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Uncontrolled Activation (uncontrolled + activation)
Selected AbstractsPrimary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasisIMMUNOLOGICAL REVIEWS, Issue 1 2005Gael Ménasché Summary:, Hemophagocytic syndrome (HS) is a severe and often fatal syndrome resulting from potent and uncontrolled activation and proliferation of T-lymphocytes, leading to excessive macrophage activation and multiple deleterious effects. The onset of HS characterizes several inherited disorders in humans. In each condition, the molecular defect impairs the granule-dependent cytotoxic activity of lymphocytes, thus highlighting the determinant role of this function in driving the immune system to a state of equilibrium following infection. It has also been shown that some of the proteins required for lytic granule secretion are required for melanocyte function, leading to associated hypopigmentation in these conditions. This review focuses on several effectors of this secretory pathway, recently identified, because their defects cause these disorders, and discusses their role and molecular interactions in granule-dependent cytotoxic activity. [source] Severe acute respiratory syndrome in childrenPEDIATRIC PULMONOLOGY, Issue 4 2003Gary W.K. Wong MD Abstract Severe acute respiratory syndrome (SARS) is a newly described and highly contagious respiratory infection. Many adult patients will develop progressive hypoxia, and a large proportion will develop respiratory distress syndrome (RDS), possibly related to massive and uncontrolled activation of the immune system. The mortality has been reported to be quite high, especially in the elderly with comorbid conditions. The causative agent has been identified as a novel coronavirus, and children appear to acquire the infection by close-contact household exposure to an infected adult. However, the severity is much milder and the clinical progression much less aggressive in young children. The exact pathophysiology of SARS is still unclear, and the medical treatment of SARS remains controversial. The main treatment regime used in Hong Kong is a combination of ribavirin and steroid. To date, there have been no reported case fatalities in children with this disease. The success of reducing the burden of this infection in children will depend on proper isolation of infected adults early in the course of illness. Strict public health policy and quarantine measures are the key in controlling the infection in the community. Pediatr Pulmonol. 2003; 36:261,266. © 2003 Wiley-Liss, Inc. [source] The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelaeAPMIS, Issue 11 2002Review article The literature dealing with the biochemical basis of bacteriolysis and its role in inflammation, infection and in post-infectious sequelae is reviewed and discussed. Bacteriolysis is an event that may occur when normal microbial multiplication is altered due to an uncontrolled activation of a series of autolytic cell-wall breaking enzymes (muramidases). While a low-level bacteriolysis sometimes occurs physiologically, due to "mistakes" in cell separation, a pronounced cell wall breakdown may occur following bacteriolysis induced either by beta-lactam antibiotics or by a large variety of bacteriolysis-inducing cationic peptides. These include spermine, spermidine, bactericidal peptides defensins, bacterial permeability increasing peptides from neutrophils, cationic proteins from eosinophils, lysozyme, myeloperoxidase, lactoferrin, the highly cationic proteinases elastase and cathepsins, PLA2, and certain synthetic polyamino acids. The cationic agents probably function by deregulating lipoteichoic acid (LTA) in Gram-positive bacteria and phospholipids in Gram-negative bacteria, the presumed regulators of the autolytic enzyme systems (muramidases). When bacteriolysis occurs in vivo, cell-wall- and -membrane-associated lipopolysaccharide (LPS (endotoxin)), lipoteichoic acid (LTA) and peptidoglycan (PPG), are released. These highly phlogistic agents can act on macrophages, either individually or in synergy, to induce the generation and release of reactive oxygen and nitrogen species, cytotoxic cytokines, hydrolases, proteinases, and also to activate the coagulation and complement cascades. All these agents and processes are involved in the pathophysiology of septic shock and multiple organ failure resulting from severe microbial infections. Bacteriolysis induced in in vitro models, either by polycations or by beta-lactams, could be effectively inhibited by sulfated polysaccharides, by D-amino acids as well as by certain anti-bacteriolytic antibiotics. However, within phagocytic cells in inflammatory sites, bacteriolysis tends to be strongly inhibited presumably due to the inactivation by oxidants and proteinases of the bacterial muramidases. This might results in a long persistence of non-biodegradable cell-wall components causing granulomatous inflammation. However, persistence of microbial cell walls in vivo may also boost innate immunity against infections and against tumor-cell proliferation. Therapeutic strategies to cope with the deleterious effects of bacteriolysis in vivo include combinations of autolysin inhibitors with combinations of certain anti-inflammatory agents. These might inhibit the synergistic tissue- and- organ-damaging "cross talks" which lead to septic shock and to additional post-infectious sequelae. [source] The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic feverARTHRITIS & RHEUMATISM, Issue 11 2009Massimo Ferretti Objective Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1, or tumor necrosis factor , (TNF,). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor,associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-,B signaling, both of which are processes that influence the development of inflammatory cells. Methods The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP -specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay. Results Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23,3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNF,. Conclusion These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function. [source] Fluorescence (Förster) resonance energy transfer imaging of oncogene activity in living cellsCANCER SCIENCE, Issue 1 2006Etsuko Kiyokawa A hallmark of cancer cells is their uncontrolled activation of growth signal transduction cascades comprised of oncogene products. Overexpression and activating mutations of the growth factor receptors Ras and Raf are frequently observed in human cancer cells. Several research groups, including our own, have been developing probes based on the principle of fluorescence (Förster) resonance energy transfer (FRET) to visualize how signaling molecules, including oncogene products, are regulated in normal and cancerous cells in the living state. In this review, we will briefly introduce the principle of FRET-based probes, present an overview of the probes reported to date, and discuss the perspectives of these probes and fluorescent imaging systems in cancer biology. (Cancer Sci 2006; 97: 8,15) [source] | ||||||||||