Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.

The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.

Interferon a (IFN-a) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-a activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN-a activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-a activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN-a activity, concordance in affected sib pairs and frequent transmission of the high IFN-a activity trait from parents to offspring. Autoantibodies to RNAbinding proteins and double-stranded DNA were associated with high IFN-a activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN-a activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-a activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

Methanogenesis, the biological production of methane, plays a pivotal role in the global carbon cycle and contributes significantly to global warming. The majority of methane in nature is derived from acetate. Here we report the complete genome sequence of an acetate-utilizing methanogen, Methanosarcina acetivorans C2A. Methanosarcineae are the most metabolically diverse methanogens, thrive in a broad range of environments, and are unique among the Archaea in forming complex multicellular structures. This diversity is reflected in the genome of M. acetivorans.

Objective. Peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) have increased expression of genes typically induced by type I interferon (IFN). However, it has been difficult to identify and quantify the factors responsible for activation of the IFN pathway in SLE. To characterize these mediators, we developed an assay that measures the functional effects of plasma or serum components on the gene expression of cultured target cells.Methods Conclusion. IFN␣ in SLE plasma is a major stimulus of IFN target gene expression and is related to expression of those genes in PBMCs from SLE patients and to the titer of anti-RBP autoantibodies. These data provide additional support for the view that IFN␣ mediates immune system activation and dysregulation in SLE.Systemic lupus erythematosus (SLE) is a multisystem disease characterized by autoimmunity directed toward nuclear particles and profound alterations of the immune system that contribute to inflammation and tissue damage. The production of pathogenic autoantibodies in SLE is T cell and antigen dependent. A current paradigm suggests that apoptotic cells provide a source of self antigens, but it is not clear why some individuals generate an immune response to those self antigens and some do not. Investigators in our laboratory are exploring the hypothesis that production of type I interferon (IFN) contributes to immune dysregulation and autoimmunity in SLE.A role of IFN␣, the prototype type I IFN, in SLE has been suggested for at least 25 years. Importantly, increased levels of IFN␣ have been detected in the serum of patients with active SLE (1,2). In addition, recombinant IFN␣ administered to patients with viral infection or malignancy can induce autoantibodies with specificities similar to those seen in lupus patients and has sometimes triggered clinical lupus, thyroiditis, or arthritis (3,4). Lupus serum has been shown to increase allogeneic stimulatory activity of monocytes, an effect that was partially inhibited by anti-IFN␣ antibody, sug-

Probiotics improve high fat diet-induced steatosis and insulin resistance. These effects of probiotics are likely due to increased hepatic NKT cell numbers and reduced inflammatory signaling.

Summary Angiogenesis is regulated by the balance of pro-angiogenic VEGF165 and anti-angiogenic VEGF165b splice isoforms. Mutations in WT1, the Wilms’ tumour suppressor gene, suppress VEGF165b and cause abnormal gonadogenesis, renal failure and Wilms’ tumours. In WT1 mutant cells, reduced VEGF165b was due to lack of WT1 mediated transcriptional repression of the splicing factor kinase SRPK1. WT1 bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding-site. In WT1 mutant cells SRPK1-mediated hyperphosphorylation of the oncogenic RNA binding protein SRSF1 regulated splicing of VEGF, and rendered WT1 mutant cells pro-angiogenic. Altered VEGF splicing was reversed by wildtype WT1, knockdown of SRSF1 or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumour growth.

Background-Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this process serially are needed. Methods and Results-MMP-targeted