RESUMEN
Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal alpha-galactosidase A which causes accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Gastrointestinal signs and symptoms-abdominal pain, nausea, diarrhea and diverticular disease--are some of the most frequently reported complaints in patients with Fabry disease but are often neglected. Gastrointestinal symptoms are due to intestinal dysmotility as well as impaired autonomic function, vasculopathy and myopathy. Since 2001, enzyme replacement therapy has been a mainstay in treatment of gastrointestinal symptoms of Fabry disease (FD), resulting in reduced gastrointestinal symptoms. Here, we report on four patients with Fabry disease (FD) who manifested early gastrointestinal involvement.
Asunto(s)
Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/metabolismo , Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/metabolismo , Tracto Gastrointestinal/metabolismo , Adolescente , Adulto , Animales , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Niño , Comorbilidad , Diagnóstico Diferencial , Enfermedad de Fabry/etiología , Femenino , Enfermedades Gastrointestinales/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Screening for Fabry disease (FD) in high risk populations yields a significant number of individuals with novel, ultra rare genetic variants in the GLA gene, largely without classic manifestations of FD. These variants often have significant residual α-galactosidase A activity. The establishment of the pathogenic character of previously unknown or rare variants is challenging but necessary to guide therapeutic decisions. OBJECTIVES: To present 2 cases of non-classical presentations of FD with renal involvement as well as to discuss the importance of high risk population screenings for FD. RESULTS: Our patients with non-classical variants were diagnosed through FD screenings in dialysis units. However, organ damage was not limited to kidneys, since LVH, vertebrobasilar dolichoectasia and cornea verticillata were also present. Lyso-Gb3 concentrations in plasma were in the pathologic range, compatible with late onset FD. Structural studies and in silico analysis of p.(Cys174Gly) and p.(Arg363His), employing different tools, suggest that enzyme destabilization and possibly aggregation could play a role in organ damage. CONCLUSIONS: Screening programs for FD in high risk populations are important as FD is a treatable multisystemic disease which is frequently overlooked in patients who present without classical manifestations.
RESUMEN
Stimulation of the human promonocytic cell line U937 with antibody-coated chicken red blood cells (Ab-CRBC), leads to inositol phosphate (IP) release in the effector cells. Neomycin (5 x 10(-4) M) completely inhibits activation of phosphoinositide breakdown, while ADCC is suppressed in a dose-dependent manner. Bordetella pertussis toxin (PT) (0.5 micrograms/ml), entirely inhibits IP release, while ADCC activity is markedly suppressed. The PKC inhibitors H-7 and propranolol also suppress ADCC. HA-1004, which has far lower PKC inhibitory activity than H-7, has a minimal effect on ADCC. The calmodulin antagonists W-7 and TFP are strongly inhibitory. These results indicate that stimulation of U937 cells for ADCC is associated to an increase in IP levels, which may provide positive transduction signals for the activation of this lytic mechanism.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/fisiología , Antígenos CD/metabolismo , Antígenos de Diferenciación/metabolismo , Receptores Fc/metabolismo , Transducción de Señal/fisiología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Calmodulina/antagonistas & inhibidores , Calmodulina/metabolismo , Humanos , Neomicina/farmacología , Toxina del Pertussis , Fosfatidilinositoles/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Receptores de IgG , Transducción de Señal/efectos de los fármacos , Factores de Virulencia de Bordetella/farmacologíaRESUMEN
We have previously shown that immune complexes triggered nonspecific cytotoxicity (NSC) towards nonsensitized target cells and antibody-dependent cellular cytotoxicity (ADCC), two functions mediated through monocyte Fc gamma receptors, employing different lytic mechanisms [Geffner, J. R., et al. (1986) Clin. Exp. Immunol. 67, 646]. In this report, we analyze some of the metabolic requirements involved in the induction of monocyte NSC and ADCC. The results showed NSC to be dependent on: (1) metabolic energy derived from glycolysis, (2) availability of external Ca2+, (3) calmodulin activity, (4) integrity of microtubules, but not the microfilament system, and (5) activation of phospholipase(s) and lipoxygenase. On the other hand, ADCC was not impaired by: (1) inhibition of glycolysis, (2) Ca2+ chelation, (3) disruption of microtubules, or (4) inhibition of calmodulin or lipoxygenase. It is concluded that monocyte NSC and ADCC are regulated by different endogenous signals.
Asunto(s)
Citotoxicidad Inmunológica , Monocitos/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos , Complejo Antígeno-Anticuerpo/inmunología , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Calcio/metabolismo , Citoesqueleto/inmunología , Metabolismo Energético , Glucólisis , Humanos , Técnicas In Vitro , Monocitos/metabolismo , Fosfolipasas/metabolismoRESUMEN
Previous reports demonstrated that cyclophosphamide (Cy) enhances two Fc gamma receptor (Fc gamma R) mediated functions: antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. In this paper we examine the mechanisms whereby Cy modifies the cytotoxic capacity of mouse splenocytes. The results indicate that the observed augmentation of ADCC could not be attributed to a higher proportion of macrophages and/or polymorphonuclear leukocytes (PMN), but rather to an enhanced activity per effector cell. Binding studies showed that this augmentation was associated with an increased number, but not an increased avidity of Fc gamma R sites. The possibility that the enhanced Fc gamma R expression by Cy may result in the alteration of other Fc gamma R-mediated functions is discussed.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Ciclofosfamida/farmacología , Receptores Fc/metabolismo , Animales , Macrófagos/inmunología , Ratones , Neutrófilos/inmunología , Bazo/citologíaRESUMEN
Antibody-dependent cellular cytotoxicity (ADCC) mediated by peripheral blood mononuclear cells (PBMC) and by isolated populations of lymphocytes and monocytes was compared for susceptibility to inhibition by soluble immune complexes (IC) and by heat-aggregated IgG (HAIgG). It was found that the decrease of ADCC was significantly higher in lymphocytes than in monocytes at all IC and HAIgG concentrations employed (P less than 0.001). The degree of inhibition of PBMC-mediated ADCC was similar to that observed in monocyte ADCC. In previous reports, we demonstrated that IC inhibition of PBMC-mediated ADCC could be reversed by normal human serum (NHS) used as a source of complement (C). In this paper, we study the effects of NHS on isolated populations of monocytes and lymphocytes. It was found that NHS was unable to modify the capacity of IC-blocked monocytes to mediate ADCC. On the contrary, NHS efficiently reversed the inhibition of both ADCC and Fc gamma R expression in IC-blocked lymphocytes. We propose that the regulation of Fc gamma R-IC interactions by C may constitute a physiological way to preserve Fc gamma R expression in lymphocytes.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Complejo Antígeno-Anticuerpo/inmunología , Proteínas del Sistema Complemento/fisiología , Linfocitos/inmunología , Monocitos/inmunología , Receptores Fc/fisiología , Sangre , Humanos , Receptores de IgGRESUMEN
During the course of this investigation we have studied different aspects related to the interaction between immune complexes (CI) and their cellular receptors for the Fc-fragment of IgG (RFc gamma). Our first approach was to demonstrate that the alternative pathway of complement is the main one responsible for the CI-dissociation from their receptors of human peripheral mononuclear cells. This modulatory effect was studied throughout the functional restoration of antibody dependent cellular cytotoxicity (CCCDA), which is a mechanism susceptible to Cl-inhibition. The results suggest that the levels of circulating Cl do not necessarily correlate with the tissue damage they produce. Secondly, we have demonstrated that cyclophosphamide (Cy), which is a potent immunomodulating drug which has been used for the treatment of diseases characterized by high levels of Cl, enhances the capacity of the mononuclear phagocytic system to remove IgG-particulate complexes in mice. Finally, we have described a nonspecific cytotoxic system triggered by Cl against different target cells, through a mechanism that involves the reactive metabolites of O2.
Asunto(s)
Complejo Antígeno-Anticuerpo/metabolismo , Activación de Complemento/fisiología , Vía Alternativa del Complemento/fisiología , Ciclofosfamida/farmacología , Receptores Fc/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Fagocitosis , Receptores Fc/efectos de los fármacosAsunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Complejo Antígeno-Anticuerpo/fisiología , Activación de Complemento , Proteínas del Sistema Complemento/fisiología , Fragmentos Fc de Inmunoglobulinas/fisiología , CME-Carbodiimida/farmacología , Vía Alternativa del Complemento/efectos de los fármacos , HumanosRESUMEN
Antibody-dependent cell-mediated cytotoxicity (ADCC) carried out by fresh and precultured peripheral blood mononuclear cells (PBMC) was compared. The results indicate that the cytotoxic capability was decreased in precultured PBMC, probably due to the effect of suppressor cells. The depletion of adherent cells before preincubation eliminated inhibitory effects, suggesting that the suppressor activity resided in this cell fraction. In addition, supernatants from adherent cell cultures were also able to suppress ADCC of non-adherent PBMC. Normal ADCC values were restored by supplementing the reaction medium with cycloheximide (Cy) 1 X 10(-3) M. The enhancing effect of Cy was exerted upon whole and adherent PBMC, while the opposite effect was observed when ADCC was carried out by non-adherent cells. The fact that Cy increased ADCC activity by precultured PBMC might rule out the possibility that suppression could be ascribed to trivial factors such as cell death, overcrowding or steric hindrance. The results presented in this report support the premise that ADCC is under active immunoregulation.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Cicloheximida/farmacología , Plaquetas/inmunología , Adhesión Celular , Separación Celular , Células Cultivadas , Humanos , Leucocitos/inmunología , Monocitos/inmunologíaRESUMEN
A progressive inhibition of both antibody-dependent cellular cytotoxicity (ADCC) and Fc gamma R expression was observed when peripheral blood mononuclear cells (PBMC) were incubated with soluble immune complexes (IC) at 37 degrees. Treatment of these IC-blocked PBMC with normal human serum (NHS) reversed both effects and increased the release of attached IC from the cell surface when compared to heat-inactivated serum (HI-NHS) or culture medium (TCM) treatments. Immunofluorescence studies demonstrated a redistribution of IC, predominantly in the form of caps in IC-blocked cells treated with HI-NHS (56%) or TCM (51%). However, when these IC-blocked cells were treated with NHS, only 11% of them showed caps redistribution. We propose that NHS regulation of Fc gamma R expression may be a physiological way of modulating the different immunological events triggered by IC.
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Sangre , Monocitos/inmunología , Receptores Fc/análisis , Animales , Citotoxicidad Celular Dependiente de Anticuerpos , Activación de Complemento , Técnica del Anticuerpo Fluorescente , Calor , Técnicas In Vitro , Receptores de IgGRESUMEN
Normal human monocytes were induced to lyse nonsensitized target cells when triggered by precipitating immune complexes (IC) or soluble heat-aggregated IgG (HAIgG). Catalase, azide, cyanide and three aminoacids employed as quenchers of ClO, significantly inhibited this nonspecific cytotoxicity (NSC), suggesting an important role for the myeloperoxidase (MPO) system. However, HO and/or 1O2 may also be involved in the lysis, since certain scavengers of these species such as mannitol, benzoate, ethanol and histidine, as well as superoxide dismutase (SOD), partially inhibited NSC. Moreover, cyanide and azide were unable to completely abrogate this lytic activity. When NSC was compared to antibody dependent cellular cytotoxicity (ADCC), it was found that neither catalase nor oxygen-species scavengers affected ADCC while azide and cyanide significantly enhanced it. Antibody-coated target cells were also destroyed by IC-triggered monocytes. However, kinetic analysis and studies on the capacity of catalase to inhibit the lysis demonstrated that it was mediated through a NSC-like mechanism. The cytotoxic system described in this report offers a suitable model to study in vitro alternative lytic mechanisms triggered through monocyte receptors for the Fc portion of IgG (Fc gamma R).
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Citotoxicidad Inmunológica , Monocitos/inmunología , Oxígeno/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Eritrocitos/inmunología , Humanos , Cinética , Peroxidasa/fisiologíaRESUMEN
The results of this study demonstrate that inhibition of antibody-dependent cell-mediated cytotoxicity (ADCC) of human peripheral blood mononuclear cells (PBMC) by ovalbumin (OA)-IgG anti-OA immune complexes (IC) can be affected by rheumatoid factors (RF). Thus, pre-incubation of IC with IgM RF reduced the blocking effect of IC on IgG-Fc receptors (FC gamma R) measured by ADCC activity. However, the opposite effect could be observed when IgM RF was added after IC-Fc gamma R interaction. IgG RF did not modify these interactions significantly. In a previous report it was demonstrated that normal human sera (NHS) lead to recovery of the ADCC activity of PBMC that had been previously blocked by IC. IgM RF enhanced the recovery of ADCC by NHS, while IgG RF did not alter, or slightly decreased the ability of NHS to restore ADCC. These effects correlated with the different capacities of RF to activate complement (C). The results obtained show a new effect of RF on the regulation of immune mechanisms.
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Receptores Fc/inmunología , Factor Reumatoide/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Activación de Complemento/efectos de los fármacos , Proteínas del Sistema Complemento/inmunología , Humanos , Monocitos/inmunología , Receptores de IgGRESUMEN
The effect of different amines on antibody-dependent cellular cytotoxicity (ADCC) activity of human mononuclear cells was tested. Whereas monocyte cytotoxic capacity was significantly stimulated in the presence of methylamine (MA), dansylcadaverine (DC) and glycine ethylester (GEE), lymphocyte ADCC was markedly suppressed by these agents. The pharmacological actions of these compounds in our system are not related to their ability to inhibit transglutaminase (TGase) enzymes, since tertiary amines such as sarcosine ethylester (SEE) and chloroquine (CQ) elicited identical responses to MA, DC and GEE. The calmodulin (CAM) inhibitors trifluoperazine (TFP) and the more specific N-(6-aminohexyl)-5-chloro-1-naphtalene sulfonamide (W-7) [Hidaka, Sasaki, Tanaka, Endo, Ohno, Fujii & Nagata (1981) Proc. natn. Acad. Sci. U.S.A., 78, 4353-4357] mimicked the effects of amines on ADCC, suggesting the possibility that a CAM-regulated process might be involved in the functional changes provoked by amines on ADCC. Finally, binding of 125I-immune complexes to the effector cells in the presence of amines showed lack of correlation between alterations in ADCC capacity and Fc gamma R expression.
Asunto(s)
Aminas/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Monocitos/efectos de los fármacos , Antígenos de Diferenciación , Calcio/metabolismo , Calmodulina/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Linfocitos/inmunología , Linfocitos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptores Fc , Receptores de IgG , Transglutaminasas/antagonistas & inhibidoresRESUMEN
We have shown previously that normal human neutrophils triggered by immune complexes displayed significant levels of cytotoxicity towards non-sensitized target cells (non-specific cytotoxicity-NSC) (Geffner, J. R. et al. 1987). Despite the fact that NSC and antibody-dependent cellular cytotoxicity (ADCC) are both mediated through neutrophil Fc gamma R and require the activation of the respiratory burst, the cytolytic mechanisms involved in each case appear to be different. In order to analyse the pathways of activation involved in the induction of NSC and ADCC, we studied here some of the metabolic requirements associated with each cytotoxic function. Our results suggest that ADCC is dependent on Na+/H+ antiporter activity, de novo protein synthesis, availability of external Ca2+ and calmodulin activity, activation of phospholipase C and activation of protein kinase C. On the other hand, NSC appears to be dependent on availability of external Ca2+ and calmodulin activity and activation of phospholipase A2. These results indicate that different pathways of activation are involved in the induction of neutrophil-mediated ADCC and NSC.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Complejo Antígeno-Anticuerpo/inmunología , Citotoxicidad Inmunológica , Neutrófilos/inmunología , Antiportadores , Ácidos Araquidónicos/metabolismo , Calcio/metabolismo , Calmodulina/metabolismo , Proteínas Portadoras , Humanos , Inmunoglobulina G/inmunología , Biosíntesis de Proteínas , Proteína Quinasa C/metabolismo , Receptores Fc/inmunología , Fosfolipasas de Tipo C/metabolismoRESUMEN
Here we analyse the ability of soluble immune complexes (IC) prepared with cationized antibodies to induce cytotoxic responses mediated by neutrophils. While cationized IC induced high levels of cytotoxicity, control IC induced very low levels of response. Inhibition of cytotoxicity by catalase but not by three haemenzyme inhibitors suggests that oxygen-dependent but myeloperoxidase-independent mechanisms are responsible for cytolysis. While the response induced by control IC was enhanced by cytochalasin B and was not modified by colchicine, that induced by cationized IC was markedly inhibited by cytochalasin B and significantly enhanced by colchicine. Cytotoxicity induced by cationized IC was completely abrogated by monoclonal antibodies to Fc gamma RII. Using control IC, a partial inhibition was observed employing either anti-Fc gamma RII or anti-Fc gamma RIII monoclonal antibodies. Treatment of neutrophils with chemotrypsin or pronase significantly enhanced cytotoxicity induced by cationized IC but not by control IC. We also found that non-specific absorptive mechanisms appear to play an important role in the binding of cationized IC, but not control IC, to the neutrophil surface. The significance of these results is discussed.
Asunto(s)
Anticuerpos/fisiología , Complejo Antígeno-Anticuerpo/inmunología , Neutrófilos/inmunología , Anticuerpos Monoclonales , Citotoxicidad Celular Dependiente de Anticuerpos/fisiología , Unión Competitiva , Cationes , Citoesqueleto/fisiología , Citotoxicidad Inmunológica/fisiología , Endopeptidasas/farmacología , Humanos , Interferón gamma/fisiología , Fagocitos/inmunología , Receptores Fc/inmunología , Receptores Fc/fisiologíaRESUMEN
The treatment of mice with a single dose of cyclophosphamide (Cy) (200 mg/kg) enhanced the chemiluminescence (CL) response of peritoneal macrophages (PM) triggered with opsonized zymosan (OpZ). The enhanced CL response could not be attributed to the stimulation of the cyanide-insensitive respiratory burst, since neither superoxide anion release nor immune complex-triggered cytotoxicity, an oxygen-dependent lytic mechanism, were increased in Cy-PM. Then, products of the oxidative metabolism of arachidonic acid were measured. It was found that Cy-PM exhibited increased release of prostaglandin E2 and leukotriene C4 in response to OpZ when compared with resident PM. In contrast, similar levels of thromboxane B2 production were observed in both populations. The activation of macrophage arachidonic acid metabolism reported here may contribute to the immunomodulating action of Cy.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Ciclofosfamida/farmacología , Macrófagos/efectos de los fármacos , Animales , Ácido Araquidónico , Dinoprostona/metabolismo , Técnicas In Vitro , Mediciones Luminiscentes , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Oxígeno/metabolismo , Cavidad Peritoneal/citología , Cavidad Peritoneal/efectos de los fármacos , Cavidad Peritoneal/metabolismo , SRS-A/metabolismo , Tromboxano B2/biosíntesisRESUMEN
Previous studies have demonstrated that the treatment of neutrophils with proteolytic enzymes markedly reduces the expression of receptor III for the Fc portion of IgG (Fc gamma RIII), but it does not affect the number of Fc gamma RII on the cell surface. In the present study, we analysed the effect of proteolytic enzymes on functional responses of neutrophils induced by immune complexes (IC). Our results showed that treatment with pronase or chymotrypsin markedly increased the binding of IgG-coated erythrocytes (IgG-E) to neutrophils, as well as their capability to display IgG-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) and chemiluminescence (CL) induced by IgG-E, responses that have been shown to be completely dependent on Fc gamma RII. A similar enhancing effect was observed, in all cases, after neutrophil treatment with neuroaminidase. We also studied the effect of proteolysis on neutrophil activation induced by other types of IC. It was found that pronase and chymotrypsin significantly enhanced CL responses induced by soluble IC (sIC) but did not modify the responses induced by either precipitating IC (pIC) or soluble IC prepared with cationized antibodies (catIC). On the other hand, neuroaminidase significantly enhanced CL induced by either sIC, pIC or catIC. Taken together, our data suggest that the activity of Fc gamma RII can be up-regulated by proteolysis. However, this effect appears to be strongly dependent on the characteristics of the IC employed as stimulus.
Asunto(s)
Neutrófilos/efectos de los fármacos , Péptido Hidrolasas/farmacología , Receptores de IgG/efectos de los fármacos , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Complejo Antígeno-Anticuerpo/inmunología , Células Cultivadas , Eritrocitos/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Mediciones Luminiscentes , Neuraminidasa/farmacología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Formación de RosetaRESUMEN
Normal human neutrophils triggered by precipitating immune complexes (IC), soluble IC (sIC) or heat-aggregated IgG (HAIgG) displayed low levels of cytotoxicity towards nonsensitized target cells. Catalase, but not heated catalase, completely impaired this nonspecific cytotoxicity (NSC), suggesting a key role for hydrogen peroxide (H2O2) in the lysis of target cells. Superoxide dismutase (SOD) and certain HO. and 1O2 scavengers were unable to exert significant effects. Three haem-enzyme inhibitors, sodium azide, sodium cyanide and 3-amino-1,2,4-triazole did not decrease neutrophil NSC, but markedly enhanced it. This data suggest that the mechanism involved was not dependent upon myeloperoxidase (MPO). The analysis of neutrophil-mediated ADCC indicates that oxygen-dependent but MPO-independent mechanisms appeared to be operative in this system. It was also found that the microfilament disrupting agents, cytochalasin B (CB) and dihydrocytochalasin B (dhCB), as well as the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), significantly enhanced NSC. In contrast, these compounds partially inhibited ADCC. This cytotoxic system provides a suitable model to study events that may occur during the course of immune complex diseases and also permits the evaluation of alternative lytic mechanisms triggered through neutrophil Fc gamma receptors.
Asunto(s)
Complejo Antígeno-Anticuerpo/inmunología , Citotoxicidad Inmunológica , Neutrófilos/inmunología , Oxígeno/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Colchicina/farmacología , Citocalasina B/análogos & derivados , Citocalasina B/farmacología , Citoesqueleto/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Cinética , Neutrófilos/metabolismo , Peroxidasa/metabolismoRESUMEN
During the course of this investigation we have studied different aspects related to the interaction between immune complexes (CI) and their cellular receptors for the Fc-fragment of IgG (RFc gamma). Our first approach was to demonstrate that the alternative pathway of complement is the main one responsible for the CI-dissociation from their receptors of human peripheral mononuclear cells. This modulatory effect was studied throughout the functional restoration of antibody dependent cellular cytotoxicity (CCCDA), which is a mechanism susceptible to Cl-inhibition. The results suggest that the levels of circulating Cl do not necessarily correlate with the tissue damage they produce. Secondly, we have demonstrated that cyclophosphamide (Cy), which is a potent immunomodulating drug which has been used for the treatment of diseases characterized by high levels of Cl, enhances the capacity of the mononuclear phagocytic system to remove IgG-particulate complexes in mice. Finally, we have described a nonspecific cytotoxic system triggered by Cl against different target cells, through a mechanism that involves the reactive metabolites of O2.