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Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control

World Journal of Gastroenterology 2015年第12期21卷 3480-3491页

作者： Juan-Ramón Larrubia Elia Moreno-Cubero joaquín miquel Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Medicine and Medical Specialties University of Alcalá Department of Biology of Systems University of Alcalá

Hepatitis C virus(HCV)-specific cytotoxic T cell(CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response(SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in na?ve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatmentinduced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferonfree regimes, based on direct-acting antivirals. nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.

关键词： Hepatitis C virus Chronic hepatitis Hepatitis C vi

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Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C

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World Journal of Gastroenterology 2009年第41期15卷 5129-5140页

作者： Juan Ramón Larrubia Selma Benito-Martínez joaquín miquel Miryam Calvino Eduardo Sanz-de-Villalobos Trinidad Parra-Cid Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Hepatitis C virus（HCV）-specific CD8^＋ T cells play an important role in the resolution of HCV infection. nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the upregulation of negative co-stimulatory molecules such us programmed death-1 （PD-1）. This molecule is upregulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8^＋ T cells are exhausted with impairment of several effector mechanisms, such as： type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand （PD-L1）. After this blockade, HCV-specific CD8^＋ T cells reacquire their functionality. nevertheless, functional restoration depends on PD-1 expression level. High PD-l-expressing intrahepatic HCV-specific CD8^＋ T cells do not restore their effector abilities after PD-1/ PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gClq receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response aclainst HCV to succeed in clearing the infection.

关键词： Chronic hepatitis Exhaustion Hepatitis C virus core Hepatitis C virus Programmed death-1 Programmed death-1 ligand

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Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

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World Journal of Gastroenterology 2013年第12期19卷 1877-1889页

作者： Juan Ramón Larrubia Megha Uttam Lokhande Silvia García-Garzón joaquín miquel Dolores Subirá Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

关键词： T cell death Specific cytotoxic T lymphocytes Hepatitis C virus immune tolerance Apoptosis Bcl-2 interacting mediator Liver tolerance Apoptotic pathways Viral hepatitis

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Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

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World Journal of Hepatology 2020年第10期12卷 754-765页

作者： Julia Peña-Asensio Eduardo Sanz-de-Villalobos joaquín miquel Juan Ramón Larrubia Department of Systems Biology Guadalajara University Hospital.University of AlcaláGuadalajara E-19002GuadalajaraSpain Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara E-19002GuadalajaraSpain

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune *** antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even *** exhaustion process is progressive and depends on the infection duration and level of *** high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to *** development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta *** cytokine downregulates tumor necrosis factor receptor(TnFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TnFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion *** with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector *** process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease *** conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

关键词： Hepatitis C virus Tumor necrosis factor receptor-associated factor 1 CD8 Exhaustion Tumor necrosis family receptor superfamily member 9 Chronic hepatitis

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Depressive symptoms in neurodegenerative diseases

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World Journal of Clinical Cases 2015年第8期3卷 682-693页

作者： miquel Baquero nuria Martín Servei de neurologia Hospital Universitari i Politècnic La Fe

Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer's disease and related conditions like Parkinson's disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have aparticular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment.

关键词： neurodegenerative diseases Alzheimer Depressive symptoms Frontotemporal degeneration Vascular dementia Lewy body disease Depression Dementia

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The Janus face of n-terminal lysines in α-synuclein

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neural Regeneration Research 2020年第10期15卷 1840-1841页

作者： Ana Belén Uceda Laura Mari?o miquel Adrover Institut Universitari d’Investigació en Ciències de la Salut (IUnICS) Institut d’Investigació Sanitària Illes Balears (Id ISBa) Departament de Química Universitat de les Illes Balears

Parkinson’s disease(PD)is the second most prevalent progressive neurodegenerative disorder after Alzheimer’s *** usually starts with a tremor in the extremities(usually in the hands)and gradually evolves with other symptoms such as bradykinesia,muscle stiffness,impaired posture,loss of automatic movements or speech *** symptoms worsen as the condition progresses and eventually lead to death.

关键词： impaired Alzheimer eventually

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Crohnology: A tale of time and times and inflammatory bowel diseases

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World Journal of Gastroenterology 2008年第36期14卷 5489-5490页

作者： Fernando Gomollón Javier P Gisbert miquel ngel Gassull Hospital Clínico Universitario Zaragoza Spain Centro de Investigación Biomédica en Enfermedades Hepáticas y Digestivas CIBEREHD IACS Spain Hospital Universitario de la Princesa CIBEREHD Madrid Spain Instituto de Investigación en Ciéncias de la Salud Fundación Germans Trias i Pujol CIBEREHD Badalona Spain

Time, times and timing are key words in inflammatory bowel diseases （IBD）. The leifmotif of this issue or World Journal of Gastroenterology is time. We have asked experts to review on the epidemiology of these diseases over time, the changes in innate immunity that could be present in the first time, and then the timing of key treatments. The correct time of using azathioprine, mercaptopurine, infliximab, cyclosporine and surgery are reviewed. We have chosen experts with not only great clinical expertise but also personal interest in clinical and basic investigation. Our goal in this monograph is to get an idea not only of the present but of the immediate future in some of the key management issues in IBD. To this end, we think that the authors are the most adequate.

关键词： Inflammatory bowel diseases Epidemiology Innate immunity Treatment

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Rifaximin,but not growth factor 1,reduces brain edema in cirrhotic rats

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World Journal of Gastroenterology 2012年第17期18卷 2084-2091页

作者： Gemmaòdena Mireia miquel Anna Serafín Amparo Galan Rosa Morillas Ramon Planas Ramon Bartolí Hepatology Unit Department of GastroenterologyGermans Trias i Pujol Health Science Research Institute08916 BadalonaSpain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas(CIBERehd) 08036 BarcelonaSpain Department of Gastroenterology CorporacióSanitària Parc Taulí08208 SabadellSpain Platform of Laboratory Animal Applied Research Parc Científic de Barcelona08028 BarcelonaSpain Department of Biochemistry Hospital Universitari Germans Trias i Pujol08916 BadalonaSpain Liver Unit Department of GastroenterologyHospital Universitari Germans Trias i Pujol08916 BadalonaSpain

AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal ***:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + *** oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was ***:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water *** and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group *** contrast,IGF-1 administration failed to improve most alterations observed in ***:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.

关键词： Hyperammonemia Low-grade brain edema Hepatic encephalopathy Rifaximin Insulin-like growth factor 1 Cirrhosis

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Low field microwave absorption and magnetization process in CoFeni electroplated wires

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Chinese Physics B 2008年第4期17卷 1430-1435页

作者： H.García-miquel G.V.Kurlyandskay E.T.S.I.Telecomunicación Dpto.Ing.ElectrónicaUniversidad Politcnica de ValenciaCamino de Vera s/nValencia 46022Spain Universidad del País Vasco UPV-EHU Dept.Electricidad y ElectrónicaApdo.644Bilbao 48080Spain Department of Physics Ferromagnetic Resonance GroupUniversity of MarylandCollege ParkMaryland 20742-4111USA

Ferromagnetic resonance （FMR）, Ferromagnetic antirresonance （FMAR） and low field magnetoimpedance （MI） are the characteristic features of high frequency losses in applied fields. While some results on FMR and FMAR in CoFeni electroplated wires were reported earlier, here we present microwave absorption in CuBe wires electroplated by 1 μm FeConi magnetic layer at very low fields. These data are comparatively analysed together with longitudinal hysteresis loops in order to reveal the correlation between power absorption and magnetization processes. Microwave studies are made by using the cavity perturbation method at 9.65 GHz for a DC field parallel to the sample axis, and with microwave magnetic field hrf parallel or perpendicular to the wire axis. Two peaks have been observed in all samples, one is due to FMR, and the other is, at very low fields, related to MI. The MI peaks represent minima in power absorption. By comparing with the hysteresis loop we remark the close correspondence between the MI phenomena in the axial mode and the concomitant magnetization process.

关键词： microwave absorption magnetoimpedance electroplated wires

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Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第36期14卷 5512-5518页

作者： María Josefina Etchevers Montserrat Aceituno miquel Sans Department of Gastroenterology Hospital Posadas Buenos Aires Argentina Department of Gastroenterology Hospital Clínic i Provincial/IDIBAPS Barcelona CIBER Enfermedades Hepáticas y Digestivas Spain

Inflammatory bowel disease (IBD) includes two entities, Crohn’s disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient’s quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn’s disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn’s disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn’s disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SOnIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn’s disease patients (AZTEC study).

关键词： Inflammatory bowel disease Crohn's disease Ulcerative colitis Immunosuppressants Azathioprine

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