Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4-related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti-laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.

Members of the insulin peptide family have conserved roles in the regulation of growth and metabolism in a wide variety of metazoans. Drosophila insulin-like peptides (Dilps) promote tissue growth through the single insulin-like receptor (InR). Despite the important role of Dilps in nutrient-dependent growth control, the molecular mechanism that regulates the activity of circulating Dilps is not well understood. Here, we report the function of a novel secreted decoy of InR (SDR) as a negative regulator of insulin signaling. SDR is predominantly expressed in glia and is secreted into the hemolymph. Larvae lacking SDR grow at a faster rate, thereby increasing adult body size. Conversely, overexpression of SDR reduces body growth non-cell-autonomously. SDR is structurally similar to the extracellular domain of InR and interacts with several Dilps in vitro independent of Imp-L2, the ortholog of the mammalian insulin-like growth factor-binding protein 7 (IGFBP7). We further demonstrate that SDR is constantly secreted into the hemolymph independent of nutritional status and is essential for adjusting insulin signaling under adverse food conditions. We propose that Drosophila uses a secreted decoy to fine-tune systemic growth against fluctuations of circulating insulin levels.

IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

No abstract

How can you combine professional-quality research with discovery-based undergraduate education? The UCLA Undergraduate Consortium for Functional Genomics provides the answer

All known cyanobacterial genomes possess multiple copies of genes encoding AbrB-like transcriptional regulators, known as cyAbrBs, which are distinct from those conserved among other bacterial species. In this study, we addressed the physiological roles of Sll0822 and Sll0359, the two cyAbrBs in Synechocystis sp. strain PCC 6803, under nonstress conditions (20 mol of photons m ؊2 s ؊1 in ambient CO 2 ). When the sll0822 gene was disrupted, the expression levels of nitrogen-related genes such as urtA, amt1, and glnB significantly decreased compared with those in the wild-type cells. Possibly due to the increase of the cellular carbon/ nitrogen ratio in the sll0822-disrupted cells, a decrease in pigment contents, downregulation of carbon-uptake related genes, and aberrant accumulation of glycogen took place. Moreover, the mutant exhibited the decrease in the expression level of cytokinesis-related genes such as ftsZ and ftsQ, resulting in the defect in cell division and significant increase in cell size. The pleiotrophic phenotype of the mutant was efficiently suppressed by the introduction of Sll0822 and also partially suppressed by the introduction of Sll0359. When His-tagged cyAbrBs were purified from overexpression strains, Sll0359 and Sll0822 were copurified with each other. The cyAbrBs in Synechocystis sp. strain PCC 6803 seem to interact with each other and regulate carbon and nitrogen metabolism as well as the cell division process under nonstress conditions.All known cyanobacterial genomes possess multiple copies of genes encoding putative transcriptional regulators having an AbrB-type DNA binding domain. cyAbrBs are structurally different from AbrB-type regulators widely conserved among other bacterial species (4, 25) in that they have a DNA binding domain in the C-terminal region instead of in the usual N-terminal region (9). To date, several research groups have reported the identification of cyAbrBs as binding factors to the upstream region of their target genes. By DNA affinity precipitation assay, Onizuka et al. (17) have identified binding of a cyAbrB to the upstream region of the rbc operon encoding the ribulose-1,5-bisphosphate carboxylase/oxygenase in Synechococcus sp. strain PCC 7002. Similarly, by DNA affinity assay, Oliveira and Lindblad (16) have isolated a cyAbrB as a binding factor to the upstream region of the hox operon encoding the bidirectional NiFe hydrogenase in Synechocystis sp. strain PCC 6803. Shalev-Malul et al. (22) have identified specific binding of a cyAbrB to the intergenic region between aoaA and aoaC encoding biosynthetic enzymes for the hepatotoxin cylindrospermopsin in Aphanizomenon ovalisporum. Furthermore, cyAbrBs have been reported to bind to the upstream regions of nitrogen-regulated genes (9), of sbtA encoding a Na ϩ /HCO 3 Ϫ symporter in Synechocystis sp. strain PCC 6803 (10), of hypC involved in the maturation of hydrogenase (1), of ftsZ encoding a key cell division protein (7), and of sodB encoding iron superoxide dismutase (2) in Nostoc sp. strain PCC 7120. It ...

No abstract

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.