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Signaling Defects (signaling + defect)
Selected AbstractsSignaling defects in anti-tumor T cellsIMMUNOLOGICAL REVIEWS, Issue 1 2008Alan B. Frey Summary: The immune response to cancer has been long recognized, including both innate and adaptive responses, showing that the immune system can recognize protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumor, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumors produce antigens and that priming occurs. Unfortunately, just as obviously, tumors grow, implying that anti-tumor immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumor immunity is suppressed. Both possibilities are supported by current data. In experimental animal models of cancer and also in patients, systemic immunity is usually not dramatically suppressed, because tumor-bearing animals and patients develop T-cell-dependent immune responses to microbes and to either model antigens or experimental cancer vaccines. However, inhibition of specific anti-tumor immunity is common, and several possible explanations of tolerance to tumor antigens or tumor-induced immunesuppression have been proposed. Inhibition of effective anti-tumor immunity results from the tumor or the host response to tumor growth, inhibiting the activation, differentiation, or function of anti-tumor immune cells. As a consequence, anti-tumor T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumor T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumor T cells, and the vanguard of experimental therapy now focuses on vaccination in combination with blockade of immunosuppressive mechanisms. This review discusses several potential mechanisms by which anti-tumor T cells may be inhibited in function. [source] Regression of systemic lupus erythematosus after development of an acquired Toll-like receptor signaling defect and antibody deficiencyARTHRITIS & RHEUMATISM, Issue 9 2009Marcella Visentini Toll-like receptor 9 (TLR-9) and TLR-7 may have a role in the production of anti-DNA and anti-RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to the development of systemic lupus erythematosus (SLE). Herein we describe a patient with SLE who had long-lasting remission of her autoimmune disease after development of an antibody deficiency resembling common variable immunodeficiency (CVID). After CVID had developed, anti,double-stranded DNA antibodies disappeared, although antinuclear antibodies remained positive for >10 years. In vitro studies revealed that the patient's B cells proliferated poorly and failed to differentiate into plasmablasts after stimulation of either TLR-9 or TLR-7, providing evidence for an acquired defect of the signaling pathway downstream of these TLRs. These observations suggest, although indirectly, that signaling through TLR-9 and TLR-7 is important in the pathogenesis of human SLE, and indicate that investigation of potential treatment strategies with TLR antagonists is warranted. [source] Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 8 2008Chih-Li Lin Abstract Insulin resistance is the primary characteristic of type 2 diabetes which as a result of insulin signaling defects. It has been suggested that the tea polyphenol (,)-epigallocatechin-3-gallate (EGCG) displays some antidiabetic effects, but the mechanism for EGCG insulin-enhancing effects is incompletely understood. In the present study, the investigations of EGCG on insulin signaling are performed in insulin-responsive human HepG2 cells cotreated with high glucose. We found that the high glucose condition causes significant increasing Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1), leading to reduce insulin-stimulated phosphorylation of Akt. As the results, the insulin metabolic effects of glycogen synthesis and glucose uptake are inhibited by high glucose. However, the treatment of EGCG improves insulin-stimulated downsignaling by reducing IRS-1 Ser307 phosphorylation. Furthermore, we also demonstrated these EGCG effects are essential depends on the 5,-AMP-activated protein kinase (AMPK) activation. Together, our data suggest a putative link between high glucose and insulin resistance in HepG2 cells, and the EGCG treatment attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway. [source] Ellis,van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 4 2009Victor L. Ruiz-Perez Abstract Ellis,van Creveld syndrome (EvC; OMIM 225500) is a recessive disorder comprising chondrodysplasia, polydactyly, nail dysplasia, orofacial abnormalities and, in a proportion of patients, cardiovascular malformations. Weyers acrodental dysostosis (Weyers; OMIM 193530) is an allelic dominant disorder comprising polydactyly, nail dysplasia, and orofacial abnormalities. EvC results from loss-of-function mutations in EVC or EVC2, the phenotype associated with the mutations in these two genes being indistinguishable. Three convincing causative mutations have been identified in patients with Weyers acrodental dysostosis, which are clustered in the last coding exon of EVC2 and lead to production of a truncated protein lacking the final 43 amino acids. Localization and function of EVC and EVC2 are inferred from studying the murine orthologs. Both Evc and Evc2 proteins localize to the basal bodies of primary cilia and analysis of an Ellis,van Creveld mouse model, which includes the limb shortening and tooth abnormalities of EvC patients, has demonstrated Hedgehog signaling defects in the absence of Evc. The loss of Evc2 has not been studied directly, but Hedgehog signaling is impaired when a mutant murine Evc2 Weyer variant is expressed in vitro. We conclude that the phenotypic abnormalities in EvC and Weyers syndrome result from tissue specific disruption of the response to Hh ligands. © 2009 Wiley-Liss, Inc. [source] Mattson MP, Chan SL, and Camandola S. Presenilin mutations and calcium signaling defects in the nervous and immune systems.BIOESSAYS, Issue 10 2001BioEssays 2001;23:73 No abstract is available for this article. [source] |