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November-December 2008 l Vol 14 l No 11-12
Research Articles
Chronic Lymphocytic Leukemia Cells Recognize Conserved Epitopes Associated with Apoptosis and Oxidation
Rosa Catera, Gregg J Silverman, Katerina Hatzi, Till Seiler, Sebastien Didier, Lu Zhang, Maxime Hervé, Eric Meffre, David G Oscier, Helen Vlassara, R Hal Scofield, Yifang Chen, Steven L Allen, Jonathan Kolitz, Kanti R Rai, Charles C Chu, and Nicholas Chiorazzi
Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic malignancy affecting Caucasian adults. The disease is characterized by a monoclonal expansion of a subset of antigen-experienced human B cells expressing surface membrane CD5. CLL cells likely derive from autoreactive B cells and Catera et al. explored whether apoptosis-associated autoantigens were relevant to the selection and expansion of leukemic cells in CLL. Their findings suggest that CLL arises from a B-cell subset which normally helps clear cellular debris and metabolic byproducts by recognition of ubiquitous, conserved autoantigens. Response to this recognition may drive the clonal expansion of leukemic cells, thereby contributing to clinical outcome.
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Pathogenic Autoantibodies in Systemic Lupus Erythematosus Are Derived from Both Self-Reactive and Non-Self-Reactive B Cells
Jie Zhang, Annett M Jacobi, Tao Wang, and Betty Diamond
Antibodies to a wide variety of autoantigens are a hallmark of systemic lupus erythematosus (SLE). Anti-double-stranded DNA (anti-dsDNA) antibodies can develop from non-DNA-reactive B cells and may play a crucial role for somatic mutation in dsDNA binding. However, only a limited number of anti-dsDNA antibodies have been analyzed previously and other mechanisms for the generation of anti-dsDNA antibodies in SLE patients cannot be excluded. Zhang et al. isolated three somatically mutated anti-dsDNA antibodies from peripheral blood B cells of a lupus patient and reverted them to their germline configuration. Two of the three reverted anti-dsDNA antibodies displayed decreased DNA binding while the third recognized dsDNA in both its mutated and germline configuration. This implies that B cell activation occurs in response to self and non-self antigens, while selection after activation may be mediated by self antigen. Future work with additional patients will be necessary to determine if multiple tolerance checkpoints must fail for a lupus-like phenotype to develop.
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Endogenous Erithropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis
Manuela Mengozzi, Ilaria Cervellini, Paolo Bigini, Sara Martone, Antonella Biondi, Rosetta Pedotti, Barbara Gallo, Sara Barbera, Tiziana Mennini, Mariaserena Boraso, Marina Marinovich, Edwige Petit, Myriam Bernaudin, Roberto Bianchi, Barbara Viviani, and Pietro Ghezzi
Systemically administered erythropoietin (EPO) crosses the blood brain barrier and is protective in several animal models of disease. Endogenous EPO is induced by hypoxic or ischemic injury, however, little is known regarding the expression of endogenous EPO in central nervous system (CNS) diseases. Mengozzi et al. investigated the expression of EPO in the spinal cord using models of experimental autoimmune encephalomyelitis (EAE), representative of multiple sclerosis. Their findings indicate EPO is induced in EAE and is negatively regulated by interferon gamma and tumor necrosis factor. This cross-talk between EPO and inflammatory cytokines in the CNS may have important implications in disease pathogenesis. Therapeutic exploitation strategies could be aimed at upregulating the endogenous EPO-mediated protective response.
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Estradiol’s Salutary Effects on Keratinocytes Following Trauma-Hemorrhage Are Mediated by Estrogen Receptor (ER)-α and ER-β
Fariba Moeinpour, Mashkoor A Choudhry, Luiz F Poli de Figueiredo, Kirby I Bland, and Irshad Chaudry
Sex hormones are known to modulate immune function in animals and humans under normal conditions as well as under stress. Administration of estrogen following trauma-hemorrhage attenuates the elevation of cytokine production and mitogen-activated protein kinase. Whether the beneficial effects of estrogen are mediated by estrogen receptor ER-α or ER-β remains unknown. In this work, Moeinpour et al. sought to determine which estrogen receptor was responsible for the salutary effects in a model of trauma-hemorrhage. Using an agonist strategy to isolate receptor subtypes, Moeinpour et al. determined that both ER-α and ER-β contribute to the beneficial effects of estrogen on keratinocytes after trauma-hemorrhage.
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Pancreatic Expression and Mitochondrial Localization of the Progestin-AdipoQ Receptor PAQR10
L Jorge Gonez, Gaetano Naselli, Ilia Banakh, Hideo Niwa, and Leonard C Harrison
Steroid hormones have been shown to rapidly modify cell function by binding to surface membrane receptors. In a screen for genes differentially expressed in mouse pancreatic β-cells, Góñez et al. identified a candidate steroid membrane receptor, the progestin and adipoQ receptor (PAQR) 10. PAQR10 is structurally related to bacterial hemolysins, pore-forming virulence factors that target mitochondria and regulate apoptosis. Góñez et al.propose PAQR10 may act at the level of the mitochondrion to regulate pancreatic endocrine cell development and survival, and further studies are likely to establish a key role of PAQR10 in pancreatic β-cell biology.
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Angiogenesis and Diabetes: Different Responses to Pro-Angiogenic Factors in the Chorioallantoic Membrane Assay
Giovana S Di Marco, Antoine Alam, Frédéric Dol, Pierre Corvol, Jean-Marie Gasc, and Etienne Larger
Diabetic patients exhibit impaired angiogenesis often leading to difficulties in wound healing and organ transplantation. Therapeutic angiogenesis or arteriogenesis may represent a beneficial strategy for patients with diabetes as well as those with peripheral or coronary artery disease ineligible for surgical revascularization. Trials involving therapeutic angiogenesis have garnered negative responses due in part to the direct effect of hyperglycemia on neovascularization. To further investigate this, Di Marco et al. tested the activity of proangiogenic molecules under hyperglycemic conditions. Of the three molecules tested, results showed the negative effects of diabetes on capillary density could be overcome only by vascular endothelial growth factor (VEGF) overexpression. This suggests proangiogenic factors may play a role in patients with diabetes and future trials involving therapeutic angiogenesis should be monitored for hyperglycemic interference.
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Acute, Muscle-Type Specific Insulin Resistance Following Injury
LaWanda H Thompson, Hyeong T Kim, Yuchen Ma, Natalia A Kokorina, and Joseph L Messina
Severe injuries such as surgical trauma, hemorrhage, thermal injury, and sepsis can lead to acute insulin resistance. The efficacy of intensive insulin therapy in these injuries suggests that understanding acute insulin resistance mechanisms may be important for development of new therapeutic strategies. Thompson et al. used a surgical trauma and hemorrhage model to determine the development, timing and muscle selectivity of hemorrhage-induced skeletal muscle insulin resistance. The data indicate defects in insulin signaling occurred rapidly and were reversible. Additionally, insulin signaling was more severe in some skeletal muscles but did not occur in cardiac muscle. The mechanisms leading to recovering insulin responsiveness may be key in reducing morbidity and mortality in the intensive care environment.
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Inhibition of COX 1 and 2 prior to Renal Ischemia/Reperfusion Injury Decreases the Development of Fibrosis
Carla Q Feitoza, Giselle M Gonçalves, Patrícia Semedo, Marcos A Cenedeze, Hélady S Pinheiro, Felipe Caetano Beraldo, Oscar Fernando Pavão dos Santos, Vicente de Paula A Teixeira, Marlene A dos Reis, Marilda Mazzali, Alvaro Pacheco-Silva, and Niels O S Câmara
Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Blockade of COX 1 and 2 is associated with organ improvement after ischemic damage. Feitoza et al. investigate the role of COX 1 and 2 in the development of fibrosis by performing COX 1 and 2 blockade immediately before IRI. Inhibition of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response. The present work demonstrates that COXs play an important role in the development of sustained inflammation. There is no effective treatment for renal fibrosis and COX blockade prior to acute injury may represent a treatment strategy for renal damage associated with fibrosis.
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Review Articles
Pharmacology of Traumatic Brain Injury: Where Is the "Golden Bullet"?
Kathryn Beauchamp, Haitham Mutlak, Wade R Smith, Esther Shohami, and Philip F Stahel
Traumatic bran injury (TBI) – a major health care problem and significant socioeconomic challenge – is the leading cause of death and disability in young people. Approximately 1.5 million patients in the United States are affected each year, and despite advances in research and improved neurointensive care, no specific pharmacological therapy for TBI patients is currently available. Beauchamp et al. review the published prospective clinical trials on pharmacological treatment modalities for TBI patients and outline future promising therapeutic options in the field.
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Adipokines and Insulin Resistance
Katja Rabe, Michael Lehrke, Klaus G Parhofer, and Uli C Broedl
Understanding the pathogenesis of obesity and its metabolic sequelae has advanced rapidly over the past decade. Due to the dramatic rise of obesity, adipose tissue – traditionally considered to be an energy storage depot – has gained tremendous scientific interest. Rabe et al. summarize current data on the effect of adipose tissue-derived hormones on insulin resistance.
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Erratum
Erratum
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