Search

Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin-IELs) in the duodenum. In ~50% of patients with RCDII, these Lin-IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of thesemalignant Lin-IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin-IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL. Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin-IELs and CD3-CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation. [ABSTRACT FROM AUTHOR]

Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3β loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity. [ABSTRACT FROM AUTHOR]

Objective Refractory coeliac disease type II (RCDII) is a severe complication of coeliac disease (CD) characterised by aberrant intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3-CD7+icCD3+ phenotype. In approximately 40% of patients with RCDII these lymphocytes develop into an invasive lymphoma. In the current study we aimed to identify the physiological counterpart of these cells. Design RCDII cell lines were compared with T-cell receptor positive (TCR+) IEL (T-IEL) lines by microarray analysis, real-time quantitative PCR and flow cytometry. This information was used to identify cells with an RCDIIassociated phenotype in duodenal biopsies from nonrefractory individuals by multicolour flow cytometry. Results RCDII lines were transcriptionally distinct from T-IEL lines and expressed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3-CD7+icCD3+ phenotype, the RCDII lines were distinguishable from other lymphocyte subsets by the absence of CD56, CD127 and CD34. Cells matching this surface lineage-negative (Lin-) CD7+CD127-CD34- phenotype expressed a functional interleukin-15 (IL-15) receptor and constituted a significant proportion of IELs in duodenal specimens of patients without CD, particularly children, and were also found in the thymus. In patients without CD, the Lin-CD7+CD127-CD34- subset was one of four subsets within the CD3-CD7+icCD3+ population that could be distinguished on the basis of differential expression of CD56 and/or CD127. Conclusion Our studies indicate that the CD3-CD7+icCD3+ population is heterogeneous and reveal the existence of a Lin- subset that is distinct from T, B, NK and lymphoid tissue inducer cells. We speculate that this IL-15 responsive population represents the physiological counterpart of aberrant cells expanded in RCDII and transformed in RCDII-associated lymphoma. [ABSTRACT FROM AUTHOR]

The textual representation of violence demands an ethical response from the reader, this being influenced to a large extent by contextual expectations of the text's verifiability, the linguistic register of the text, and the inter-subjective ethical framework at the moment of reading. The aesthetic evaluation of the narrative, which is closely associated with its linguistic features, is also closely related to this ethical perspective. However, normative systems of ethics often seem inadequate in the face of the plurality of meaning and possibilities inherent in representations of violence. This article considers the potential of postmodern ethics to generate an appropriate ethical and aesthetic response to such representations by investigating four texts which represent the violence of the Holocaust in dissimilar ways. Through such an approach, the reader is better equipped to confront the ethical dilemmas and contradictions inherent within these texts, in a manner that cannot be limited, categorised, bifurcated or rendered harmless by the processes of normative ethical systems. Recognition of postmodern ethical characteristics such as ambiguity, aporia, non-universalisation, and the encounter with the Other, results in a more nuanced flexibility of moral outlook, allowing the reader to generate a subtler evaluation of the ethical difficulties suggested by the textual representation of violence. [ABSTRACT FROM AUTHOR]

The article features Louise Arbour, the current United Nations (UN) High Commissioner for Human Rights and a former Supreme Court justice of Canada and was a graduate of the Montreal University. She says that the most dramatic event in his political career was the enactment of the War Measures Act. She once confronted then Foreign Affairs Minister Lloyd Axworthy on the margins of the North Atlantic Treaty Organization (NATO) ministerial meeting in 1999 during the heat of the Kosovo crisis. She replaced Sergio Vieria de Mello as high commissioner when he was killed in August 2003 in the bombing of the UN headquarters in Baghdad, Iraq.

In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the diseaseassociated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these. Moreover, gluten presentation by HLA-DQ2 homozygous antigen-presenting cells was superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells in terms of T cell proliferation and cytokine secretion. Gluten presentation by HLA-DQ2.5/2.2 heterozygous antigen-presenting cells induced intermediate T cell stimulation. These results correlated with peptide binding to the antigenpresenting cells. Finally, we demonstrate that HLA-DQ trans dimers formed in HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. Our findings explain the strongly increased risk of disease development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals, and they are indicative of a quantitative model for disease development, where HLA-DQ expression and the available number of T cell-stimulatory gluten peptides are critical limiting factors. This model may have important implications for disease prevention. [ABSTRACT FROM AUTHOR]

Human monocyte-derived dendritic cells (DC) use mannose receptor (MR)-mediated endocytosis for efficient antigen capture and targeting to the endosomal/lysosomal compartment. Active biosynthesis of the MR takes place in such cells. We now report that a substantial percentage (up to 20%) of these newly synthesized MR are secreted into the culture medium. The secretion of the soluble MR (sMR) was found to be proportional to the rate of synthesis. The addition of the inflammatory mediator lipopolysaccharide (LPS) to DC, known to induce maturation, strongly reduced MR synthesis, expression and shedding of the MR. The sMR is ~10 kDa smaller than the membrane-bound form, but contains an intact N-terminus, indicating the lack of the cytoplasmic and transmembrane region. The sMR appeared to be directly generated from the cell-bound form, indicative of proteolytic cleavage. Importantly, the sMR has maintained its mannose-binding properties since it was capable of binding a mannosylated ligand. The high amount of sMR released by DC and its ability to bind mannosylated ligand might indicate that this molecule plays a role in the transport of mannosylated proteins from the site of inflammation to other parts of the body. Whether that contributes to the generation of immune responses remains to be determined. [ABSTRACT FROM PUBLISHER]

The inexperienced cross-cultural manager may be seriously misled when he interprets Thai labour processes using assumptions drawn from other societies. On these assumptions Thai labour processes seem unsophisticated and exploitative. Despite power differences, which can be exploited, Thais believe that a coincidence of interest between the parties is the norm. That rests upon the productive significance which they attach to harmonious workplace interactions, which in turn explains an emphasis upon company level dialogue, and a distrust of formal or legalised procedures. Although the dangers of unstructured relationships are recognised, labour analysts are cautious about relinquishing the advantages of traditional relationships. [ABSTRACT FROM AUTHOR]

The population of HLA-A2-positive individuals, currently considered serologically homogeneous, can be divided into three subtypes on the basis of antigen recognition by various HLA-A2-specific cytotoxic T lymphocytes (CTLs). When these three types of HLA-A2 antigens were analyzed biochemically, they were found to be distinct. Isoelectric focusing (IEF) of HLA antigens digested with neuraminidase (NANAse) suggested that the difference(s) reside in the polypeptide backbone of the HLA-A2 heavy chain. Biochemical analysis distinguishes three distinct categories of HLA-A2 antigens: (1) a major subtype, designated HLA-A2.I, (2) a minor subtype, designated HLA-A2.II, possessing a more basic isoelectric point (IEP) and (3) a minor HLA-A2 subtype more acidic in its IEP than HLA-A2.I, designated HLA-A2.III. A fourth HLA-A2 subtype could be defined by discordance between cell-mediated lympholysis (CML) typing and biochemical analysis. The latter HLA-A2 antigen was defined as a variant by CTL, but was biochemically indistinguishable from the major subtype HLA-A2.I. [ABSTRACT FROM AUTHOR]

Assessing whether the other party is likely to fulfill all obligations can he arduous when a transaction is international. The mechanisms that underpin compliance with agreements, and the functional detail of these mechanisms, may vary in relative importance between countries, perplexing the foreign operative. Additionally, a foreigner may suffer from informational constraints, communication distortions, and difficulty in achieving full acceptance in the local business culture. [ABSTRACT FROM AUTHOR]

Focuses on a study that compared the absorption and utilization of thiamine propyl disulfide with that of thiamine hydrochloride. Materials and methods; Results; Discussion.

Australian studies of industrial, labour and economic history in the second half of the 19th century have long relied on manufacturing statistics published annually in the colonial Statistical Registers. This reliance could become even more pronounced through the influence of Professor N. G. Butlin, who drew heavily upon these sources. This article suggests, however, that these Statistic Registers are unreliable and indeed—for certain purposes—misleading. If this is so, some popular historical interpretations will have to be reviewed. We shall have to reconsider why Victoria adopted a protective tariff in the 1860s and also reconsider the subsequent effects of the tariff. We shall have to re-examine the effects of the gold-rushes on the growth of manufacturing. We shall have to reject much of Butlin's pioneering work on the rise of manufacturing in Victoria and Australia between 1861 and 1901, and we shall have to reconsider the role of manufacturing in the boom of the 1880s and the recovery from the depression of the 1890s. The statistics and the estimates based on them are also relevant to such questions as how manufacturing influenced the growth of cities, how urban living standards moved, and how the economic and social climate affected the growth of unionism and welfare legislation. Moreover, unless the manufacturing statistics are handled with a new discretion, the infection of error may spread to problems in local history, industrial history, colonial and national history; for these statistics are as basic to industrial history as detailed voting returns are to political history. [ABSTRACT FROM AUTHOR]