Cutting edge: MHC class I-Ly49 interaction regulates neuronal function

MHC class I molecules (MHC-I) have been implicated in nervous system development in the mouse. In this study we present evidence for the interaction of MHC-I with the NK cell receptor Ly49 in primary cortical neuronal cultures. We show that MHC-I and Ly49 are expressed on neuronal soma and axon surfaces, with Ly49 also present on dendrites. Anti-MHC-I Abs reduce synapsin-I expression and enhance neurite outgrowth and neuronal death. Conversely, anti-Ly49 mAbs increase synapsin-I expression, reduce neurite outgrowth, and promote neuron viability. Because we show that Ly49 genes are selectively expressed in the adult brain, these findings suggest an unsuspected role for the MHC-I-Ly49 interaction in the development and function of the brain.     

Geographic and topographic determinants of local FMD transmission applied to the 2001 UK FMD epidemic

Background

Models of Foot and Mouth Disease (FMD) transmission have assumed a homogeneous landscape across which Euclidean distance is a suitable measure of the spatial dependency of transmission. This paper investigated features of the landscape and their impact on transmission during the period of predominantly local spread which followed the implementation of the national movement ban during the 2001 UK FMD epidemic. In this study 113 farms diagnosed with FMD which had a known source of infection within 3 km (cases) were matched to 188 control farms which were either uninfected or infected at a later timepoint. Cases were matched to controls by Euclidean distance to the source of infection and farm size. Intervening geographical features and connectivity between the source of infection and case and controls were compared.

Results

Road distance between holdings, access to holdings, presence of forest, elevation change between holdings and the presence of intervening roads had no impact on the risk of local FMD transmission (p > 0.2). However the presence of linear features in the form of rivers and railways acted as barriers to FMD transmission (odds ratio = 0.507, 95% CIs = 0.297,0.887, p = 0.018).

Conclusion

This paper demonstrated that although FMD spread can generally be modelled using Euclidean distance and numbers of animals on susceptible holdings, the presence of rivers and railways has an additional protective effect reducing the probability of transmission between holdings.

     

A novel influenza A virus mitochondrial protein that induces cell death.

While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.     

Defective presentation of endogenous antigens by a murine sarcoma. Implications for the failure of an anti-tumor immune response

MHC class I-restricted CTL play a central role in the immune response against methylcholanthrene (MCA)-induced sarcomas in mice. We, therefore, hypothesized that MCA-induced tumors may evade immune recognition by failing to present Ag to CD8+ CTL. Of a number of previously described MCA-induced sarcomas, one, MCA 101, fails to induce CTL, is nonimmunogenic, and grows rapidly and lethally in nonimmunosuppressed recipients. To better understand the nonimmunogenicity of MCA 101 we examined its ability to present foreign Ag to CTL. Unlike immunogenic sarcomas, MCA 101 failed to present endogenously synthesized influenza virus Ag to influenza virus-specific CTL. The deficiency in presentation of endogenous Ag by MCA 101 was attributed to a markedly reduced rate of synthesis of class I molecules because up-regulation of class I synthesis by IFN-gamma greatly increased the presentation of influenza A virus Ag. Despite low levels of cell surface class I expression, MCA 101 presented exogenous peptide Ag to anti-influenza CTL with efficiency similar to immunogenic MCA sarcoma cell lines. These findings could not be attributed to deficiencies in class I assembly or transport, as has been suggested by others who have studied mutant cells with defective Ag presentation. Furthermore, our studies suggest that some tumor cells can escape recognition by CTL and subsequent immune eradication by suppressing presentation of endogenous Ag.     

Glucosylation of flavonoids in petals of Petunia hybrida

During the biosynthesis of anthocyanins in Petunia hybrida, the 3-hydroxyl group is glucosylated. Their supposed biosynthetic precursors, the dihydroflavonols, are glucosylated at the 7 or 4 positions. The question arose of whether these glucosides or the aglucones act as a substrate in anthocyanin synthesis. Using isolated flower buds of white flowering mutants that were blocked in an earlier step of biosynthesis, it was found that anthocyanin-3-glucosides and dihydroquercetin-7-glucoside were synthesized if dihydroquercetin, dihydroquercetin-7-glucoside, or dihydroquercetin-4-glucoside were used as precursors in these experiments. Intracellular dihydroquercetin-glucosides were not used as a substrate for anthocyanin synthesis. The results are explained by deglucosylation of dihydroquercetin-glucosides during uptake by isolated flower limbs. Dihydroquercetin-7-glucoside, formed intracellularly, is not available as a precursor for anthocyanins. We conclude that the aglucone form of dihydroquercetin acts as a substrate in anthocyanin biosynthesis.Abbreviations dHO dihydroquercetin - dHQ-7=g dihydroquercetin-7-glucoside - dHQ-4-g dihydroquercetin-4-glucoside     

Unexpected binding motifs for subnucleosomal particles revealed by atomic force microscopy

The structure of individual nucleosomes organized within reconstituted 208-12 arrays at different levels of compaction was examined by tapping mode atomic force microscopy in air and liquid. Reconstitution at lower histone octamer to DNA weight ratios showed an extended beads-on-a-string morphology with less than the expected maximum of 12 nucleosome core particles per array, each particle located in the most favored positioning site. A correlation of the contour lengths of these arrays with the number of observed particles revealed two distinct populations of particles, one with approximately 50 nm of bound DNA and a second population with approximately 25 nm. The measured nucleosome center-to-center distances indicate that this approximately 25 nm is not necessarily symmetrically bound about the dyad axis, but can also correspond to DNA bound from either the entry or exit point of the particle to a location at or close to the dyad axis. An assessment of particle heights suggests that particles wrapping approximately 25 nm of DNA are most likely to be subnucleosomal particles, which lack either one or both H2A-H2B dimers. At a higher reconstitution ratio, folded compact arrays fully populated with 12 nucleosome core particles, were observed. Liquid measurements demonstrated dynamic movements of DNA loops protruding from these folded arrays.