Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis

Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.     

Small-molecule cyclic alpha V beta 3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion

Abnormal adhesion of sickle red blood cells (SS RBCs) to vascular endothelium may play an important role in vasoocclusion in sickle cell disease. Accruing evidence shows that endothelial alpha V beta 3-integrin has an important role in SS RBC adhesion because of its ability to bind several adhesive proteins implicated in this interaction. In the present studies, we tested therapeutic efficacy of small-molecule cyclic pentapeptides for their ability to block alpha V beta 3-mediated SS RBC adhesion by using two well-established assay systems, i.e., cultured human umbilical vein endothelial cells (HUVEC) and artificially perfused mesocecum vasculature of the rat under flow conditions. We tested the efficacy of two RGD-containing cyclic pentapeptides, i.e., cRGDFV (EMD 66203) and cRGDF-ACHA (alpha-amino cyclohexyl carboxylic acid) (EMD 270179), based on their known ability to bind alpha V beta 3. An inactive peptide, EMD 135981 (cR beta-ADFV) was used as control. Cyclization and the introduction of D-Phe (F) results in a marked increase in the ability of cyclic peptides to selectively bind alpha V beta 3 receptors. In the mesocecum vasculature, both EMD 66203 and EMD 270179 ameliorated platelet-activating factor-induced enhanced SS RBC adhesion, postcapillary blockage, and significantly improved hemodynamic behavior. Infusion of a fluorescent derivative of EMD 66203 resulted in colocalization of the antagonist with vascular endothelium. Also, pretreatment of HUVEC with either alpha V beta 3 antagonist resulted in a significant decrease in SS RBC adhesion. Because of their metabolic stability, the use of these cyclic alpha V beta 3 antagonists may constitute a novel therapeutic strategy to block SS RBC adhesion and associated vasoocclusion under flow conditions.     

Self-incompatibility: Smi silences through a novel sRNA pathway

Self-incompatibility in Brassicaceae is determined by the interaction between S-Locus Protein 11 (SP11) on the pollen and S-receptor kinase (SRK) in the stigma. Pollen from heterozygotes generally displays products of both SP11 alleles, but in some heterozygotes SP11 expression is monoallelic, with one allele (SP11(R)) being silenced by promoter methylation. An exciting development in understanding the mechanism behind monoallelic silencing came recently when Y. Tarutani et al. [Nature 2010;466:983-986] identified a 24-nucleotide sRNA (termed Smi) derived from a non-coding gene within the dominant S-haplotype, and suggested that Smi directs promoter methylation. We propose that rather than having a direct effect on DNA methylation, Smi is the first step in a novel cis-acting siRNA pathway that directs widespread monoallelic SP11(R) promoter methylation.     

A Plant Orthologue of RNase L Inhibitor (RLI) Is Induced in Plants Showing RNA Interference

RNase L inhibitors (RLIs) correspond to a group of soluble proteins from the large ATP binding cassette (ABC) family of proteins. Structurally, RLIs have an N-terminal Fe–S domain and two nucleotide binding domains. Orthologous RLI sequences with more than 48% identity have been found from Archea to Eukaryota, but have not as yet been identified in Eubacteria. Some organisms, like Arabidopsis thaliana and human, have paralogous genes with differential expression patterns, the function of which remains to be determined. Expression of Arabidopsis RLI2 was slightly increased in transgenic plants showing RNA interference, suggesting a role in this pathway     

Regulation of phosphate starvation responses in higher plants

Background

Phosphorus (P) is often a limiting mineral nutrient for plant growth. Many soils worldwide are deficient in soluble inorganic phosphate (P_i), the form of P most readily absorbed and utilized by plants. A network of elaborate developmental and biochemical adaptations has evolved in plants to enhance P_i acquisition and avoid starvation.

Scope

Controlling the deployment of adaptations used by plants to avoid P_i starvation requires a sophisticated sensing and regulatory system that can integrate external and internal information regarding P_i availability. In this review, the current knowledge of the regulatory mechanisms that control P_i starvation responses and the local and long-distance signals that may trigger P_i starvation responses are discussed. Uncharacterized mutants that have P_i-related phenotypes and their potential to give us additional insights into regulatory pathways and P_i starvation-induced signalling are also highlighted and assessed.

Conclusions

An impressive list of factors that regulate P_i starvation responses is now available, as is a good deal of knowledge regarding the local and long-distance signals that allow a plant to sense and respond to P_i availability. However, we are only beginning to understand how these factors and signals are integrated with one another in a regulatory web able to control the range of responses demonstrated by plants grown in low P_i environments. Much more knowledge is needed in this agronomically important area before real gains can be made in improving P_i acquisition in crop plants.     

Collagen-induced arthritis is exacerbated in IL-10-deficient mice

IL-10 is a potent immunoregulatory cytokine attenuating a wide range of immune effector and inflammatory responses. In the present study, we assess whether endogenous levels of IL-10 function to regulate the incidence and severity of collagen-induced arthritis. DBA/1 wildtype (WT), heterozygous (IL-10^+/-) and homozygous (IL-10^-/-) IL-10-deficient mice were immunized with type II collagen. Development of arthritis was monitored over time, and collagen-specific cytokine production and anticollagen antibodies were assessed. Arthritis developed progressively in mice immunized with collagen, and 100% of the WT, IL-10^+/-, and IL-10^-/- mice were arthritic at 35 days. However, the severity of arthritis in the IL-10^-/- mice was significantly greater than that in WT or IL-1^+/- animals. Disease severity was associated with reduced IFN-γ levels and a dramatic increase in CD11b-positive macrophages. Paradoxically, both the IgG₁ and IgG_2a anticollagen antibody responses were also significantly reduced. These data demonstrate that IL-10 is capable of controlling disease severity through a mechanism that involves IFN-γ. Since IL-10 levels are elevated in rheumatoid arthritis synovial fluid, these findings may have relevance to rheumatoid arthritis.     

Eukaryotic transposable elements and genome evolution

The changes in DNA sequence that have taken place during the evolution of eukaryotic genomes cannot be accounted for simply by base substitutions; some more complex mutations must have taken place as well. Transposable elements can affect gene structure and expression in several ways that suggest that they may have contributed to these evolutionary events.     

Long-term Domiciliary Oxygen in Chronic Bronchitis with Pulmonary Hypertension

Five patients with chronic bronchitis and pulmonary hypertension were treated with oxygen in their homes for periods of between 6 and 24 months. Oxygen was supplied for 15 hours daily from cylinders or from an oxygen concentrator and few practical difficulties arose. After 23 to 59 weeks of treatment there were significant decreases in pulmonary arterial pressure and vascular resistance, and four of the five patients no longer had pulmonary hypertension at rest. Two of these patients had shown little response after three weeks of treatment. There was a reduction in the number of episodes of congestive cardiac failure compared with the corresponding period before treatment. Two of the patients improved enough to return to work. These results are encouraging enough to justify a controlled trial of the treatment in a large number of patients.