Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice

Indirect evidence suggests that type-I interferons (IFN-alpha/beta) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the alpha-chain of IFN-alpha/betaR, the common receptor for the multiple IFN-alpha/beta species. Compared with littermate controls, homozygous IFN-alpha/betaR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-alpha/betaR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.     

Cell type and gender-dependent differential regulation of the p202 and Aim2 proteins: implications for the regulation of innate immune responses in SLE

Upon sensing cytosolic double-stranded DNA (dsDNA), the murine Aim2 (encoded by the Aim2 gene) protein forms an inflammasome and promotes the secretion of proinflammatory cytokines, such as IL-1β and IL-18. In contrast, the p202 protein (encoded by the Ifi202 gene) does not form an inflammasome. Previously, we have reported that the interferon (IFN) and female sex hormone-induced increased nuclear levels of p202 protein in immune cells are associated with increased susceptibility to develop a lupus-like disease. However, signaling pathways that regulate the expression of Aim2 protein remain unknown. Here we report that the expression of Aim2 gene is induced in bone marrow-derived macrophages (BMDMs) by IFN-α treatment and the expression is, in part, STAT1-dependent. However, treatment of splenic T or B cells with IFN-α or their stimulation, which induced the expression of Ifi202 gene, did not induce the expression of Aim2 gene. Furthermore, treatment of cells with the male hormone androgen increased levels of Aim2 mRNA and protein. Moreover, treatment of murine macrophage cell lines (RAW264.7 and J774A.1) with IFN-α differentially induced the expression of Aim2 and p202 proteins and regulated their sub-cellular localization. Additionally, activation of Toll-like receptors (TLR3, 4, and 9) in BMDMs and cell lines also differentially regulated the expression of Aim2 and Ifi202 genes. Our observations demonstrate that cell type and gender-dependent factors differentially regulate the expression of the Aim2 and p202 proteins, thus, suggesting opposing roles for these two proteins in innate immune responses in lupus disease.     

Antiplasmodial activity of [(aryl)arylsulfanylmethyl]Pyridine

A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (K(D) = 12 to 20 muM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H(2)O(2), and hydroxyl radical (.OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (DeltaPsim) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of .OH may be mainly responsible for the antimalarial effect of AASMP since .OH scavengers such as mannitol, as well as spin trap alpha-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.     

Comment on: The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function

SIR, We read with interest the letter by Bupp et al. [1] concerningthe candidate lupus susceptibility gene Ifi202a. They concludethat the Ifi202a gene is largely dispensable for B-cell function.However, we feel that Bupp et al. provided incomplete informationin their letter concerning Ifi202 genes. Moreover, before weconclude that the Ifi202a gene is largely dispensable for B-cellfunction, we feel there are a number of observations that needto be considered. A study by Wang et al. [2] revealed that Ifi202a gene     

Measurement of entrance skin dose and estimation of organ dose during pediatric chest radiography

Entrance skin dose (ESD) was measured to calculate the organ doses from the anteroposterior (AP) and posteroanterior (PA) chest x-ray projections for pediatric patients in an Indian hospital. High sensitivity tissue-equivalent thermoluminescent dosimeters (TLD, LiF: Mg, Cu, P chips) were used for measuring entrance skin dose. The respective organ doses were calculated using the Monte Carlo method (MCNP 3.1) to simulate the examination set-up and a three-dimensional mathematical phantom for representing an average 5-y-old Indian child. Using this method, conversion coefficients were derived for translating the measured ESD to organ doses. The average measured ESDs for the chest AP and PA projections were 0.305 mGy and 0.171 mGy, respectively. The average calculated organ doses in the AP and the PA projections were 0.196 and 0.086 mSv for the thyroid, 0.167 and 0.045 mSv for the trachea, 0.078 and 0.043 mSv for the lungs, 0.110 and 0.013 mSv for the liver, 0.002 and 0.016 mSv for the bone marrow, 0.024 and 0.002 mSv for the kidneys, and 0.109 and 0.023 mSv for the heart, respectively. The ESD and organ doses can be reduced significantly with the proper radiological technique. According to these results, the chest PA projection should be preferred over the AP projection in pediatric patients. The estimated organ doses for the chest AP and PA projections can be used for the estimation of the associated risk.     

Supracardiac total anomalous pulmonary venous connection with cor triatriatum sinister: A rare diagnosis confirmed by saline contrast echocardiography

In cor triatriatum sinister, the left atrium is divided by a membrane into a proximal and a distal chamber. Usually proximal chamber receives all the pulmonary veins and drains through an opening in the dividing membrane into distal chamber, which empties into left ventricle through the mitral valve. Rarely, the two chambers lack a communication and there is associated total anomalous pulmonary venous connection (TAPVC). We report a 1-month-old infant with cyanosis and heart failure, who had cor triatriatum sinister associated with supracardiac TAPVC. The case is reported for rarity of the association with a focus on contrast echocardiographic imaging.     

Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus

The Nba2 locus is a major genetic contribution to disease susceptibility in the (NZB x NZW)F(1) mouse model of systemic lupus. We generated C57BL/6 mice congenic for this NZB locus, and these mice produced antinuclear autoantibodies characteristic of lupus. F(1) offspring of congenic and NZW mice developed high autoantibody levels and severe lupus nephritis similar to (NZB x NZW)F(1) mice. Expression profiling with oligonucleotide microarrays revealed only two differentially expressed genes, interferon-inducible genes Ifi202 and Ifi203, in congenic versus control mice, and both were within the Nba2 interval. Quantitative PCR localized increased Ifi202 expression to splenic B cells and non-T/non-B cells. These results, together with analyses of promoter region polymorphisms, strain distribution of expression, and effects on cell proliferation and apoptosis, implicate Ifi202 as a candidate gene for lupus.     

Design,synthesis and evaluation of novel thiazolidinedione derivatives as anti-hyperglycemic and anti-hyperlipidemic agents

A novel series of thiazolidine-2,4-diones was designed, synthesized and investigated for anti-diabetic activity. The (2,4-dioxo-1,3-thiazolidin-5-yl)methylphenylbenzamide derivatives contain an amide linkage between the central aryl ring and the hydrophobic tail. Structures of the compounds were confirmed by spectroscopic techniques fourier transform infrared spectroscopy, ¹H-nuclear magnetic resonance and elemental (C, H, N) analysis. The synthesized compounds were evaluated for their in-vivo pharmacological activity (blood glucose and triglyceride lowering activity), where compounds thiazolidinediones-C and thiazolidinediones-E showed significant effects, comparable to the standard pioglitazone. Computational studies positively substantiated the nature and interaction of the designed compounds with peroxisome proliferator-activated receptor gamma.