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1.
Scand J Immunol ; 76(4): 371-7, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22725135

RESUMEN

We aim to investigate the additive value of B cell-activating factor (BAFF) when added to oligodeoxynucleotides (ODN)-activated B cells with respect to TLR-9, CD69, MHC-II expression, IL-6 and IL-10 secretion and B cell cycling. Therefore, B cells from healthy individuals were incubated under the following conditions: (1) B cells with medium, (2) B cells with ODN 0.5 µm, (3) B cells with BAFF 20 µm and (4) B cells with both ODN 0.5 µm and BAFF 20 µm. We found that addition of BAFF did not enhance the expression of TLR-9, CD69 and MHC-II in ODN-activated B cells. Incubation of B cells with BAFF and ODN together leads to a marked elevation of IL-6 and IL-10 levels compared to ODN alone. Synthesis and mitosis were higher in B cells stimulated by BAFF than in B cells stimulated by ODN. These findings suggest that both BAFF and TLR-9 contribute independently to B cell function.


Asunto(s)
Factor Activador de Células B/farmacología , Linfocitos B/metabolismo , Interleucina-10/biosíntesis , Interleucina-6/biosíntesis , Oligodesoxirribonucleótidos/farmacología , Receptor Toll-Like 9/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/metabolismo , Factor Activador de Células B/inmunología , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Islas de CpG/genética , Islas de CpG/inmunología , Interacciones Farmacológicas , Regulación de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Interleucina-10/inmunología , Interleucina-6/inmunología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Activación de Linfocitos/efectos de los fármacos , Oligodesoxirribonucleótidos/inmunología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Receptor Toll-Like 9/genética
2.
Clin Exp Immunol ; 167(3): 422-8, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22288585

RESUMEN

Patients with hereditary angioedema (HAE) tend to produce autoantibodies and have a propensity to develop immunoregulatory disorders. We characterize the profile of autoantibodies in a group of HAE patients and investigate their memory B cells' phenotype and activation status. We studied the activity status phenotype, Toll-like receptor (TLR)-9 expression and total phosphotyrosine in B cells isolated from HAE patients. Additionally, the following autoantibodies were assessed in the serum of 61 HAE patients: anti-nuclear, rheumatoid factor, anti-cardiolipin, anti-tissue transglutaminase, anti-endomysial, anti-Saccharomyces cerevisiae, anti-thyroid and anti-neutrophil cytoplasmic antibodies. In 47·5% of HAE patients we detected at least one of the tested autoantibodies. Expression of CD69, CD5 and CD21 was found to be significantly higher on memory B cells from HAE patients compared to healthy controls (4·59 ± 4·41 versus 2·06 ± 1·81, P = 0·04, 8·22 ± 7·17 versus 3·65 ± 3·78, P = 0·05, 2·43 ± 0·54 versus 1·92 ± 0·41, P = 0·01, respectively). Total phosphotyrosine in B cells from HAE patients was significantly higher compared to healthy controls (4·8 ± 1·1 versus 2·7 ± 1·3, P = 0·0003). Memory B cells isolated from the HAE group contained higher amounts of TLR-9 compared to healthy controls (8·17 ± 4·1 versus 4·56 ± 1·6, P = 0·0027). Furthermore, the expression of TLR-9 in memory B cells from HAE patients with autoantibodies was significantly higher than the control group (10 ± 4·7 versus 4·56 ± 1·6, P = 0·0002) and from that in HAE patients without autoantibodies (10 ± 4·7 versus 5·8 ± 0·9, P = 0·036). HAE patients have enhanced production of autoantibodies due most probably to the increased activation of B cells, which was found to be in association with a high expression of TLR-9.


Asunto(s)
Autoinmunidad , Linfocitos B/inmunología , Proteínas Inactivadoras del Complemento 1/deficiencia , Angioedema Hereditario Tipos I y II/inmunología , Adulto , Anciano , Autoanticuerpos/sangre , Linfocitos B/clasificación , Estudios de Casos y Controles , Proteína Inhibidora del Complemento C1 , Femenino , Angioedema Hereditario Tipos I y II/etiología , Humanos , Memoria Inmunológica , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Transducción de Señal/inmunología , Receptor Toll-Like 9/metabolismo , Adulto Joven
3.
Clin Exp Rheumatol ; 29(4): 697-700, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21813064

RESUMEN

BACKGROUND: IL-6 mediated inflammation is induced by binding to IL-6 receptor (IL-6R) or IL-6/IL-6R complex binding gp130. Tocilizumab, a recombinant humanised monoclonal antibody that acts as IL-6R antagonist has been recently introduced for the treatment of rheumatoid arthritis (RA). OBJECTIVES: To evaluate whether tocilizumab therapy may induce B cells to undergo phenotypic changes compatible with regulatory function. METHODS: B cells from treated RA patients were isolated before and after 3 months of treatment with tocilizumab and were stained for the expression of intracellular TGF-ß, IL-10, membrane CD69, and MHCII. These markers were assessed in CD25(high) B cells considered to belong to a regulatory/suppressive subset of B cells. All markers were expressed in mean flow cytometry intensity (MFI), with results given in mean ± SEM. Data was compared before and after tocilizumab treatment. RESULTS: Clinical improvement was noted three months following the initiation of tocilizumab, namely: DAS improvement from 6.8 ± 0.3 at baseline to 3.1 ± 0.4, p<0.002, and ESR decrease from 44.4 ± 8.6 at baseline to 7.4 ± 2.3, p<0.006. This clinical benefit was found to occur in association with the expansion of a B cell subset with regulatory properties namely: the expression of intracellular TGF-ß in CD25-high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p<0.02); In addition, the expression of MHC-II and of CD69 on B cells were significantly reduced (from 9.1 ± 2.2 at baseline to 4.2 ± 0.4; p<0.04), and (from 7.6 ± 2.4 at baseline to 2.7 ± 0.7; p<0.03) respectively. CONCLUSIONS: The present finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-ß expression and the alteration in the activation status (CD69 expression) and APC properties (MHC-II expression) in CD25(high) B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Receptores de Interleucina-6/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Biomarcadores/metabolismo , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunofenotipificación/métodos , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Israel , Lectinas Tipo C/metabolismo , Activación de Linfocitos/efectos de los fármacos , Receptores de Interleucina-6/inmunología , Factores de Tiempo , Factor de Crecimiento Transformador beta/metabolismo , Resultado del Tratamiento
4.
Clin Sci (Lond) ; 100(2): 221-9, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11171292

RESUMEN

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.


Asunto(s)
Anorexia/fisiopatología , Colitis/complicaciones , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Neuropéptido Y/fisiología , Adaptación Fisiológica/fisiología , Animales , Anorexia/sangre , Anorexia/etiología , Glucemia/metabolismo , Peso Corporal/fisiología , Proteínas Portadoras/farmacología , Colitis/inducido químicamente , Colitis/fisiopatología , Corticosterona/sangre , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Hormonas Hipotalámicas/farmacología , Insulina/sangre , Masculino , Melaninas/farmacología , Neuropéptido Y/metabolismo , Neuropéptido Y/farmacología , Neuropéptidos/farmacología , Orexinas , Hormonas Hipofisarias/farmacología , Ratas , Ratas Wistar , Ácido Trinitrobencenosulfónico
5.
Gut ; 46(5): 694-700, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10764714

RESUMEN

BACKGROUND: Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known. AIMS: To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis. METHODS: Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation). RESULTS: Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44-60%. CONCLUSIONS: It seems likely that approximately 30-40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.


Asunto(s)
Colitis/complicaciones , Trastornos del Crecimiento/etiología , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Trastornos Nutricionales/complicaciones , Animales , Colitis/inducido químicamente , Colitis/fisiopatología , Suplementos Dietéticos , Femenino , Trastornos del Crecimiento/metabolismo , Interleucina-6/metabolismo , Masculino , Trastornos Nutricionales/fisiopatología , Ratas , Ratas Wistar , Ácido Trinitrobencenosulfónico , Aumento de Peso/fisiología
6.
Gastroenterology ; 118(3): 544-53, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10702205

RESUMEN

BACKGROUND & AIMS: Experimental colitis is associated with anorexia that is attenuated by treatment with an interleukin (IL)-1 receptor antagonist. Serotonin (5-hydroxytryptamine [5-HT]) is a potent inhibitor of feeding, and its release from the hypothalamus is stimulated by IL-1. We have tested the hypotheses that anorexia associated with experimental colitis results from increased activity of hypothalamic 5-HT neurons and that the increase in activity occurs secondary to an increase in availability of tryptophan, the precursor of 5-HT. METHODS: In vivo 5-HT release and regional hypothalamic 5-HT and tryptophan concentrations were measured in rats with 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced colitis, healthy controls, and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after depletion of brain 5-HT by p-chlorophenylalanine (PCPA). RESULTS: In the colitic group, release of 5-HT from the hypothalamic paraventricular nucleus (PVN) was 3-fold (P = 0.01) and 14-fold (P < 0.001) higher than in control and pair-fed groups, respectively. Concentrations of tryptophan were similar in each group in all hypothalamic regions. Food intake was significantly increased in the colitic group after PCPA treatment but was not restored to control values. CONCLUSIONS: In animals with TNBS-induced colitis, 5-HT release from the PVN is increased. The increase in food intake after depletion of brain 5-HT suggests that hypothalamic 5-HT contributes to anorexia but is not the only mediator. Increased 5-HT release in the colitic group was not driven by increased precursor availability.


Asunto(s)
Anorexia/etiología , Colitis/complicaciones , Hipotálamo Medio/fisiopatología , Serotonina/fisiología , Aminoácidos/sangre , Animales , Colitis/sangre , Colitis/metabolismo , Colitis/fisiopatología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Fenclonina/farmacología , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/metabolismo , Hipotálamo Medio/metabolismo , Hipotálamo Medio/patología , Masculino , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Wistar , Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Distribución Tisular , Triptófano/sangre , Triptófano/metabolismo
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