968 resultados para Chronic lymphoproliferative disorders. Immunophenotyping. Immune system lymphoma


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Biologic agents have substantially advanced the treatment of immunological disorders, including chronic inflammatory and autoimmune diseases. However, these drugs are often associated with adverse events (AEs), including allergic, immunological and other unwanted reactions. AEs can affect almost any organ or system in the body and can occur immediately, within minutes to hours, or with a delay of several days or more after initiation of biologic therapy. Although some AEs are a direct consequence of the functional inhibition of biologic-agent-targeted antigens, the pathogenesis of other AEs results from a drug-induced imbalance of the immune system, intermediary factors and cofactors, a complexity that complicates their prediction. Herein, we review the AEs associated with biologic therapy most relevant to rheumatic and immunological diseases, and discuss their underlying pathogenesis. We also include our recommendations for the medical management of such AEs. Increased understanding and improved risk management of AEs induced by biologic agents will enable better use of these versatile immune-response modifiers.

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Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.

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Lapoptosi s un procs fisiolgic que controla el nombre de cllules en organismes superiors. Lapoptosi est estrictament regulada i sha vist que est implicada en la patognesi dalgunes malalties del sistema nervis. En aquest sentit, un excs de mort cellular contribueix a les malalties neurodegenerati- ves, mentre que, el seu dficit s una de les raons del desenvolupament de tumors. El punt principal de regulaci del procs apopttic s lactivaci de les caspases, cistena-proteases que tenen especificitat pels residus asprtic. Les caspases es poden activar per dos mecanismes principals: (1) alliberament de citocrom C dels mitocondris alterats al citoplasma i (2) lactivaci dels receptors de la membrana anomenats receptors de mort (DR, de langls death receptor). Aquests receptors shan caracteritzat extensament en el sistema immunitari, mentre que en el sistema nervis les seves funcions sn encara desconegudes. El present article se centra en el paper dels DR en la patognesi de malalties neurodegeneratives i suggereix el seu potencial des del punt de vista teraputic. Tamb es descriuen diverses molcules intracellulars caracteritzades per la seva habilitat en la modulaci dels DR. Entre elles, presentem dues noves protenes lifeguard i FAIM que sexpressen especficament al sistema nervis.

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Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

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Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

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Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

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Chronic granulomatous disease (CGD) is an inherited disorder of the innate immune system characterized by a defective oxidative burst of phagocytes and subsequent impairment of their microbicidal activity. Mutations in one of the NADPH-oxidase components affect gene expression or function of this system, leading to the phenotype of CGD. Defects in gp91-phox lead to X-linked CGD, responsible for approximately 70% of CGD cases. Investigation of the highly heterogeneous genotype of CGD patients includes mutation analysis, Northern blot or Western blot assays according to the particular case. The aim of the present study was to use reverse transcription (RT)-PCR for the analysis of molecular defects responsible for X-linked CGD in eight Brazilian patients and to assess its potential for broader application to molecular screening in CGD. Total RNA was prepared from Epstein B virus-transformed B-lymphocytes and reverse transcribed using random hexamers. The resulting cDNA was PCR-amplified by specific and overlapping pairs of primers designed to amplify three regions of the gp91-phox gene: exons 1-5, 3-9, and 7-13. This strategy detected defective gp91-phox expression in seven patients. The RT-PCR results matched clinical history, biochemical data (nitroblue tetrazolium or superoxide release assay) and available mutation analysis in four cases. In three additional cases, RT-PCR results matched clinical history and biochemical data. In another case, RT-PCR was normal despite a clinical history compatible with CGD and defective respiratory burst. We conclude that this new application of RT-PCR analysis - a simple, economical and rapid method - was appropriate for screening molecular defects in 7 of 8 X-linked CGD patients.

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Chronic Chagas' disease cardiomyopathy (CCC) is an often fatal outcome of Trypanosoma cruzi infection, with a poorer prognosis than other cardiomyopathies. CCC is refractory to heart failure treatments, and is the major indication of heart transplantation in Latin America. A diffuse myocarditis, plus intense myocardial hypertrophy, damage and fibrosis, in the presence of very few T. cruzi forms, are the histopathological hallmarks of CCC. To gain a better understanding of the pathophysiology of CCC, we analyzed the protein profile in the affected CCC myocardium. Homogenates from left ventricular myocardial samples of end-stage CCC hearts explanted during heart transplantation were subjected to two-dimensional electrophoresis with Coomassie blue staining; protein identification was performed by MALDI-ToF mass spectrometry and peptide mass fingerprinting. The identification of selected proteins was confirmed by immunoblotting. We demonstrated that 246 proteins matched in gels from two CCC patients. They corresponded to 112 distinct proteins. Along with structural/contractile and metabolism proteins, we also identified proteins involved in apoptosis (caspase 8, caspase 2), immune system (T cell receptor chain, granzyme A, HLA class I) and stress processes (heat shock proteins, superoxide dismutases, and other oxidative stress proteins). Proteins involved in cell signaling and transcriptional factors were also identified. The identification of caspases and oxidative stress proteins suggests the occurrence of active apoptosis and significant oxidative stress in CCC myocardium. These results generated an inventory of myocardial proteins in CCC that should contribute to the generation of hypothesis-driven experiments designed on the basis of the classes of proteins identified here.

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Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-β signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed.

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Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

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The balance of T helper (Th) cell differentiation is the fundamental process that ensures that the immune system functions correctly and effectively. The differentiation is a fine tuned event, the outcome of which is driven by activation of the T-cell in response to recognition of the specific antigen presented. The co-stimulatory signals from the surrounding cytokine milieu help to determine the outcome. An impairment in the differentiation processes may lead to an imbalance in immune responses and lead to immune-mediated pathologies. An over-representation of Th1 type cytokine producing cells leads to tissue-specific inflammation and autoimmunity, and excessive Th2 response is causative for atopy, asthma and allergy. The major factors of Th-cell differentiation and in the related disease mechanisms have been extensively studied, but the fine tuning of these processes by the other factors cannot be discarded. In the work presented in this thesis, the association of T-cell receptor costimulatory molecules CTLA4 and ICOS with autoimmune diabetes were studied. The underlying aspect of the study was to explore the polymorphism in these genes with the different disease rates observed in two geographically close populations. The main focus of this thesis was set on a GTPase of the immunity associated protein (GIMAP) family of small GTPases. GIMAP genes and proteins are differentially regulated during human Th-cell differentiation and have been linked to immune-mediated disorders. GIMAP4 is believed to contribute to the immunological balance via its role in T-cell survival. To elucidate the function of GIMAP4 and GIMAP5 and their role in human immunity, a study combining genetic association in different immunological diseases and complementing functional analyses was conducted. The study revealed interesting connections with the high susceptibility risk genes. In addition, the role of GIMAP4 during Th1-cell differentiation was investigated. A novel function of GIMAP4 in relation to cytokine secretion was discovered. Further assessment of GIMAP4 and GIMAP5 effect for the transcriptomic profile of differentiating Th1-cells revealed new insights for GIMAP4 and GIMAP5 function.

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The immune response and immune suppression are equally essential for the immune system to protect the host against an infection and to protect self-molecules in different pathophysiological conditions. Pregnancy is one of the conditions where the maternal immune system remains resistant against microbes and yet attains tolerance to protect the fetus, whose genetic material differs partially from the mothers. However, if the balance of immune suppression is not precise in the host it can favor conditions which lead to diseases, such as cancer and autoimmune disorders. This study was initiated to investigate the expression and functions of CLEVER-1/Stabilin-1, a multifunctional protein expressed on subsets of endothelial cells and type II macrophages, as an immune suppressive molecule. Firstly, the expression of CLEVER-1/stabilin-1 and its function in human placental macrophages were examined. Secondly, the expression profile and functional significance of stabilin-1 on healthy human monocytes was investigated. The results clarified the expression of CLEVER-1/stabilin-1 on placental macrophages, and verified that CLEVER-1/stabilin-1 functions as an adhesion and scavenging molecule on these cells. The data from normal monocytes revealed that the monocytes with low stabilin-1 expression carried a pro-inflammatory gene signature, and that stabilin-1 can directly or indirectly regulate pro-inflammatory genes in monocytes. Finally, it was shown that monocyte CLEVER-1/stabilin-1 dampens IFN production by T cells. To conclude, CLEVER-1/stabilin-1 is defined as an immune suppressive molecule on monocytes and macrophages. Strikingly, anti-stabilin-1 antibodies may have the potential to promote the Th1 dependent inflammatory response and counteract the tumor induced immune suppression.

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Once thought to occur only during specific periods of development, it is now clear that neurogenesis occurs in the rat hippocampus into adulthood. It is wellestablished that stress during adulthood decreases the rate of neurogenesis, but during adolescence, the effects of stress are much less understood. I investigated the effect of short-term or chronic stress during adolescence (daily lhr isolation and change of cage partner from postnatal day (PND) 30-32 or 30-45) on hippocampal neurogenesis. In experiment 1, rats were administered Bromodeoxyuridine (BrdU) daily on PND 30-32, or 46-48, to mark neurogenesis at the beginning of the stressor or after the stressor had ceased, respectively. Neither short-term nor chronic stress had an effect on proliferation or survival (evidenced by BrdU and Doublecortin (Dcx) immunohistochemistry respectively) of cells born at the beginning of the stress procedure. Compared to controls, BrdU-labeling showed chronic stress significantly increased proliferation of cells generated after the stressor had ceased, but survival of new neurons was not supported (Dcx-Iabeling). However, it may be that BrdU injections are inherently stressful. In experiment 2, the stressor (described above) was applied in the absence of BrdU injections. Ki67 (a marker of proliferation) showed that stress transiently increased cell proliferation. Dcx-Iabeling showed that stress also increased neuron survival into adulthood. Labeling with OX.,.42 (a marker of macro phages) suggested that the immune system plays a role in neurogenesis, as stress transiently decreased the number of activated microglia in the hippocampus. It can be concluded that in the adolescent male rat, chronic mild stress increases neurogenesis.

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Le fer, un mtal de transition, est requis pour la survie de presque tout les organismes vivant cause de son habilit accepter ou donner un lectron et donc catalyser plusieurs ractions biochimique fondamentales. Cependant, la mme proprit permet aussi au fer ionique dacclrer la formation de radicaux libres et donc le fer peut potentiellement avoir des effets nfastes. Consquemment, lhomostasie du fer doit tre troitement rgul, tant au niveau cellulaire que systmique. Notre tude met lemphase sur deux molcules importante pour rgulation du mtabolisme du fer : la lipocaline 2 (Lcn2) et lhepcidine. Lcn2, une protine de phase aigu, est implique dans le transport du fer par les sidrophores. Lcn2 est un candidat potentiel comme transporteur du fer qui pourrait tre responsable de laccumulation excessive du fer non li la transferrine dans le foie des patients atteints dhmochromatose hrditaire (HH). Nous avons gnr des souris double-dficiente HfeLcn2 pour valuer limportance de Lcn2 dans la pathogense de surcharge en fer hpatique dans les souris knock-out Hfe (Hfe -/-). Notre tude rvle que la dltion de Lcn2 dans les souris Hfe-/- ninfluence pas leur accumulation de fer hpatique ou leur rponse une surcharge en fer. Le phnotype des souries HfeLcn2-/- demeure indiscernable de celui des souris Hfe-/-. Nos donnes impliquent que Lcn2 nest pas essentiel pour la livraison du fer aux hpatocytes dans lHH. Lhepcidine, un rgulateur cl du mtabolisme du fer, est un petit peptide antimicrobien produit par le foie et qui rgule labsorption intestinale du fer et son recyclage par les macrophages. Lexpression de lhepcidine est induite par la surcharge en fer et linflammation, tandis que, l'inverse, elle est inhibe par l'anmie et l'hypoxie. Dans certaine situations pathologique, lhepcidine est rgule dans des directions opposes par plus dun rgulateur. Nous avons, en outre, analys comment les diffrents facteurs influencent lexpression de lhepcidine in vivo en utilisant un modle de souris avec un mtabolisme du fer altr. Nous avons examin la rgulation de lhepcidine en prsence de stimuli opposs, ainsi que la contribution des mdiateurs et des voix de signalisation en aval de lexpression de lhepcidine. Nous avons dmontr que l'rythropose, lorsque stimul par lrythropotine, mais pas par lhypoxie, diminue lexpression de lhepcidine dune faon dpendante de la dose, mme en prsence de lipopolysaccharides ou de surcharge de fer alimentaire, qui peuvent agir de manire additive. De plus, lentranement rythropotique inhibe tant la voix inflammatoire que celle de dtection du fer, du moins en partie, par la suppression du signal IL-6/STAT3 et BMP/SMAD4 in vivo. Au total, nos donnes suggrent que le niveau dexpression de lhepcidine en prsence de signaux opposs est dtermin par la force du stimulus individuel plutt que par une hirarchie absolue. Ces dcouvertes sont pertinentes pour le traitement de lanmie des maladies chronique et les dsordres de surcharge en fer.

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Le virus de lhpatite C (VHC) est un virus ARN simple brin positif (ssARN) qui se replique dans le foie. Deux cents millions de personnes sont infectes par le virus dans le monde et environ 80% dentre elles progresseront vers un stade chronique de linfection. Les thrapies anti-virales actuelles comme linterfron (IFN) ou la ribavirin sont de plus en plus utilises mais ne sont efficaces que dans la moiti des individus traits et sont souvent accompagnes dune toxicit ou deffets secondaires indsirables. Le systme immunitaire inn est essentiel au contrle des infections virales. Les rponses immunitaires innes sont actives suite la reconnaissance par les Pathogen Recognition Receptors (PRRs), de motifs macromolculaires drivs du virus appels Pathogen-Associated Molecular Patterns (PAMPs). Bien que l'activation du systme immunitaire par l'ARN ou les protines du VHC ait t largement tudie, trs peu de choses sont actuellement connues concernant la dtection du virus par le systme immunitaire inn. Et mme si lon peut trs rapidement dceler des rponses immunes in vivo aprs infection par le VHC, laugmentation progressive et continue de la charge virale met en vidence une incapacit du systme immunitaire contrler linfection virale. Une meilleure comprhension des mcanismes dactivation du systme immunitaire par le VHC semble, par consquent, essentielle au dveloppement de stratgies antivirales plus efficaces. Dans le prsent travail nous montrons, dans un modle de cellule primaire, que le gnome ARN du VHC contient des squences riches en GU capables de stimuler spcifiquement les rcepteurs de type Toll (TLR) 7 et 8. Cette stimulation a pour consquence la maturation des cellules dendritiques plasmacytodes (pDCs), le production dinterfron de type I (IFN) ainsi que linduction de chmokines et cytokines inflammatoires par les diffrentes types de cellules prsentatrices dantignes (APCs). Les cytokines produites aprs stimulation de monocytes ou de pDCs par ces squences ssARN virales, inhibent la production du virus de faon dpendante de lIFN. En revanche, les cytokines produites aprs stimulation de cellules dendritiques mylodes (mDCs) ou de macrophages par ces mmes squences nont pas deffet inhibiteur sur la production virale car les squences ssARN virales ninduisent pas la production dIFN par ces cellules. Les cytokines produites aprs stimulation des TLR 7/8 ont galement pour effet de diminuer, de faon indpendante de lIFN, lexpression du rcepteur au VHC (CD81) sur la ligne cellulaire Huh7.5, ce qui pourrait avoir pour consquence de restreindre linfection par le VHC. Quoiquil en soit, mme si les rcepteurs au VHC comme le CD81 sont largement exprims la surface de diffrentes sous populations lymphocytaires, les DCs et les monocytes ne rpondent pas aux VHC, Nos rsultats indiquent que seuls les macrophages sont capables de reconnatre le VHC et de produire des cytokines inflammatoires en rponse ce dernier. La reconnaissance du VHC par les macrophages est lie lexpression membranaire de DC-SIGN et lengagement des TLR 7/8 qui en rsulte. Comme dautres agonistes du TLR 7/8, le VHC stimule la production de cytokines inflammatoires (TNF-, IL-8, IL-6 et IL-1b) mais ninduit pas la production dinterfron-beta par les macrophages. De manire attendue, la production de cytokines par des macrophages stimuls par les ligands du TLR 7/8 ou les squences ssARN virales ninhibent pas la rplication virale. Nos rsultats mettent en vidence la capacit des squences ssARN drives du VHC stimuler les TLR 7/8 dans diffrentes populations de DC et initier une rponse immunitaire inne qui aboutit la suppression de la rplication virale de faon dpendante de lIFN. Quoiquil en soit, le VHC est capable dchapper sa reconnaissance par les monocytes et les DCs qui ont le potentiel pour produire de lIFN et inhiber la rplication virale aprs engagement des TLR 7/8. Les macrophages possdent quant eux la capacit de reconnatre le VHC grce en partie lexpression de DC-SIGN leur surface, mais ninhibent pas la rplication du virus car ils ne produisent pas dIFN. Lchappement du VHC aux dfenses antivirales pourrait ainsi expliquer lchec du systme immunitaire inn contrler linfection par le VHC. De plus, la production de cytokines inflammatoires observe aprs stimulation in vitro des macrophages par le VHC suggre leur potentielle contribution dans linflammation que lon retrouve chez les individus infects par le VHC.