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Differential Structural Features of Two Mutant ADAR1p150 Zα Domains Associated with Aicardi-Goutières Syndrome.

The Zα domain of ADARp150 is critical for proper Z-RNA substrate binding and is a key factor in the type-I interferon response pathway. Two point-mutations in this domain (N173S and P193A), which cause neurodegenerative disorders, are linked to decreased A-to-I editing in disease models. To understand this phenomenon at the molecular level, we biophysically and structurally characterized these two mutated domains, revealing that they bind Z-RNA with a decreased affinity. Less efficient binding to Z-RNA can be explained by structural changes in beta-wing, part of the Z-RNA-protein interface, an

Множественный склероз

В докладах, представленных в этой главе, иллюстрируется картина множественного склероза как провокационного расстройства центральной нервной системы, вызванного сложным взаимодействием множественных генетических резистентных аллей и неизвестных экологических спусковых механизмов. Множественный склероз — это болезнь, в которой происходит первое обезвоживание нервов, за которым следует аксонное дегенерация. Обезвоживание вызвано воспалением, о чем свидетельствует синтез иммуноглобулинов в рамках CNS, и магнитная резонансная визуализация показала, что симптомы вызывают лишь незначительное число п

Совпадение в аннотации оригинала
The papers in this chapter illustrate the picture that has emerged of multiple sclerosis as an inflammatory disorder of the central nervous … eries were made in the twentieth century, which ended with the first demonstration that a treatment—interferon-beta—could influence the natural history of the disease.

Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy.

Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from multiple sclerosis. We describe the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. Our findings support autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. Adherence

Management of malignant pleural effusion secondary to breast cancer: talc pleurodesis and pleuroperitoneal shunting.

Malignant pleural effusion is a frequent complication of metastatic breast cancer, leading to a significant degree of morbidity. Drainage of the effusion by thoracocentesis and subsequent pleurodesis is an established means of symptomatic relief in these patients. Several sclerosing agents have been reported in the literature, including doxycylin, minocyclin, tetracyclines, bleomycin, cisplatin, etoposide, fluorouracil, interferon-beta, Corynebacterium parvum, and talc which gives the best results. The condition of the lung's parenchyma must be evaluated prior to the procedure to rule out lymp…

Histiocytic haemophagocytosis in a patient with Kawasaki disease: changes in the hypercytokinaemic state.

UNLABELLED: A 32-month-old Japanese boy exhibited haemophagocytic syndrome (HPS) during the recurrent course of Kawasaki disease. Despite repeated gamma-globulin therapy, he developed cytopenia with marked hepatomegaly and evidence of histiocytic haemophagocytosis in the bone marrow. Serum levels of interferon-gamma and tumour necrosis factor, but not of interleukin-1 beta, increased in parallel with his symptoms. No confirmation was obtained of the association of toxic reactions to the used drugs. No coronary lesions remained as sequelae. CONCLUSION: Cytopenia in Kawasaki disease could heral

Chlorpromazine inhibits human natural killer cell activity and antibody-dependent cell-mediated cytotoxicity.

The phenothiazine antipsychotic drug chlorpromazine, a potent calmodulin antagonist, inhibited human natural killer cell-mediated cytotoxicity in a dose-dependent manner. This inhibition of natural killer cell activity was not due to interference with conjugate formation, nor was it due to toxicity to the natural killer cells or nonspecific alteration of the target cells. Chlorpromazine also suppressed antibody-dependent cell-mediated cytotoxicity in a dose-dependent fashion, suggesting that the two activities share a calmodulin-dependent step. Finally, it was not possible to overcome chlorpro

Decoding adult murine pancreatic islet cell diversity through cell type-resolved proteomics and phosphoproteomics.

Islets of Langerhans are micro-organs scattered throughout the pancreas. They are composed of insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells. While their transcriptome has been extensively analyzed, protein-level information remains limited due to cell scarcity and purification challenges. Here, we combine cell sorting with highly sensitive mass spectrometry to create the first in-depth proteomic resource of pancreatic islet cells. We achieved a depth exceeding 6000 proteins per endocrine cell population, discovering new cell type-enriched

Role of antioxidants and trace elements in health and immunity of transition dairy cows.

A number of antioxidants and trace minerals have important roles in immune function and may affect health in transition dairy cows. Vitamin E and beta-carotene are important cellular antioxidants. Selenium (Se) is involved in the antioxidant system via its role in the enzyme glutathione peroxidase. Inadequate dietary vitamin E or Se decreases neutrophil function during the perpariturient period. Supplementation of vitamin E and/or Se has reduced the incidence of mastitis and retained placenta, and reduced duration of clinical symptoms of mastitis in some experiments. Research has indicated tha

Immunopathogenesis of folliculitis decalvans: clues in early lesions.

Folliculitis decalvans (FD) is a rare variant of primary cicatricial alopecia, for which the etiopathogenesis remains unclear. Our purpose was to evaluate whether certain immunologic mechanisms might have a significant role in the pathogenesis of FD. Lesional scalp biopsy specimens from 7 patients with FD, 7 with lichen planopilaris, and 4 with alopecia areata were studied immunohistochemically by using monoclonal antibodies to CD1a, CD3, CD4, CD8, CD20, CD25, HLA-DR, interleukin (IL)-1beta, IL-4, IL-8, interferon gamma, tumor necrosis factor alpha, basic fibroblast growth factor (b-FGF), tran

Detection of mRNA for the cytokines, interleukin-1 alpha and interleukin-8, in corneas from patients with pseudophakic bullous keratopathy.

PURPOSE: Cytokines have been implicated in corneal inflammatory diseases. The authors sought to determine if corneal diseases with different patterns of inflammation are accompanied by characteristic patterns of cytokine expression. METHODS: The authors used reverse transcription-polymerase chain reaction to detect mRNA for 12 specific cytokines from patients with Fuch's dystrophy (n = 7), pseudophakic bullous keratopathy (n = 12), or normal corneas (n = 4). RESULTS: Using Wilcoxon rank sum analysis, mRNA for interleukin (IL)-1 alpha or IL-8 was significantly more abundant in corneas from pa

Immunopathology of experimental African sleeping sickness: detection of cytokine mRNA in the brains of Trypanosoma brucei brucei-infected mice.

The immunopathology of Trypanosoma brucei brucei in the central nervous system was studied by using an experimental model of chronic meningoencephalitis in outbred CD-1 mice. Mice infected with T. b. brucei were treated with a subcurative dose of the trypanocidal compound diaminazine aceturate. These mice relapsed and were again drug treated. The brains were examined histologically and by immunocytochemistry to identify activated astrocytes. The polymerase chain reaction was used to detect cytokine RNA transcripts. The infected and treated animals developed severe chronic meningoencephalitis c

Analysis of gene expression in Lassa virus-infected HuH-7 cells.

The pathogenesis of Lassa fever is poorly understood. As the liver is a major target organ of Lassa virus, gene expression in Lassa virus-infected HuH-7 cells, a differentiated human hepatoma cell line, was studied. Cellular mRNA levels were measured at the late phase of acute infection, when virtually all cells expressed large amounts of nucleoprotein, and virus RNA concentration had reached>10(8) copies (ml supernatant)-1. Two types of transcription array were used: cDNA-based macroarrays with a set of 3500 genes (Atlas Human 1.2 arrays; Clontech) and oligonucleotide-based microarrays coveri

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis.

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1

Cytokine and cytokine receptor concentrations in bone marrow supernatant from patients with HIV: correlation with hematologic parameters.

BACKGROUND: To determine the concentrations of tumor necrosis factor (TNF) alpha, soluble TNF receptors (sTNFR), interleukin (IL)-1 beta, gamma-interferon (IFN), macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES to which hematopoietic progenitors are exposed in vivo in HIV patients and the correlation of these concentrations with hematologic parameters, cytokine and cytokine receptor concentrations were measured by ELISA in bone marrow aspirate supernatants from 19 HIV patients undergoing diagnostic evaluation and 14 healthy paid volunteer controls. IL-1 beta and gamma-IFN

Gene Expression Profile of Human Cytokines in Response to Burkholderia pseudomallei Infection.

Melioidosis is an underreported infectious disease, caused by the Gram-negative bacterium Burkholderia pseudomallei. Understanding the disease susceptibility and pathogenesis is crucial for developing newer diagnostic and therapeutic strategies for this life-threatening infection. In this study, we aimed to analyze the gene expression levels of important cytokines in melioidosis patients and establish useful correlates with disease biomarkers compared to cases of sepsis infection caused by other pathogens and healthy individuals. A Qiagen common human cytokines array profiling the gene express

Rhinovirus-induced anti-viral interferon secretion is not deficient and not delayed in sinonasal epithelial cells of patients with chronic rhinosinusitis with nasal polyp.

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 sti

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency.

Inborn errors of TLR3-dependent IFN-α/β- and IFN-λ-mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded I

IFN Regulatory Factor 3 in Health and Disease.

Immunity to viruses requires an array of critical cellular proteins that include IFN regulatory factor 3 (IRF3). Consequently, most viruses that infect vertebrates encode proteins that interfere with IRF3 activation. This review describes the cellular pathways linked to IRF3 activation and where those pathways are targeted by human viral pathogens. Moreover, key regulatory pathways that control IRF3 are discussed. Besides viral infections, IRF3 is also involved in resistance to some bacterial infections, in anticancer immunity, and in anticancer therapies involving DNA damage agents. A recent

Microglial responses to peripheral type 1 interferon.

BACKGROUND: Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated syn

Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes.

BACKGROUND & AIMS: Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. METHODS: HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points