of thymic selection. From the above observations, it is plausible that the introduction of foreign viral antigen into the thymus may lead to subsequent acquired central tolerance.     

Immunolocalization and endocytosis of the uterine secretory protein, uteroferrin, in pre-implantation pig trophectoderm on day 11 of pregnancy

Summary Uteroferrin is a progesterone-induced, iron-binding glycoprotein secreted by the glandular epithelium of the pig endometrium. Evidence is presented that maternal uteroferrin is present in trophectoderm of pre-implantation pig blastocysts on day 11 of pregnancy. Although [³⁵S]-methionine was not incorporated into uteroferrin during in vitro culture of blastocysts, solubilized tissue extracts from 10–20-mm-diameter blastocysts contained uteroferrin by western blotting with monospecific antiserum to uteroferrin. Uteroferrin was detected in the apical and basolateral cytoplasm of trophectoderm by immunocytochemistry of paraffin-embedded blastocysts. Immunostaining was excluded from cells of the endoderm and the inner cell mass. Further-more, blastocysts internalized fluorescein-labeled uteroferrin from medium during in vitro culture in a temperature-dependent manner. Fluorescent label was located in apical and basolateral cytoplasm in a punctate distribution, and clustered in the supranuclear region of trophectoderm. Addition of a threefold excess of unlabeled uteroferrin to culture medium did not inhibit uptake. These results suggest that the pre-implantation pig blastocyst actively endocytoses uteroferrin from glandular secretions in utero. Uptake was restricted to trophectoderm.     

Examining closure rates of rural hospitals: an assessment of a strategic taxonomy.

This article reports a study of rural hospital failure. Testing a model previously suggested by Drain and Godkin (1996), analysis incorporated four financial ratios used to graphically depict the external environment of a hospital or portfolio of hospitals relative to that of an average facility. Applied to a random sample of rural hospitals, the evidence supports the model's ability to exhibit clustering differences on five of seven selected structure-related variables, and trend activity for the group of hospitals that failed during the period under study.     

Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors

Foxp3⁺ regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3⁺ T-bet⁺ ‘T_H1-like’ Tregs which are thymus-derived Helios⁺ cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the T_H1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69⁺ Tregs are more suppressive than their CD69⁻ counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.     

Clinical characteristics of hepatitis E in a “Non‐Endemic” population

Hepatitis E virus (HEV) is a ribonucleic acid (RNA) virus with predominant fecal oral spread. Traditionally in Western Europe it is associated with travel to endemic countries, but an increasing number of locally acquired cases have been reported throughout England. Patients presenting with acute non‐travel associated HEV infection in south Wales over a 25‐month period were monitored, in an attempt to understand the clinical picture and epidemiology in our patient population. Twenty‐four patients were identified with non‐travel associated HEV infection and studied prospectively. Patient demographics, symptoms, and serial laboratory results were recorded. There was a male/female ratio of 3:1, with a median patient age of 65.5 years old. Patients developed a significant icteric hepatitis (median peak bilirubin: 139 µmol/L, median peak AST: 1,973 IU/L and ALT: 2,021 IU/L), with liver function remaining abnormal for ～7 weeks. All patients in whom HEV RNA was isolated were infected with genotype 3. Forty‐six percent of patients presented during winter months. The data show a group mortality rate of 4.2%, similar to that reported in endemic countries. HEV results in a severe and occasionally fatal hepatitis. Testing for hepatitis E is now recommended in any patient presenting with acute hepatitis of unknown etiology. J. Med. Virol. 82:1899–1902, 2010. © 2010 Wiley‐Liss, Inc.