Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and alphaEbeta7 integrin (CD103) by CD8+ T cells

At both cutaneous and mucosal sites, interleukin (IL)-10, IL-12 and transforming growth factor (TGF)-beta are important regulators of chronic inflammatory disease, where cutaneous lymphocyte-associated antigen (CLA) and alphaE integrin (CD103) may be expressed. Stimulation with streptococcal pyrogenic exotoxin C (SpeC) increased the expression of CD103 by CD8+ but not CD4+ T cells. While adding IL-12 augmented the expression of CLA, superantigen-induced expression of CD103 was markedly suppressed by IL-12, which could be reversed by TGF-beta. Antibodies against TGF-beta inhibited, and a combination of anti-TGF-beta and IL-12 completely abrogated the induced CD103 expression. IL-10 strongly decreased the frequency of CLA+ and although not increasing the frequency of CD103+CD8+ T cells, the amount of CD103 expressed per cell was markedly increased. Thus, the expression of CLA and CD103 may be antagonistically regulated by IL-10 and IL-12 and the balance between these cytokines could influence the T cell migration of inflammatory cells into epithelial tissues.     

Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

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Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.     

Effects of the Ebbinghaus figure on grasping are not only due to misjudged size

It is not evident how the small effects of the flankers of the Ebbinghaus figure on peak grip aperture (PGA) should be interpreted. One interpretation is that the flankers influence the estimated size, which in turn influences the grasp. If this interpretation is correct, then only the size-dependent aspects of the grasping movement should depend on the spatial positions of the flankers. An alternative interpretation is that the effect on grip aperture is caused by a change in judgement of the required precision, in which case various aspects of the grasping movement could be influenced by the size and position of the flankers. We presented subjects with a display consisting of a central disk surrounded by four large or small flankers. The array of circular flankers could be rotated by 45°. There were two tasks: to reproduce the perceived size of the central disk, and to grasp the central disk. As in other studies, the reproduced size and the PGA were both influenced by the size of the flankers. The effect on reproduced size settings was independent of the flankers spatial position. Nevertheless, the flankers position did influence the final grip aperture and the grip orientation at PGA and at movement offset. Because the flankers changed more than only the PGA, we conclude that the effect of the flankers on prehension cannot only be because of misjudgement of the size of the central disk.     

The V599E BRAF mutation is uncommon in biliary tract cancers.

Activating point mutations of the BRAF oncogene have been identified in several solid tumors, most commonly in cutaneous melanomas and papillary carcinomas of the thyroid. A specific point mutation--V599E--accounts for the overwhelming majority of these mutational events. We explored the frequency of the V599E BRAF mutation in biliary tract cancers. In all, 62 archival biliary tract cancers, including 15 gallbladder cancers, 15 extrahepatic, and 10 intrahepatic cholangiocarcinomas from the United States, and 22 gallbladder carcinomas from Chile were analyzed for the V599E mutation of the BRAF gene using three distinct methods: direct sequencing, a primer extension method (Mutector assay), and the highly sensitive quantitative Gap Ligase Chain Reaction. The common V599E mutation was not identified in any of the 62 biliary cancer samples using these three methods of detection. The V599E somatic mutation of the BRAF gene is absent in biliary tract cancers, at least in the two geographic populations (United States and Chile) examined. Activation of the RAS/RAF/MAP kinase pathway in biliary tract cancers is likely to be secondary to oncogenic RAS mutations, or due to mutations of the BRAF gene at nucleotide positions not explored in the current study.     

Vaccination of the Leishmania major susceptible BALB/c mouse. I. The precise selection of peptide determinant influences CD4+ T cell subset expression

BALB/c mice are susceptible to cutaneous lelshmanlasls uponinfection with Leishmania major while C57BL/6 are not. Thereis a major promastigote surface protease (PSP or gp63) whichis available in both native and recomblnant forms, and for whichthe primary amlno acid sequence is known. Immunization withPSP has been shown to offer some protection against challengewith the live organism. Therefore, we attempted to develop apeptide vaccine with PSP peptldes. In the first experiments,recall prollferatlve responses to PSP were measured using aset of 15mer peptldes spanning the entire PSP molecule whichallowed designation of major determinant regions in BALB/c,C57BL/6, and CBA mice. Several of these determinants were promiscuousand shared almost the identical core amlno acid residues inthe different strains. Immunization with major determinant peptldeswas recalled vigorously with L. major soluble antigen as wellas with PSP. The response to peptide was almost entirely T_h1as measured by a localized ELISA assay for single-cell productionof IFN-. A similar assay for IL-5, which overcomes problemsof sensitivity and inhibition by lymphoklnes produced by T_h1cells, Indicates very little production of T_h1 cells even byBALB/c. It was found that if a major responsive peak was examinedby recall with overlapping peptldes, the highest, central peptidegave a mainly Th1 response while the boundary, less efficientpeptldes gave more of a T_h2 response. Possible reasons for thiswere discussed. These results point to the importance of selectingthe exactly appropriate peptide in considering a vacclnogenthat might protect susceptible individuals. Even the choiceof a somewhat immunogenlc peptide within the determinant envelopemight actually exacerbate infection by steering the responsein a T_h2 direction.     

Evolutionary conservation of brain Thy-1 glycoprotein in vertebrates and invertebrates

The evolutionary conservation of brain Thy-1 glycoprotein in 24 vertebrate and invertebrate species has been investigated by means of a soluble phase radioimmunoassay (RIA) and by the "Western blot" technique. The brain glycoproteins from virtually all the vertebrate species inhibited the precipitation of mouse Thy-1.1 by a rabbit anti-rat Thy-1 antiserum. Most reagents also inhibited the binding of a mouse anti-rat Thy-1 monoclonal antibody to rat Thy-1. Whole tissue glycoproteins from earthworm, snail and oyster and ganglia glycoproteins of a locust species were also found to be inhibitory. Western blotting analysis on NaDod SO4 polyacrylamide gel electrophoresis under reducing conditions revealed a Thy-1 homologous molecule (22-25 KD) in mammals, birds, fish, reptiles and invertebrate species. The snail Thy-1-like molecule was eluted from the gel and was shown to specifically inhibit the serological reaction. The rabbit anti-rat Thy-1 antiserum also detected a doublet molecule of approximately 85,000 KD, which is conserved in all species, including yeast and bacteria. The origin and nature of the presumed glycoproteins is unknown. Our results suggest that the Thy-1 molecule has been conserved throughout metazoan evolution and that the Thy-1 gene is the most conserved among the immune related genes (immunoglobulins, beta 2-microglobulin and major histocompatibility) which share extensive amino acid homology.     

A unique pattern of lymphokine synthesis is a characteristic of certain antigen-specific suppressor T cell clones

We report that the lymphokines (IFN-) and IL-10 are co-syntheslzedby previously described CD3⁺ TCRß⁺, minor antigen-specificsuppressor T cell clones. IFN- and IL-10 are known to (I) becharacteristically produced by different helper T cell types,T_h1 and T_h2 respectively, and (II) inhibit the function of thereciprocal subset of T cells: IFN- Inhibits the function ofT_h2 and IL-10 that of T_h1 cells. Although Th0 cells are alsoknown to synthesize cytoklnes of both the T_h1- and T_h2-typeT cells, the suppressor T cells described in this report aredifferent from T_h0 cells in that they produce (I) neither IL-2nor IL-4 molecules and (II) stimulation via their CD3-TCR systemseems independent of both IL-2 and IL-4, the typical autocrinemolecules for T cell proliferation. The lymphokine profile ofthese suppressor T (TJ cell clones, as well as those of humanantigen-specific T. cells reported earlier, suggests that co-synthesisof some T_h1-llke and some T_h2-like cytoklnes may be a characteristicof antigen-specific T, cells as opposed to the type of reciprocalinhibition mediated through IFN- or IL-10, which is antigennon-specific.