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Search Results: 1 - 10 of 227527 matches for " Lars R?nnblom "
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Potential role of IFNα in adult lupus
Lars Rnnblom
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2884
Abstract: Systemic lupus erythematosus, or lupus, is one of the most intriguing diseases due to its diverse clinical picture, variable course and in the single patient also its unpredictable outcome. The etiopathogenesis of lupus has been studied intensively for many years and the disease has long been regarded as the prototype autoimmune disease. The reason for this is that a large number of different autoantibodies are produced in lupus patients and that most, if not all, cells in the immune system seem to be involved in the disease process.The most prominent feature in lupus is an immune response to nucleic acid and associated proteins, which results in autoantibody production, immune complex (IC) formation and organ inflammation. In addition, most lupus patients display several signs of an increased IFNα production, which during the past years has attracted much interest regarding the possible role of this cytokine in the disease process. This interest has been further inspired by the observation that IFNα administration to individuals without any autoimmune condition can trigger the production of antinuclear autoantibodies, and occasionally also a lupus syndrome.In the present review, the possible reason(s) behind the ongoing IFNα production in lupus will be reviewed, as well as the role of IFNα in the etiopathogenesis and the clinical manifestations of the disease. The potential application in clinical practice of our present knowledge of the type I interferon system in lupus will also be discussed.The first described cytokine abnormality in lupus patients was an increased serum level of interferon [1], which subsequently was characterized as IFNα [2]. Early studies also demonstrated that lupus patients have increased levels of IFNα-induced proteins, such as 2',5'-adenylate synthetase [3] and MxA [4]. The latter report showed that >90% of lupus patients displayed increased expression of MxA, even if measurable serum IFNα levels could not be detected. Further studies sho
Systemic lupus erythematosus and the type I interferon system
Lars Rnnblom, Gunnar V Alm
Arthritis Research & Therapy , 2003, DOI: 10.1186/ar625
Abstract: Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease, characterized by the occurrence of many different autoantibodies, the formation of immune complexes (ICs), and inflammation in different organs. Studies in both mice and humans have demonstrated several genetic susceptibility loci involved in immune activation and regulation, as well as clearance of apoptotic cells [1,2]. Among the cells in the immune system, the B cells have a crucial role as producers of the autoantibodies, which are typically directed to nucleic acid and associated proteins. The B cells in SLE patients have several abnormalities that might account for the ongoing autoantibody production observed in these patients [3]. The B cell response is clearly antigen-driven and several lupus autoantigens are located in apoptotic bodies and apoptotic blebs [4,5]. It is unknown why the immune response is directed mainly towards apoptotic cell material, but SLE patients have both increased apoptosis and a defective clearance of such material [6,7]. Consequently, apoptotic bodies and nucleosomes are accessible to the immune system in SLE patients for longer than in normal individuals, which might contribute to the autoimmune response [8]. In addition, abnormal T cell activation, complement deficiency and the production of several cytokines might be critical for the initiation and maintenance of the autoimmune reaction [9-12].Increased serum levels of many cytokines have been noted in SLE patients, reflecting the activation of the immune system and inflammation in this disease. In the present review we focus on the type I interferon (IFN) system in SLE, because emerging data suggest that IFN-α and the natural IFN-α-producing cells (NIPCs), often termed plasmacytoid dendritic cells (PDCs), have a pivotal role in the etiopathogenesis of SLE.Raised serum levels of IFN-α in SLE patients have been noted for more than 20 years [13], and these levels are correlated with both disease activit
Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis
Amal Elfaitouri, Bj?rn Herrmann, Agnes B?lin-Wiener, Yilin Wang, Carl-Gerhard Gottfries, Olof Zachrisson, R?diger Pipkorn, Lars Rnnblom, Jonas Blomberg
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081155
Abstract: Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.
RNA-Seq for Enrichment and Analysis of IRF5 Transcript Expression in SLE
Rivka C. Stone, Peicheng Du, Di Feng, Kopal Dhawan, Lars Rnnblom, Maija-Leena Eloranta, Robert Donnelly, Betsy J. Barnes
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054487
Abstract: Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients. Given that human IRF5 exists as multiple alternatively spliced transcripts with distinct function(s), it is important to determine whether the IRF5 transcript profile expressed in healthy donor immune cells is different from that expressed in SLE patients. Moreover, it is not currently known whether an IRF5-SLE risk haplotype defines the profile of IRF5 transcripts expressed. Using standard molecular cloning techniques, we identified and isolated 14 new differentially spliced IRF5 transcript variants from purified monocytes of healthy donors and SLE patients to generate an IRF5 variant transcriptome. Next-generation sequencing was then used to perform in-depth and quantitative analysis of full-length IRF5 transcript expression in primary immune cells of SLE patients and healthy donors by next-generation sequencing. Evidence for additional alternatively spliced transcripts was obtained from de novo junction discovery. Data from these studies support the overall complexity of IRF5 alternative splicing in SLE. Results from next-generation sequencing correlated with cloning and gave similar abundance rankings in SLE patients thus supporting the use of this new technology for in-depth single gene transcript profiling. Results from this study provide the first proof that 1) SLE patients express an IRF5 transcript signature that is distinct from healthy donors, 2) an IRF5-SLE risk haplotype defines the top four most abundant IRF5 transcripts expressed in SLE patients, and 3) an IRF5 transcript signature enables clustering of SLE patients with the H2 risk haplotype.
Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus
Deborah S. Cunninghame Graham,David L. Morris,Tushar R. Bhangale,Lindsey A. Criswell,Ann-Christine Syv?nen,Lars Rnnblom,Timothy W. Behrens,Robert R. Graham,Timothy J. Vyse
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002341
Abstract: Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ~8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (Pcomb<5×10?8): NCF2 (Pcomb = 2.87×10?11), IKZF1 (Pcomb = 2.33×10?9), IRF8 (Pcomb = 1.24×10?8), IFIH1 (Pcomb = 1.63×10?8), and TYK2 (Pcomb = 3.88×10?8). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ~30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.
Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus
Andreas J?nsen, Sara C Nilsson, Emma Ahlqvist, Elisabet Svenungsson, Iva Gunnarsson, Karin G Eriksson, Anders Bengtsson, Agneta Zickert, Maija-Leena Eloranta, Lennart Truedsson, Lars Rnnblom, Gunnel Nordmark, Gunnar Sturfelt, Anna M Blom
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3539
Abstract: The exons of complement inhibitor genes CD46 and CFH (factor H) were fully sequenced using the Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and in healthy controls (n = 523).We found nonsynonymous, heterozygous mutations in CFH in 6.1% patients with nephritis, in comparison with 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two nonsynonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients versus 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in noncoding regions of CD46, which were previously implicated in aHUS.SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease affecting multiple organs that is characterized by circulating antibodies to nuclear antigens. Many studies have demonstrated a strong genetic component to SLE. Several susceptibility loci have recently been identified in genes encoding proteins involved in many immunological pathways [1], including B-cell signaling and development, cytokine production [2], the type I interferon pathway [3,4], signaling through Toll-like receptors, and neutrophil function [5].One of the immune system cascades involv
Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis
Karin Bolin, Johanna K. Sandling, Agneta Zickert, Andreas J?nsen, Christopher Sj?wall, Elisabet Svenungsson, Anders A. Bengtsson, Maija-Leena Eloranta, Lars Rnnblom, Ann-Christine Syv?nen, Iva Gunnarsson, Gunnel Nordmark
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084450
Abstract: Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7×10?9, OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6×10?3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
Small Size Hashes with Enhanced Security
Lars R Knudsen
International Journal of Network Security , 2006,
Abstract: This paper contains techniques for enhancing the strength of any cryptographic hash function. For an ``ideal'', traditional hash function with an m-bit result, the complexity of a collision attack is approximately 2^{m/2}. Here constructions are presented where collisions are harder to find.
How to Live with the Enemy: Understanding Tolerance to Parasites
Lars R?berg
PLOS Biology , 2014, DOI: 10.1371/journal.pbio.1001989
Abstract: How do we defend ourselves against pathogenic microbes and other parasites infecting us? Research on defence against parasites has traditionally focused on resistance—the ability to prevent infection or limit parasite replication. The genetics, physiology, and evolutionary ecology of such traits are now relatively well understood. During the last few years it has been realized that another, conceptually different type of defence also plays an important role in animal host–parasite interactions. This type of defence is called tolerance, and can be defined as the ability to limit the health effects of parasites without preventing infection or controlling parasite replication. Our understanding of the causes and consequences of variation in tolerance is, however, still rudimentary. Three recent studies shed light on these questions. In a study of HIV in humans, Regoes et al. show that an MHC class I gene affects not only resistance (as previously known) but also tolerance. In a study of voles, Jackson et al. identify a transcription factor mediating age differences in tolerance to macroparasites. Finally, Hayward et al. demonstrate that tolerance to intestinal parasites in sheep is under positive directional selection, but that most of the variation is environmentally induced rather than heritable. These studies increase our knowledge of the genetic and physiological sources of variation in tolerance, and how this variation affects Darwinian fitness. In addition, they illustrate different approaches to untangle tolerance from other factors determining the health effects of infectious disease.
Low-Level Laser on Hearing: Is There an Effect?
Jan Tunér,Lars Hode
ISRN Otolaryngology , 2013, DOI: 10.1155/2013/839256
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