RESUMEN
A 32-year-old lady with a history of bulimia nervosa was noted to have a raised adjusted calcium of 2.94mmol/L associated with high parathyroid hormone (PTH) 17.2pmol/L. On review, she had an apparent hypercalcaemia for at least three years, and also had a chronic, severe alkalosis with a bicarbonate up to 81.9mEQ/L. Ionised calcium during that time had actually been low, down to 1.03mmol/L. This case highlights the effects of alkalosis on calcium, as more albumin is available for binding to ionised calcium. This results in a low ionised calcium, which triggers PTH release and overall leads to raised adjusted calcium levels. Clinicians may misdiagnose a similar patient with primary hyperparathyroidism and treatment would cause worsening of true hypocalcaemia.
Asunto(s)
Alcalosis , Hiperparatiroidismo Primario , Femenino , Humanos , Adulto , Calcio , Hiperparatiroidismo Primario/diagnóstico , Hormona Paratiroidea/metabolismoRESUMEN
Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.
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Neoplasias/radioterapia , Exposición a la Radiación/efectos adversos , Glándula Tiroides/efectos de la radiación , Neoplasias de la Tiroides/etiología , Detección Precoz del Cáncer/métodos , Humanos , SobrevivientesRESUMEN
INTRODUCTION: BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. AIM: This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. METHODS: Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. RESULTS: A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was 'excellent' in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were 'excellent' except for one minor (dental) procedure which was rated 'good'. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. CONCLUSION: These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adulto , Anticuerpos Neutralizantes/sangre , Coagulantes/química , Coagulantes/farmacocinética , Factor VIII/genética , Factor VIII/metabolismo , Semivida , Hemofilia A/sangre , Hemorragia/prevención & control , Hemostasis , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa , Polietilenglicoles/química , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Procedimientos Quirúrgicos Operativos , Resultado del Tratamiento , Adulto JovenRESUMEN
The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases.
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Interleucina-13/inmunología , Macrófagos Alveolares/inmunología , Neumonía/inmunología , Esquistosomiasis mansoni/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Antígenos Ly/genética , Antígenos Ly/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Fibrosis , Regulación de la Expresión Génica , Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina/inmunología , Interleucina-13/genética , Pulmón/inmunología , Pulmón/parasitología , Pulmón/patología , Macrófagos Alveolares/parasitología , Macrófagos Alveolares/patología , Ratones , Ratones Transgénicos , Nippostrongylus/inmunología , Nippostrongylus/patogenicidad , Neumonía/parasitología , Neumonía/patología , Pyroglyphidae/inmunología , Schistosoma mansoni/inmunología , Schistosoma mansoni/patogenicidad , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/patología , Transducción de Señal , Infecciones por Strongylida/parasitología , Infecciones por Strongylida/patología , Células Th2/parasitología , Células Th2/patologíaRESUMEN
BACKGROUND: Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood. OBJECTIVE: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung. METHODS: We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). RESULTS: We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. CONCLUSION: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production.
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Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Receptores de Interleucina-21/metabolismo , Transducción de Señal , Células Th2/inmunología , Células Th2/metabolismo , Alérgenos/inmunología , Animales , Hiperreactividad Bronquial/genética , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hipersensibilidad/genética , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptores de Interleucina-21/deficiencia , Receptores de Interleucina-21/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
How the immune system adapts to malnutrition to sustain immunity at barrier surfaces, such as the intestine, remains unclear. Vitamin A deficiency is one of the most common micronutrient deficiencies and is associated with profound defects in adaptive immunity. Here, we found that type 3 innate lymphoid cells (ILC3s) are severely diminished in vitamin A-deficient settings, which results in compromised immunity to acute bacterial infection. However, vitamin A deprivation paradoxically resulted in dramatic expansion of interleukin-13 (IL-13)-producing ILC2s and resistance to nematode infection in mice, which revealed that ILCs are primary sensors of dietary stress. Further, these data indicate that, during malnutrition, a switch to innate type 2 immunity may represent a powerful adaptation of the immune system to promote host survival in the face of ongoing barrier challenges.
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Inmunidad Adaptativa , Inmunidad Innata , Linfocitos/inmunología , Micronutrientes/deficiencia , Deficiencia de Vitamina A/inmunología , Vitamina A/inmunología , Animales , Citrobacter rodentium/inmunología , Infecciones por Enterobacteriaceae/inmunología , Proteínas de Homeodominio/genética , Interleucina-13/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones MutantesRESUMEN
The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T cell-dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here, we find that allergic pathology driven by constitutive TL1A expression depends on interleukin-13 (IL-13), but not on T, NKT, mast cells, or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell-dependent and -independent models of allergic disease. By contrast, DR3-deficient ILC2 can still differentiate, expand, and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings.
Asunto(s)
Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Inmunidad Innata , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Interleucina-13/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis TumoralRESUMEN
Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial-derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLFs) with conditioned media from damaged lung epithelial cells significantly upregulated interleukin IL-6, IL-8, monocyte chemotactic protein-1, and granulocyte macrophage colony-stimulating factor expression (P<0.05). This effect was reduced with anti-IL-1α or IL-1Ra but not anti-IL-1ß antibody. Costimulation with a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I:C), significantly accentuated the IL-1α-induced inflammatory phenotype in PHLFs, and this effect was blocked with inhibitor of nuclear factor kappa-B kinase subunit beta and TGFß-activated kinase-1 inhibitors. Finally, Il1r1-/- and Il1a-/- mice exhibit reduced bronchoalveolar lavage (BAL) neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1α plays a pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of double-stranded RNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease.
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Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Interleucina-1alfa/metabolismo , Neumonía/metabolismo , Animales , Línea Celular , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Células Epiteliales/patología , Fibroblastos/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-1alfa/genética , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Estrés Oxidativo , Fenotipo , Neumonía/tratamiento farmacológico , Neumonía/genética , Neumonía/patología , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transducción de SeñalRESUMEN
The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.
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Enteritis/inmunología , Interleucina-13/inmunología , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Animales , Antígenos CD2/genética , Antígenos CD2/inmunología , Colitis/inmunología , Colitis/patología , Células Dendríticas/inmunología , Relación Dosis-Respuesta Inmunológica , Enteritis/patología , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica/inmunología , Orden Génico , Células HEK293 , Humanos , Memoria Inmunológica/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Interleucina-13/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Linfocitos TRESUMEN
OBJECTIVES: To test the hypotheses that older people and their informal carers are not disadvantaged by home-based rehabilitation (HBR) relative to day hospital rehabilitation (DHR) and that HBR is less costly. DESIGN: Two-arm randomised controlled trial. SETTING: Four trusts in England providing both HBR and DHR. PARTICIPANTS: Clinical staff reviewed consecutive referrals to identify subjects who were potentially suitable for randomisation according to the defined inclusion criteria. INTERVENTIONS: Patients were randomised to receive either HBR or DHR. MAIN OUTCOME MEASURES: The primary outcome measure was the Nottingham Extended Activities of Daily Living (NEADL) scale. Secondary outcome measures included the EuroQol 5 dimensions (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Therapy Outcome Measures (TOMs), hospital admissions and the General Health Questionnaire (GHQ-30) for carers. RESULTS: Overall, 89 subjects were randomised and 42 received rehabilitation in each arm of the trial. At the primary end point of 6 months there were 32 and 33 patients in the HBR and DHR arms respectively. Estimated mean scores on the NEADL scale at 6 months, after adjustment for baseline, were not significantly in favour of either HBR or DHR [DHR 30.78 (SD 15.01), HBR 32.11 (SD 16.89), p = 0.37; mean difference -2.139 (95% CI -6.870 to 2.592)]. Analysis of the non-inferiority of HBR over DHR using a 'non-inferiority' limit (10%) applied to the confidence interval estimates for the different outcome measures at 6 months' follow-up demonstrated non-inferiority for the NEADL scale, EQ-5D and HADS anxiety scale and some advantage for HBR on the HADS depression scale, of borderline statistical significance. Similar results were seen at 3 and 12 months' follow-up, with a statistically significant difference in the mean EQ-5D(index) score in favour of DHR at 3 months (p = 0.047). At the end of rehabilitation, a greater proportion of the DHR group showed a positive direction of change from their initial assessment with respect to therapist-rated clinical outcomes; however, a lower proportion of HBR patients showed a negative direction of change and, overall, median scores on the TOMs scales did not differ between the two groups. Fewer patients in the HBR group were admitted to hospital on any occasion over the 12-month observation period [18 (43%) versus 22 (52%)]; however, this difference was not statistically significant. The psychological well-being of patients' carers, measured at 3, 6 and 12 months, was unaffected by whether rehabilitation took place at day hospital or at home. As the primary outcome measure and EQ-5D(index) scores at 6 months showed no significant differences between the two arms of the trial, a cost-minimisation analysis was undertaken. Neither the public costs nor the total costs at the 6-month follow-up point (an average of 213 days' total follow-up) or the 12-month follow-up point (an average of 395 days' total follow-up) were significantly different between the groups. CONCLUSIONS: Compared with DHR, providing rehabilitation in patients' own homes confers no particular disadvantage for patients and carers. The cost of providing HBR does not appear to be significantly different from that of providing DHR. Rehabilitation providers and purchasers need to consider the place of care in the light of local needs, to provide the benefits of both kinds of services. Caution is required when interpreting the results of the RCT because a large proportion of potentially eligible subjects were not recruited to the trial, the required sample size was not achieved and there was a relatively large loss to follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN71801032.
Asunto(s)
Centros de Día , Servicios de Atención de Salud a Domicilio , Rehabilitación/organización & administración , Anciano , Anciano de 80 o más Años , Ansiedad , Análisis Costo-Beneficio , Centros de Día/estadística & datos numéricos , Depresión , Inglaterra , Femenino , Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Hospitales Públicos , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Calidad de Vida , Rehabilitación/psicología , Medicina Estatal , Encuestas y CuestionariosRESUMEN
Pulmonary fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary fibrotic diseases is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis (IPF), is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary fibrotic diseases. A three phase model of wound repair is reviewed that includes; (1) injury; (2) inflammation; and (3) repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGFbeta1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.
Asunto(s)
Lesión Pulmonar/fisiopatología , Fibrosis Pulmonar/etiología , Animales , Asma/etiología , Asma/inmunología , Asma/fisiopatología , Colágeno/metabolismo , Citocinas/inmunología , Fibroblastos/fisiología , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Fibrosis Pulmonar Idiopática/etiología , Fibrosis Pulmonar Idiopática/inmunología , Fibrosis Pulmonar Idiopática/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-13/inmunología , Lesión Pulmonar/inmunología , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/fisiopatología , Regeneración , Factor de Crecimiento Transformador beta1/inmunologíaRESUMEN
BACKGROUND: IL-13 plays a key regulatory role in asthmatic responses and immunity to parasitic infection. In vivo, IL-13R-alpha2 is a critical modulator of IL-13 bioactivity. When inducibly expressed on the surface of fibroblasts and other cell types under inflammatory conditions, IL-13R-alpha2 contributes to resolution of IL-13 responses. A soluble form of IL-13R-alpha2 (sIL-13R-alpha2) can be detected in murine circulation, and functions as a regulator of IL-13 bioactivity. In humans, sIL-13R-alpha2 has been more difficult to detect. Recently, novel assay systems have been described to quantitate sIL-13R-alpha2 in human circulation, and revealed unexpectedly high levels of sIL-13R-alpha2 in healthy subjects. OBJECTIVE: To verify sIL-13R-alpha2 quantitation in human plasma samples under stringent conditions of signal verification and false-positive detection. METHODS: A standard ELISA protocol was evaluated for specificity using false-positive detection reagents. A more stringent ELISA protocol was developed by optimizing the composition of blocking and dilution buffers. RESULTS: Using the stringent assay protocol, endogenous sIL-13R-alpha2 was undetectable in plasma samples from a total of 120 asthmatics and 20 healthy subjects, and in bronchoalveolar lavage fluid from 10 asthmatics and eight healthy subjects undergoing allergen challenge. CONCLUSION: These results underscore the necessity to perform rigorous assay controls in the biological matrix to be tested. Because the soluble form could not be demonstrated, our findings question a role for sIL-13R-alpha2 in the regulation of IL-13 bioactivity, and highlight the potentially important contribution of the membrane-bound form of IL-13R-alpha2 in humans.
Asunto(s)
Asma/sangre , Subunidad alfa2 del Receptor de Interleucina-13/sangre , Líquido del Lavado Bronquioalveolar/química , Ensayo de Inmunoadsorción Enzimática/métodos , Ensayo de Inmunoadsorción Enzimática/normas , Reacciones Falso Positivas , Humanos , Subunidad alfa2 del Receptor de Interleucina-13/biosíntesis , Valor Predictivo de las Pruebas , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , SolubilidadRESUMEN
Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
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Fibrosis/inmunología , Angiotensina II/fisiología , Quimiocinas/inmunología , Quimiotaxis/inmunología , Citocinas/inmunología , Progresión de la Enfermedad , Fibroblastos/patología , Fibrosis/patología , Humanos , Inmunidad Innata , Interleucinas/inmunología , Células TH1/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
The eosinophil-associated ribonucleases (Ears) are rapidly evolving proteins found in multigene clusters that are unique to each rodent species. Of the 15 independent genes in the Mus musculus cluster, only mEars 1 and 2 are expressed at significant levels at homeostasis. Here we characterize the expression of mEar 6 in the liver and spleen in mice in response to infection with the helminthic parasite, Schistosoma mansoni. Interestingly, expression of mEar 6 is not directly related to the elevated levels of serum IL-5 or tissue eosinophilia characteristic of this disease, as no mEar 6 transcripts were detected in the liver or the spleen from uninfected IL-5-transgenic mice. The coding sequence of mEar 6 has diverged under positive selection pressure (K(a)/K(s) > 1.0) and has a unique unpaired cysteine near the carboxy-terminus of the protein. The high catalytic efficiency of recombinant mEar 6 (k(cat)/K(m) = 0.9 x 10(6)/M/s) is similar to that of the cluster's closest human ortholog, eosinophil-derived neurotoxin (EDN/RNase 2). In summary, we have identified mEar 6 as one of only two RNase A superfamily ribonucleases known to be expressed specifically in response to pathophysiologic stress in vivo.
Asunto(s)
Proteína Catiónica del Eosinófilo/genética , Expresión Génica , Schistosoma mansoni , Esquistosomiasis mansoni/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Northern Blotting , Cartilla de ADN , Proteína Catiónica del Eosinófilo/metabolismo , Evolución Molecular , Immunoblotting , Hígado/metabolismo , Hígado/patología , Ratones , Datos de Secuencia Molecular , Proteínas Recombinantes/metabolismo , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/patología , Selección Genética , Alineación de Secuencia , Análisis de Secuencia de ADN , Bazo/metabolismo , Bazo/patologíaRESUMEN
Hepatic fibrosis is the hallmark of Schistosoma mansoni infection and often results in portal hypertension and bleeding from esophageal varices. The fibrotic process is highly dependent on type 2 cytokines, yet their role in the regulation of extracellular matrix remodeling genes remains largely unknown. Here, we examined the expression of matrix metalloproteases (MMP) -2, -3, -9, -12, and -13 and their inhibitors, tissue inhibitor of metalloproteases (TIMP) -1, -2, and -3, in the livers of infected mice and correlated their expression profiles with fibrosis and type 2 cytokine production. Expression of MMP-2, -3, -9, -12, and -13 and of TIMP-1 and -2 mRNA rapidly increased at the onset of egg laying in infected mice, while TIMP-3 was unchanged. Because TIMP are presumed to be important regulators of the extracellular matrix, and their expression correlated with the development of fibrosis, we studied their role in fibrogenesis by infecting TIMP-1- and TIMP-2-deficient mice. Strikingly, our data revealed no role for TIMP-1 or -2 in the fibrotic pathology induced by S. mansoni eggs. Because of these findings, we infected IL-10/IFN-gamma-deficient mice that develop an exaggerated fibrotic response to determine whether changes in type 2 cytokine dominance influence the pattern of MMP and TIMP expression. Fibrosis and type 2 cytokine production correlated with increased MMP-2/MMP-9 vs TIMP-1/TIMP-2 expression. These data, in addition to our knockout studies, demonstrate that TIMP-1/TIMP-2 play no essential role in fibrogenesis in schistosomiasis. Indeed, our findings suggest that inhibiting profibrotic cytokines or specific MMP may be a more effective strategy to ameliorate fibrotic pathology.
Asunto(s)
Cirrosis Hepática/inmunología , Metaloproteinasas de la Matriz/biosíntesis , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Inhibidor Tisular de Metaloproteinasa-1/fisiología , Inhibidor Tisular de Metaloproteinasa-2/fisiología , Animales , Citocinas/biosíntesis , Interferón gamma/genética , Interferón gamma/fisiología , Interleucina-10/genética , Interleucina-10/fisiología , Cinética , Hígado/enzimología , Hígado/patología , Cirrosis Hepática/enzimología , Cirrosis Hepática/patología , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/biosíntesis , Esquistosomiasis mansoni/enzimología , Esquistosomiasis mansoni/patología , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-2/genética , Activación TranscripcionalRESUMEN
Some pathogens (e.g., Mycobacterium tuberculosis, Toxoplasma gondii, Leishmania spp) have been shown to persist in their host after clinical cure, establishing the risk of disease reactivation. We analyzed the conditions necessary for the long term maintenance of Leishmania major in genetically resistant C57BL/6 mice after spontaneous healing of their dermal lesions. Interleukin (IL)-10 was found to play an essential role in parasite persistence as sterile cure was achieved in IL-10-deficient and IL-4/IL-10 double-deficient mice. The requirement for IL-10 in establishing latency associated with natural infection was confirmed in IL-10-deficient mice challenged by bite of infected sand flies. The host-parasite equilibrium was maintained by CD4+ and CD8+ T cells which were each able to release IL-10 or interferon (IFN)-gamma, and were found to accumulate in chronic sites of infection, including the skin and draining lymph node. A high frequency of the dermal CD4+ T cells released both IL-10 and IFN-gamma. Wild-type mice treated transiently during the chronic phase with anti-IL-10 receptor antibodies achieved sterile cure, suggesting a novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Interleucina-10/fisiología , Leishmania major/fisiología , Leishmaniasis Cutánea/terapia , Receptores de Interleucina/antagonistas & inhibidores , Piel/parasitología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interferón gamma/fisiología , Interleucina-4/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-10 , Piel/inmunologíaRESUMEN
Type 2 cytokines regulate fibrotic liver pathology in mice infected with Schistosoma mansoni. Switching the immune response to a type 1-dominant reaction has proven highly effective at reducing the pathologic response. Activation of NOS-2 is critical, because type 1-deviated/NO synthase 2 (NOS-2)-deficient mice completely fail to control their response. Here, we demonstrate the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis. Using cytokine-deficient mice and two granuloma models, we show that induction of Arg-1 is type 2 cytokine dependent. Schistosome eggs induce Arg-1, while Mycobacterium avium-infected mice develop a dominant NOS-2 response. IFN-gamma suppresses Arg-1 activity, because type 1 polarized IL-4/IL-10-deficient, IL-4/IL-13-deficient, and egg/IL-12-sensitized animals fail to up-regulate Arg-1 following egg exposure. Notably, granuloma size decreases in these type-1-deviated/Arg-1-unresponsive mice, suggesting an important regulatory role for Arg-1 in schistosome egg-induced pathology. To test this hypothesis, we administered difluoromethylornithine to block ornithine-aminodecarboxylase, which uses the product of arginine metabolism, L-ornithine, to generate polyamines. Strikingly, granuloma size and hepatic fibrosis increased in the ornithine-aminodecarboxylase-inhibited mice. Furthermore, we show that type 2 cytokine-stimulated macrophages produce proline under strict arginase control. Together, these data reveal an important regulatory role for the arginase biosynthetic pathway in the regulation of inflammation and demonstrate that differential activation of Arg-1/NOS-2 is a critical determinant in the pathogenesis of granuloma formation.
Asunto(s)
Arginasa/metabolismo , Arginina/metabolismo , Granuloma/inmunología , Granuloma/patología , Óxido Nítrico Sintasa/metabolismo , Células TH1/inmunología , Células Th2/inmunología , Animales , Arginasa/antagonistas & inhibidores , Arginasa/biosíntesis , Células Cultivadas , Modelos Animales de Enfermedad , Eflornitina/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Activación Enzimática/inmunología , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/genética , Inducción Enzimática/inmunología , Inhibidores Enzimáticos/farmacología , Femenino , Granuloma/enzimología , Granuloma/prevención & control , Interleucina-12/fisiología , Hígado/enzimología , Cirrosis Hepática/enzimología , Cirrosis Hepática/patología , Enfermedades Pulmonares Parasitarias/enzimología , Enfermedades Pulmonares Parasitarias/genética , Enfermedades Pulmonares Parasitarias/inmunología , Enfermedades Pulmonares Parasitarias/patología , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium avium/inmunología , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Inhibidores de la Ornitina Descarboxilasa , Óvulo/inmunología , Prolina/biosíntesis , Esquistosomiasis mansoni/enzimología , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/patología , Células TH1/enzimología , Células Th2/enzimología , Tuberculosis/enzimología , Tuberculosis/genética , Tuberculosis/inmunología , Tuberculosis/patología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
In this communication the authors analyzed the pattern of expression of IFN-gamma as a surrogate type 1 response in different clinical forms of schistosomiasis in response to stimulation involving T-cell dependent and T-cell independent pathways, to investigate which pathways were functional in human schistosomiasis, and to further characterize the nature of Th1 response impairment in this parasitic disease.
Asunto(s)
Antígenos CD40/fisiología , Ligando de CD40/fisiología , Interferón gamma/metabolismo , Esquistosomiasis mansoni/metabolismo , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Humanos , Inmunidad Celular , Esquistosomiasis mansoni/inmunología , Staphylococcus aureus/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Development of polarized immune responses controls resistance and susceptibility to many microorganisms. However, studies of several infectious, allergic, and autoimmune diseases have shown that chronic type-1 and type-2 cytokine responses can also cause significant morbidity and mortality if left unchecked. We used mouse cDNA microarrays to molecularly phenotype the gene expression patterns that characterize two disparate but equally lethal forms of liver pathology that develop in Schistosoma mansoni infected mice polarized for type-1 and type-2 cytokine responses. Hierarchical clustering analysis identified at least three groups of genes associated with a polarized type-2 response and two linked with an extreme type-1 cytokine phenotype. Predictions about liver fibrosis, apoptosis, and granulocyte recruitment and activation generated by the microarray studies were confirmed later by traditional biological assays. The data show that cDNA microarrays are useful not only for determining coordinated gene expression profiles but are also highly effective for molecularly "fingerprinting" diseased tissues. Moreover, they illustrate the potential of genome-wide approaches for generating comprehensive views on the molecular and biochemical mechanisms regulating infectious disease pathogenesis.
Asunto(s)
Perfilación de la Expresión Génica , Hepatopatías/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , Apoptosis/genética , Eosinófilos/patología , Fibrosis , Genotipo , Hidroxiprolina/metabolismo , Inflamación/etiología , Inflamación/genética , Inflamación/mortalidad , Mediadores de Inflamación/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-12/deficiencia , Interleucina-12/genética , Interleucina-4/deficiencia , Interleucina-4/genética , Hígado/metabolismo , Hígado/patología , Hepatopatías/etiología , Hepatopatías/mortalidad , Macrófagos/patología , Ratones , Ratones Noqueados , Infiltración Neutrófila , Neutrófilos/patología , Schistosoma mansoni/crecimiento & desarrollo , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/parasitología , Tasa de Supervivencia , Factores de TiempoRESUMEN
To explore the roles of chemokines in type 1 and type 2 responses in vivo, we examined mRNA expression for a panel of up to 17 chemokines in experimental mouse models using Schistosoma mansoni. These studies revealed that Mig (monokine induced by gamma interferon), cytokine-responsive gene 2/10-kDa interferon-inducible protein, RANTES, lymphotactin, macrophage inflammatory protein 1beta (MIP-1beta), JE/monocyte chemoattractant protein 1, and MIP-2 are associated with type 1 egg-induced responses and that thymus-derived chemotactic agent 3 (TCA3), eotaxin, MIP-1alpha, and MIP-1gamma are associated with type 2 egg-induced responses. After cercarial infection, both type 1-associated and type 2-associated chemokines were elevated in the livers of infected mice presensitized with eggs and recombinant interleukin-12 (rIL-12), a regimen that diminishes pathology. Neutralization of IL-12 or gamma interferon during egg deposition reversed the effects of prior treatment with rIL-12, leading to a return to larger granulomas; persistently elevated expression of TCA3, eotaxin, and MIP-1alpha; and a marked reduction in the expression of type 1-associated chemokines despite the maintenance of a dominant type 1 cytokine response in the draining lymph nodes. Our findings suggest that there are patterns of coordinate chemokine expression characteristic of type 1 and type 2 responses in vivo; that the cells recruited by a given pattern of chemokines may differ, depending on the composition of peripheral populations; and that patterns of tissue expression of chemokines may determine the character of an inflammatory response independently of the dominant pattern of differentiation of antigen-specific T cells. Our data reveal new relationships between chemokines and polarized immune responses and suggest that end organ inflammation might be altered by chemokine blockade without necessitating reversal of the phenotype of the majority of differentiated T cells.