Essential role for the p110delta phosphoinositide 3-kinase in the allergic response

Inflammatory substances released by mast cells induce and maintain the allergic response. Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE). Activated SCF receptors and high-affinity receptors for IgE (FcvarepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals. Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3)K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies.     

Magnetoreception and its trigeminal mediation in the homing pigeon

Two conflicting hypotheses compete to explain how a homing pigeon can return to its loft over great distances. One proposes the use of atmospheric odours and the other the Earth's magnetic field in the 'map' step of the 'map and compass' hypothesis of pigeon homing. Although magnetic effects on pigeon orientation provide indirect evidence for a magnetic 'map', numerous conditioning experiments have failed to demonstrate reproducible responses to magnetic fields by pigeons. This has led to suggestions that homing pigeons and other birds have no useful sensitivity to the Earth's magnetic field. Here we demonstrate that homing pigeons (Columba livia) can discriminate between the presence and absence of a magnetic anomaly in a conditioned choice experiment. This discrimination is impaired by attachment of a magnet to the cere, local anaesthesia of the upper beak area, and bilateral section of the ophthalmic branch of the trigeminal nerve, but not of the olfactory nerve. These results suggest that magnetoreception (probably magnetite-based) occurs in the upper beak area of the pigeon. Traditional methods of rendering pigeons anosmic might therefore cause simultaneous impairment of magnetoreception so that future orientation experiments will require independent evaluation of the pigeon's magnetic and olfactory systems.     

Adaptive immune responses in acute and chronic hepatitis C virus infection

The hepatitis C virus (HCV) persists in the majority of infected individuals and is a significant cause of human illness and death globally. Recent studies have yielded important insights into immunity to HCV, in particular revealing the central role of T cells in viral control and clearance. Other key features of adaptive immune responses remain obscure, including mechanisms by which T cells control HCV replication, the role of antibodies in conferring protection and how cellular and humoral immunity are subverted in persistent infection.     

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.     

The structural basis of Arfaptin-mediated cross-talk between Rac and Arf signalling pathways

Small G proteins are GTP-dependent molecular switches that regulate numerous cellular functions. They can be classified into homologous subfamilies that are broadly associated with specific biological processes. Cross-talk between small G-protein families has an important role in signalling, but the mechanism by which it occurs is poorly understood. The coordinated action of Arf and Rho family GTPases is required to regulate many cellular processes including lipid signalling, cell motility and Golgi function. Arfaptin is a ubiquitously expressed protein implicated in mediating cross-talk between Rac (a member of the Rho family) and Arf small GTPases. Here we show that Arfaptin binds specifically to GTP-bound Arf1 and Arf6, but binds to Rac.GTP and Rac.GDP with similar affinities. The X-ray structure of Arfaptin reveals an elongated, crescent-shaped dimer of three-helix coiled-coils. Structures of Arfaptin with Rac bound to either GDP or the slowly hydrolysable analogue GMPPNP show that the switch regions adopt similar conformations in both complexes. Our data highlight fundamental differences between the molecular mechanisms of Rho and Ras family signalling, and suggest a model of Arfaptin-mediated synergy between the Arf and Rho family signalling pathways.     

Carcinogenic action of dimethylnitrosamine in trout not related to methylation of nucleic acids and protein in vivo

Zusammenfassung Zur Klärung des Zusammenhanges zwischen carcinogener und alkylierender Wirkung von Dimethylnitrosamin wurde die Bildung von¹⁴C-7-Methylguanin in der Leber-RNA von Tauben, Fröschen und Forellen nach Gabe von¹⁴C-Dimethylnitrosamin untersucht. Dabei konnte¹⁴C-7-Methylguanin in der Leber-RNS von Tauben und Fröschen nachgewiesen werden, während RNA, DNS und Protein der Leber bei Forellen nicht markiert wurden.