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Hydroxyl Radical Modification of Immunoglobulin G Generated Cross-Reactive Antibodies: Its Potential Role in Systemic Lupus Erythematosus
Hani A. Al-Shobaili, Ahmad A. Al Robaee, Abdullateef Alzolibani, Muhammad Ismail Khan and Zafar Rasheed
Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders , 2012, DOI: 10.4137/CMAMD.S6793
Abstract: Objective: Role of reactive oxygen species (ROS) modified human Immunoglobulin G (IgG) in systemic lupus erythematosus (SLE) has been investigated. Methods: Human IgG was modified by hydroxyl-radicals. Immunogenicity of native and modified human IgG was probed by inducing polyclonal antibodies in rabbits. Cross-reactions of induced antibodies with nucleic acid, chromatin, different blood proteins and their ROS modified conformers were determined by competitive inhibition ELISA. The binding characteristics of circulating autoantibodies in SLE patients (n = 72) against native and modified IgG were screened by direct binding and competition ELISA and the results were compared with healthy age-matched controls (n = 39). Results: Induced antibodies against ROS-modified human IgG exhibited diverse antigen binding characteristics. Native DNA, native chromatin and their ROS-modified conformers were found to be effective inhibitors of induced antibody-immunogen interaction. Induced antibodies against native human IgG showed negligible binding to the above mentioned nucleic acid antigens. SLE sera (48.6%) showed strong binding to ROS-human IgG in comparison with its native analogue (P < 0.01). Normal human sera (NHS) showed negligible binding with either antigen (P > 0.05). Conclusion: ROS-induced modifications in human IgG present neo-epitopes, and make it a potential immunogen. The induced antibodies against ROS-modified human IgG resembled the diverse antigen-binding characteristics of naturally occurring SLE anti-DNA autoantibodies. ROS-modified IgG may be one of the factors for the induction of circulating SLE autoantibodies.
The role of adult educators towards (potential) participants and their contribution to increasing participation in adult education - insights into existing research  [cached]
Aiga von Hippel,Rudolf Tippelt
European Journal for Research on the Education and Learning of Adults , 2010,
Abstract: Increasing participation in adult education and addressing certain (disadvantaged) target groups is not only a professed aim of educational politics on both the national and the international level, but also a pedagogical goal. Target group and participant orientation are fundamental concepts in this process. This article discusses results of a recent German research project which examined the perspective of adult educators. The question is raised as to how far adult educators believe that target groups and participant oriented quality and the promotion of competences among adult educators may contribute to an increase in enrolment in further education. By examining the attitudes of adult educators with regard to target groups and participant orientation possible ways of improving target group participation and participant orientation on the institutional level are suggested. Furthermore, the article touches upon research questions, asking how research on potential participants and actual participants could be linked to research on educational programmes and the profession.
The Role of Cytokine in the Lupus Nephritis
Yasunori Iwata,Kengo Furuichi,Shuichi Kaneko,Takashi Wada
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/594809
Abstract: Lupus nephritis (LN) is a major clinical manifestation of systemic lupus erythematosus (SLE). Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ) and dendritic cells (DCs), secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN.
Hyperosmotic stimulus induces reversible angiogenesis within the hypothalamic magnocellular nuclei of the adult rat: a potential role for neuronal vascular endothelial growth factor
Gérard Alonso, Evelyne Galibert, Anne Duvoid-Guillou, Anne Vincent
BMC Neuroscience , 2005, DOI: 10.1186/1471-2202-6-20
Abstract: Our results provide evidence that cell proliferation occurring within the SON of osmotically stimulated adult rats corresponds to local angiogenesis. We show that 1) a large majority of the SON proliferative cells is associated with capillary vessels, 2) this proliferative response correlates with a progressive increase in density of the capillary network within the nucleus, and 3) SON capillary vessels exhibit an increased expression of nestin and vimentin, two markers of newly formed vessels. Contrasting with most adult CNS neurons, hypothalamic magnocellular neurons were found to express vascular endothelial growth factor (VEGF), a potent angiogenic factor whose production was increased by osmotic stimulus. When VEGF was inhibited by dexamethasone treatment or by the local application of a blocking antibody, the angiogenic response was strongly inhibited within the hypothalamic magnocellular nuclei of hyperosmotically stimulated rats.This study shows that the functional stimulation of hypothalamic magnocellular neurons of adult rats induces reversible angiogenesis via the local secretion of neuronal VEGF. Since many diseases are driven by unregulated angiogenesis, the hypothalamic magnocellular nuclei should provide an interesting model to study the cellular and molecular mechanisms involved in the regulation of angiogenesis processes within the adult CNS.Within the CNS, capillary blood vessels form a network of highly interconnected tubes that direct and maintain blood flow throughout the different regions. In the adult CNS, the vascular supply is not homogenous and marked differences exist in the capillary density present within specific brain regions. Since blood glucose represents the major metabolic support of neurons, it has been proposed that the density of the vasculature network is related to the different levels of the metabolic activity [1]. It is generally admitted that the adult vasculature is essentially quiescent and that adjustment of blood supply
Adult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cells  [cached]
Philippe Taupin
International Journal of Medical Sciences , 2008,
Abstract: The pathogenesis of neurological diseases and disorders remains mostly unknown. Neuroinflammation has been proposed as a causative factor for neurological diseases. The confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals has tremendous implications for our understanding of the physio- and pathology of the nervous system. The generation of newborn neuronal cells in the adult brain is modulated in neurological diseases and during inflammation. This suggests that adult neurogenesis is involved in the pathogenesis of neurological diseases and disorders, particularly during neuroinflammation. In this manuscript, we will review the modulation of adult neurogenesis in neurological diseases and during neuroinflammation. We will discuss the role and contribution of neuroinflammation and adult neurogenesis to neurological diseases and disorders, and for the therapeutic potential of adult NSCs.
Natural Treg and role of IL-2 in lupus
Gabriela Riemekasten, Jens Y Humrich
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3411
Abstract: The role of naturally occurring regulatory T cells (Treg) and of IL-2 was studied in vitro and in vivo by using flow cytometry and the NZB/W lupus mouse model.In healthy individuals as well as in young lupus prone mice without any signs of the disease, effector T cells are tightly controlled by naturally occurring regulatory T cells (Treg) that can be shown by different approaches: 1. After depletion of Treg cells by anti-CD25 therapy, murine lupus is strongly accelerated. 2. After passive transfer of Treg (CD4+CD25+ T cells consisting of 95% FoxP3+ T cells), murine lupus improved reflected by reduced proteinuria and increased survival compared to control mice [1]. 3. In vitro depletion of Treg lead to better detection of autoantigen-specific effector T cells with frequencies above the detection limit for flow cytometry. The frequency of autoangien-specific T cells correlate with the disease activity in human and murine lupus. The control of effector T cells by Treg cells can be also used for studying the phenotype of effector T cell and their function at an autoantigen-specific level. However; as shown in the murine NZB/W lupus model, there is a progressive loss of Treg/Tcon homeostasis during lupus development in different compartments with a progressive Treg deficiency. In lupus mice with proteinuria, the phenotype of effector T cells is very similar to the T cell phenotype obtained in IL-2 deficient mice. As known from the literature, IL-2 levels are decreased in SLE patients. According to the characteristics of Treg, they are more sensitive to IL-2 deficiency. Supporting this, addition of IL-2 resulted in a dominant proliferation of Treg cells. In murine lupus, IL-2 improved survival and decreased proteinuria in diseased NZB/W mice.Our data support the possible role of Treg and of IL-2 supplementation in lupus therapy. Further studies are underway to evaluate IL-2 supplementation and its effects on immune cells and disease symptoms in lupus.
Role of Cytokines in Systemic Lupus Erythematosus: Recent Progress from GWAS and Sequencing
John J. Connolly,Hakon Hakonarson
Journal of Biomedicine and Biotechnology , 2012, DOI: 10.1155/2012/798924
Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, known to have a strong genetic component. Concordance between monozygotic twins is approximately 30–40%, which is 8–20 times higher than that of dizygotic twins. In the last decade, genome-wide approaches to understanding SLE have yielded many candidate genes, which are important to understanding the pathophysiology of the disease and potential targets for pharmaceutical intervention. In this paper, we focus on the role of cytokines and examine how genome-wide association studies, copy number variation studies, and next-generation sequencing are being employed to understand the etiology of SLE. Prominent genes identified by these approaches include BLK, FCγR3B, and TREX1. Our goal is to present a brief overview of genomic approaches to SLE and to introduce some of the key discussion points pertinent to the field.
B-cell targeted therapy in systemic lupus erythematosus: potential of rituximab
Wiesik-Szewczyk E, Olesinska M
Biologics: Targets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/BTT.S25407
Abstract: -cell targeted therapy in systemic lupus erythematosus: potential of rituximab Review (2077) Total Article Views Authors: Wiesik-Szewczyk E, Olesinska M Published Date September 2012 Volume 2012:6 Pages 347 - 354 DOI: http://dx.doi.org/10.2147/BTT.S25407 Received: 08 May 2012 Accepted: 21 July 2012 Published: 26 September 2012 E Wiesik-Szewczyk, M Olesinska Institute of Rheumatology, Department of Connective Tissue Diseases, Warsaw, Poland Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology, and the limited available therapeutic options for this disease, are frustrating to both clinicians and patients. However, recent advances in the understanding of disease mechanisms have given rise to numerous studies on specific approaches to SLE treatment. Rituximab, the first chimeric, mouse-human monoclonal antibody which is directed against CD20, seems to be a new therapeutic option. The purpose of this review is to explain the current clinical evidence on the therapeutic use of rituximab in adult SLE patients. Two randomized clinical trials with rituximab (the EXPLORER and LUNAR studies) failed to prove efficacy of this drug on SLE. Ongoing data analysis continues to explain the reasons behind why this treatment fails to work. However data from open source and observational studies contrast with clinical trials results. The global analysis of this data supports the off-label use of rituximab in subsets of SLE that are refractory to standard treatment.
Role of RUNX in autoimmune diseases linking rheumatoid arthritis, psoriasis and lupus
Marta E Alarcón-Riquelme
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1203
Abstract: The study of the genetics of complex diseases is now advancing rapidly as new genes are being discovered that are involved in susceptibility for a variety of diseases. However, more impressive is the fact that the identification of the genes and the polymorphisms involved in susceptibility is opening new avenues of study. The best example at hand is the recent identification of a polymorphism in the PDCD1 (programmed cell death 1) gene as a susceptibility factor for systemic lupus erythematosus, coding for the immunoreceptor PD-1 [1]. The polymorphism identified, named PD1.3 and whose allele A is strongly associated with the disease, is so far the only polymorphism within the PDCD1 gene that can provide a functional explanation for the susceptibility related to this gene. Furthermore, the same allele A was associated to diabetes type 1 [2]. Association was also identified with rheumatoid arthritis [3].The PD1.3 polymorphism is located in the fourth intron of the PDCD1 gene [1]. Within the fourth intron there is a sequence of 160 base pairs enriched in binding sites for various transcription factors important in hematopoiesis, suggesting that this element might act as a regulatory enhancer. Importantly, the regulator element is not conserved in the mouse (ME Alarcón-Riquelme and L Prokunina, unpublished data), suggesting that the regulation of PD-1 is different in both species. The polymorphism associated with human lupus changed a common G nucleotide to an A nucleotide, thereby disrupting a binding site for what seemed to be the RUNX1 transcription factor. The binding was tested on a simple band-shift assay (electrophoretic mobility-shift assay) with specific antibodies, experiments that supported the notion that the associated allelic variant did not allow binding of a protein complex and that the complex included, among other proteins, RUNX1 [1], thereby providing a functional explanation for the genetic association.The potential role of RUNX1 was underscored by t
Murine Models of Systemic Lupus Erythematosus
Daniel Perry,Allison Sang,Yiming Yin,Ying-Yi Zheng,Laurence Morel
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/271694
Abstract: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.
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