RESUMEN
Deficiency in Daf1, a complement regulatory protein, has been shown to exacerbate development of various autoimmune diseases and recent studies have suggested that this may be explained by Daf1 acting to limit T-cell hyper-responsiveness. It has been suggested that the absence of Daf1 aggravates autoimmune disease in a complement-dependent manner, but others have shown that activation of T cells in the absence of Daf1 can be complement independent. However, the relationship between Daf1, complement components, lymphocyte activation, cytokine expression and antibody production remains to be determined in mice that are not Daf1 deficient. We have recently demonstrated, in murine mercury-induced autoimmunity (mHgIA), that an accumulation of CD44(high) Daf(low) CD4(+) T cells is associated with the development of autoimmunity. In this study we observed that complement depletion does not affect the accumulation of activated CD4(+) T cells, elevation of splenic interleukin-4 expression and autoantibody production in mHgIA. In addition, neither the accumulation of CD44(high) Daf(low) CD4(+) T cells nor the down-regulation of Daf1 expression on CD4(+) T cells was influenced by a lack of complement. In conclusion, these studies show that initiating events in xenobiotic-induced autoimmunity, including lymphocyte activation, cytokine expression and autoantibody production, are not dependent on complement.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Inactivadores del Complemento/farmacología , Proteínas del Sistema Complemento/metabolismo , Venenos Elapídicos/farmacología , Cloruro de Mercurio/inmunología , Xenobióticos/inmunología , Animales , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Linfocitos T CD4-Positivos/inmunología , Antígenos CD55/metabolismo , Complemento C3/metabolismo , Citocinas/metabolismo , Activación de Linfocitos , Cloruro de Mercurio/administración & dosificación , Ratones , Ratones NoqueadosRESUMEN
Biological impairments due to mercury discharge into the environment are now an issue of global concern. From the three forms of mercury found in aquatic ecosystems, the immunotoxic effects of mercury chloride were examined in the model animal, the blue mussel. In order to investigate the toxic potency of this chemical, three exposure regimes were carried out: chronic exposure of groups of individuals, a new protocol "in tubo" designed for sub-acute exposures of individuals, and acute exposures of target cells. Chronic exposure revealed significant immunotoxic effects after 7 days at 10(-6)M, while acute exposures showed significant inhibition of phagocytosis at 10(-4)M and 10(-3)M. In sub-acute exposures both circulating haemocytes and haemocyte mortality increased at 10(-4)M and 10(-3)M while phagocytosis and the clearance rate drew hormetic toxic effects on healthy individuals. These results suggest the use of the "in tubo" design for bivalve toxicological individual studies.
Asunto(s)
Cloruro de Mercurio/toxicidad , Mytilus edulis/inmunología , Animales , Muerte Celular , Hemocitos/efectos de los fármacos , Hemocitos/patología , Cloruro de Mercurio/inmunología , Cloruro de Mercurio/farmacocinética , Mytilus edulis/efectos de los fármacos , Mytilus edulis/metabolismo , Fagocitosis/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Inorganic mercury (mercuric chloride--HgCl(2)) induces in mice an autoimmune syndrome (HgIA) with T cell-dependent polyclonal B cell activation and hypergammaglobulinemia, dose- and H-2-dependent production of autoantibodies targeting the 34 kDa nucleolar protein fibrillarin (AFA), and systemic immune-complex deposits. The organic mercury species methylmercury (MeHg) and ethylmercury (EtHg--in the form of thimerosal) induce AFA, while the other manifestations of HgIA seen after treatment with HgCl(2) are present to varying extent. Since these organic Hg species are converted to the autoimmunogen Hg(2+) in the body, their primary autoimmunogen potential is uncertain and the subject of this study. A moderate dose of HgCl(2) (8 mg/L drinking water--internal dose 148 micro gHg/kg body weight [bw]/day) caused the fastest AFA response, while the induction was delayed after higher (25 mg/L) and lower (1.5 and 3 mg/L) doses. The lowest dose of HgCl(2) inducing AFA was 1.5 mg/L drinking water which corresponded to a renal Hg(2+) concentration of 0.53 micro g/g. Using a dose of 8 mg HgCl(2)/L this threshold concentration was reached within 24 h, and a consistent AFA response developed after 8-10 days. The time lag for the immunological part of the reaction leading to a consistent AFA response was therefore 7-9 days. A dose of thimerosal close to the threshold dose for induction of AFA (2 mg/L drinking water--internal dose 118 micro gHg/kg bw per day), caused a renal Hg(2+) concentration of 1.8 micro g/g. The autoimmunogen effect of EtHg might therefore be entirely due to Hg(2+) formed from EtHg in the body. The effect of organic and inorganic Hg species on T-helper type 1 and type 2 cells during induction of AFA was assessed as the presence and titre of AFA of the IgG1 and IgG2a isotype, respectively. EtHg induced a persistent Th1-skewed response irrespectively of the dose and time used. A low daily dose of HgCl(2) (1.5-3 mg/L) caused a Th1-skewed AFA response, while a moderate dose (8 mg/L) after 2 weeks resulted in a balanced or even Th2-skewed response. Higher daily doses of HgCl(2) (25 mg/L) caused a balanced Th2-Th1 response already from onset. In conclusion, while metabolically formed Hg(2+) might be the main AFA-inducing factor also after treatment with EtHg, the quality of the Hg-induced AFA response is modified by the species of Hg as well as the dose.
Asunto(s)
Autoinmunidad/inmunología , Activación de Linfocitos/efectos de los fármacos , Cloruro de Mercurio/toxicidad , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Animales , Anticuerpos Antinucleares/inmunología , Proteínas Cromosómicas no Histona/sangre , Relación Dosis-Respuesta a Droga , Femenino , Técnica del Anticuerpo Fluorescente , Inmunoglobulina G/clasificación , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Riñón/química , Riñón/efectos de los fármacos , Activación de Linfocitos/inmunología , Cloruro de Mercurio/química , Cloruro de Mercurio/inmunología , Ratones , Proteínas Nucleares/sangre , Órbita/irrigación sanguínea , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Timerosal/química , Timerosal/inmunología , Timerosal/toxicidad , Factores de TiempoRESUMEN
Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway rats is a spontaneously resolving autoimmune response driven by the activation of T helper type 2 lymphocytes (Th2 cells). Treatment with antibody to OX40-ligand (OX40-L) from the time of the first HgCl2 injection for 12 days had little effect. Delayed treatment commenced 8 days after the first HgCl2 injection significantly suppressed immunoglobulin E production, splenomegaly, weight loss and mortality. This makes OX40/OX40-L signalling an attractive therapeutic target for Th2-driven autoimmune diseases. Intravenous administration of the murine antibody to OX-40-L elicited a vigorous anti-mouse immunoglobulin antibody response that was significantly enhanced compared to the response to control immunoglobulin. It is likely that this response significantly reduced the plasma half-life of the anti-OX40-L antibody and this observation has clear implications for the interpretation of data from experiments where anti-OX40-L is used in vivo.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/prevención & control , Glicoproteínas de Membrana/inmunología , Células Th2/inmunología , Factores de Necrosis Tumoral/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Autoinmunidad/efectos de los fármacos , Antígeno B7-1/inmunología , Antígeno B7-2/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Inmunoglobulina E/biosíntesis , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Cloruro de Mercurio/inmunología , Tamaño de los Órganos , Ratas , Ratas Endogámicas BN , Transducción de Señal/inmunología , Bazo/patología , Análisis de Supervivencia , Inhibidores del Factor de Necrosis TumoralRESUMEN
The initiation and severity of systemic autoimmune diseases are influenced by a variety of genetic and environmental factors, in particular bacterial infections and products. Here, we have employed bacterial lipopolysaccharide (LPS), which non-specifically activates the immune system, to explore the involvement of innate immunity in mercury-induced autoimmunity in mice. Following treatment of mouse strains resistant [DBA/2 (H-2(d))] or susceptible [SJL(H-2(s))] to such autoimmunity with mercuric chloride and/or LPS or with physiological saline alone (control), their immune/autoimmune responses were monitored. Resistant DBA/2 mice were rendered susceptible to mercury-induced autoimmunity by co-administration of LPS, exhibiting pronounced increases in the synthesis of IgG1 and IgE, high titres of IgG1 deposits in the kidneys and elevated circulating levels of IgG1 antibodies of different specificities. Furthermore, the percentages of the T cells isolated from the spleens of DBA/2 mice exposed to both mercury and LPS that produced pro-inflammatory cytokines were markedly increased by in vitro stimulation with phorbol myristate acetate (PMA) and ionomycin, which was not the case for splenic T cells isolated from mice receiving mercuric chloride, LPS or saline alone. In addition, exposure of susceptible SJL mice to mercury in combination with LPS aggravated the characteristic features of mercury-induced autoimmunity, including increased synthesis of IgG1 and IgE, the production of IgG1 anti-nucleolar antibodies (ANolA) and the formation of renal deposits of IgG1. In summary, our findings indicate that activation of the innate immune system plays a key role in both the induction and severity of chemically induced autoimmunity.
Asunto(s)
Autoinmunidad/inmunología , Lipopolisacáridos/inmunología , Cloruro de Mercurio/inmunología , Animales , Autoanticuerpos/biosíntesis , Autoinmunidad/efectos de los fármacos , Susceptibilidad a Enfermedades , Femenino , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Riñón/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos , Bazo/inmunología , Linfocitos T/inmunologíaRESUMEN
In susceptible mice, mercuric chloride induces a systemic autoimmune response that is characterized by elevated serum levels of immunoglobulin G1 (IgG1) and immunoglobulin E (IgE), production of anti-nucleolar antibodies (ANolAs) and the formation of renal IgG deposits. We have previously shown that mercury can also enhance immune/autoimmune responses in mouse strains genetically prone to develop spontaneous autoimmune disease. Here, we investigated whether mercury can enhance the severity of murine collagen-induced arthritis (CIA), an inducible (acquired) autoimmune disease that cannot be induced by mercury itself. While mercury administered prior to the induction phase of CIA exerted little, if any, influence, administration of mercury during the induction phase and following onset aggravated the symptoms of this disease and increased the serum levels of IgE and IgG2a antibodies directed against collagen type II (CII). Furthermore, while animals injected with mercury alone exhibited a significant decrease in the ratio of the levels of interferon-gamma (IFN-gamma) to interleukin-4 (IL-4) mRNA in their spleens, this ratio was increased in mice with CIA, with or without administration of mercury. Finally, the production of anti-nuclear antibodies, a hallmark of autoimmunity in response to mercury, was observed in all mice with CIA treated with this heavy metal. Our findings suggest that exposure to mercury during the development of CIA may influence immunological factors in such a way as to synergistically promote disease development.
Asunto(s)
Artritis Experimental/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Cloruro de Mercurio/toxicidad , Animales , Anticuerpos Antinucleares/biosíntesis , Artritis Experimental/inmunología , Artritis Experimental/patología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Colágeno Tipo II/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Interferón gamma/biosíntesis , Interferón gamma/genética , Interleucina-4/biosíntesis , Interleucina-4/genética , Cloruro de Mercurio/inmunología , Ratones , Ratones Endogámicos DBA , ARN Mensajero/genética , Bazo/inmunologíaRESUMEN
Administration of mercuric chloride to Brown Norway rats results in T helper type 2 (Th2)- dominated autoimmunity characterized by high immunoglobulin E (IgE) concentrations, the production of multiple IgG autoantibodies, including those to glomerular basement membrane (GBM), arthritis and caecal vasculitis. After 14 days animals immunoregulate and auto-immunity resolves even if mercuric chloride injections are continued. In a third phase, if animals are re-challenged with mercuric chloride 6 weeks later, they show only attenuated autoimmunity with lower anti-GBM antibody concentrations and arthritis scores. Resistance to the induction of anti-GBM antibodies can also be achieved following an initial challenge with low-dose (one-tenth standard dose) mercuric chloride. We have now studied this resistant phase in more detail. We have shown, first, that following an initial full-dose mercuric chloride challenge, resistance also affects susceptibility to caecal vasculitis. Second, following an initial full-dose mercuric chloride challenge, the IgE response upon re-challenge is initially accelerated but subsequently enters a resistant phase and third, following an initial challenge with low-dose mercuric chloride, resistance is also seen to the induction of caecal vasculitis but is not seen in IgE serology (where results suggest competing effector and regulatory cell populations). Studying such regulatory phases in animal models of autoimmunity may be of benefit in the future in designing new therapies for human vasculitis.
Asunto(s)
Autoinmunidad/inmunología , Vasculitis/inmunología , Animales , Artritis/inmunología , Membrana Basal/inmunología , Enfermedades del Ciego/inmunología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta Inmunológica , Inmunoglobulina E/análisis , Masculino , Cloruro de Mercurio/inmunología , Ratas , Ratas Endogámicas BN , Células Th2RESUMEN
In susceptible mice, mercuric chloride induces a systemic autoimmune disease characterized by increased serum levels of immunoglobulin (Ig) G1 and IgE, production of anti-nucleolar autoantibodies (ANolA) and formation of renal IgG deposits. We have previously hypothesized that mercury confers more adverse immunological effects on those mouse strains, which are genetically prone to develop spontaneous autoimmune diseases than on normal strains. In this study, we tested our hypothesis in tight skin 1 (Tsk1/+) mice, a murine model for human scleroderma. As a support for our hypothesis, we observed that in Tsk1/+ mice, B cells were spontaneously hyperactive and that treatment with mercury induced a strong immune/autoimmune response in these mice, but not in their non-Tsk (+/+) littermates. This response was characterized by the formation of high numbers of splenic IgG1, IgG2b and IgG3 antibody-secreting cells, increased serum levels of IgE, production of IgG1 antibodies against single-stranded DNA (ssDNA), trinitrophenol (TNP) as well as thyroglobulin and the development of renal IgG1 deposits. Neither Tsk1/+ mice nor F1 hybrid crosses between this strain, and mercury susceptible B10.S (H-2(s)) were able to produce IgG1-ANolA in response to mercury. Moreover, mercury-induced immune activation in Tsk1/+ was not able to potentiate the progression of skin fibrosis in this strain. Thus, exposure to mercury accelerates the immune dysregulation, but not the development of skin fibrosis in Tsk1/+ mice.
Asunto(s)
Fibrosis/inmunología , Cloruro de Mercurio/inmunología , Cloruro de Mercurio/toxicidad , Esclerodermia Sistémica/inmunología , Piel/efectos de los fármacos , Animales , Autoanticuerpos/biosíntesis , Autoanticuerpos/efectos de los fármacos , Linfocitos B/inmunología , ADN de Cadena Simple/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrosis/patología , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/efectos de los fármacos , Isotipos de Inmunoglobulinas , Riñón/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Mutantes , Picratos/inmunología , Piel/inmunología , Piel/patología , Tiroglobulina/inmunologíaRESUMEN
A rise in interleukin (IL) 4-dependent immunoglobulin E (IgE) is a hallmark of the mercuric chloride (HgCl2)-induced Th2-mediated autoimmune syndrome in the Brown Norway (BN) rat, and one of the mediators in allergic asthma in human. Oxidative stress, a potential factor related to the pathogenesis of allergy and asthma, has been shown to up-regulate IL-4 in mast cells and predispose to degranulation in vitro. However, it remains unknown whether oxidative/antioxidative imbalance plays a role in this Th2-driven model of autoimmunity in the rat. Here we show that administration of the non-sulphydryl-containing antioxidant desferrioxamine i.p. and s.c. to BN rats reduces HgCl2-enhanced IL-4 gene expression and inhibits HgCl2-induced Th2-mediated autoimmunity. Desferrioxamine treatment suppresses significantly IgE production and lymphoproliferation, and reduces tissue injury in the form of caecal vasculitis in the HgCl2-induced autoimmune syndrome. These results support a role for oxidative stress in the pathogenesis of the HgCl2-induced Th2-dominated autoimmune syndrome. This finding might have implications for understanding the mechanisms involved in Th2 cell responses as seen in allergy and asthma and thereby aid the development of new therapeutic strategies for these diseases.
Asunto(s)
Autoinmunidad/inmunología , Deferoxamina/farmacología , Interleucina-4/inmunología , Quelantes del Hierro/farmacología , Células Th2/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Ensayo de Inmunoadsorción Enzimática/métodos , Expresión Génica/inmunología , Inmunoglobulina E/biosíntesis , Interferón gamma/inmunología , Masculino , Cloruro de Mercurio/inmunología , Estrés Oxidativo/inmunología , Ratas , Ratas Endogámicas BN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Bazo/inmunología , Vasculitis/inmunologíaRESUMEN
T-helper cells type 1 (Th1) and type 2 (Th2) play an important role in the pathogenesis of autoimmune diseases. In many Th1-dependent autoimmune models, treatment with recombinant interleukin-12 (rIL-12) accelerates the autoimmune response. Mercury-induced autoimmunity (HgIA) in mice is an H-2 regulated condition with antinucleolar antibodies targeting fibrillarin (ANoA), systemic immune-complex (IC) deposits and transient polyclonal B-cell activation (PBA). HgIA has many characteristics of a Th2 type of reaction, including a strong increase of IgE, but disease induction is critically dependent on the Th1 cytokine IFN-gamma. The aim of this study was to investigate if a strong deviation of the immune response in HgIA towards Th1 would aggravate HgIA. Injections of both rIL-12 and anti-IL-4 monoclonal antibody (alpha-IL-4) reduced the HgCl2-(Hg-)induced concentration of the Th2-dependent serum IgE and IgG1, but increased the Th1-dependent serum IgG2a. The IgG-ANoA developed earlier and attained a higher titre after combined treatment, and the ANoA titre of the IgG1 isotype decreased while the ANoA titre of the Th1-associated IgG2a, IgG2b and IgG3-ANoA isotypes increased. Treatment with rIL-12 alone increased the Hg-induced IgG2a and IgG3 ANoA titres, the PBA, and the IC deposits in renal and splenic vessel walls, while treatment with alpha-IL-4 + Hg inhibited renal but not splenic vessel wall IC deposits. We conclude that manipulating the cytokine status, by altering the Th1/Th2 balance, will influence autoimmune disease manifestations. This might be an important way of modulating human autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Cloruro de Mercurio/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Complejo Antígeno-Anticuerpo/metabolismo , Enfermedades Autoinmunes/inmunología , Autoinmunidad , Linfocitos B/inmunología , Femenino , Inmunoglobulina G/biosíntesis , Isotipos de Inmunoglobulinas/inmunología , Interleucina-12/inmunología , Interleucina-4/inmunología , Riñón/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos , Proteínas Recombinantes/inmunología , Bazo/inmunologíaRESUMEN
The repeated administration of mercury to Brown Norway (BN) rats induces the production of autoantibodies to laminin 1 and other autoantigens, accompanied by renal deposition of immunoglobulins and a membranous glomerulonephropathy. A graft-versus-host-like (GVHL) syndrome, characterized by widespread necrotizing leukocytoclastic vasculitis of the bowel, skin, and other tissues, has also been observed after mercury treatment of BN rats. These findings have suggested that the autoimmunity caused by the administration of mercury to BN rats may result as a xenobiotic-induced GVHL effect under the control of OX22+ T lymphocytes. However, previous studies of mercury-induced autoimmunity have never reported any evidence of GVHL lesions. Therefore, we have carefully examined various tissues from a large group of BN rats injected with HgCl(2) to identify possible areas of inflammatory reactions that may have been unnoticed in previous investigations. In addition, we have determined by flow cytometry whether exposure to mercury results in percentage and numerical alterations of OX22+ or other lymphocyte subpopulations in lymphoid organs of HgCl(2)-treated BN rats. The present article confirms that mercury induces autoimmune responses to laminin 1 but does not corroborate the hypothesis of a GVHL syndrome regulated by OX22+ lymphocytes. First, changes in OX22+ cells during treatment with HgCl(2) were infrequent and had no significant correlation with the kinetics of autoimmune responses to laminin 1. Second, we detected no GVHL lesions in skin and intestine of mercury-treated BN rats.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Laminina/inmunología , Cloruro de Mercurio/toxicidad , Animales , Autoanticuerpos/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Directa , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/patología , Enfermedad Injerto contra Huésped/patología , Riñón/inmunología , Riñón/patología , Ganglios Linfáticos/inmunología , Masculino , Cloruro de Mercurio/inmunología , Ratas , Ratas Endogámicas BN , Bazo/inmunología , Timo/inmunologíaRESUMEN
Immunological tolerance can be achieved in animals by exposure of newborn to a foreign antigen. Depending on the dose and timing of the antigenic challenge, tolerance has been reported to result in clonal deletion, anergy or active suppression. In this latter case, regulatory T cells prevent autoimmunity by suppressing the reactivity of pathogenic self-reactive T cells. We have previously reported the generation of a neonatal, mercury-specific, and dominant tolerance to autoimmunity induced by mercury salts in rats. Chronic exposure to mercury salts can lead to SLE-like autoimmune responses, mediated by autoreactive CD4+ Th2 cells, that regulate and are followed by a resistant state mediated by protective CD8+ T cells. The aim of the study was to compare the resistance to the neonatal tolerance to mercury disease, and to further characterize the CD8+ T cells endowed with regulatory capacity in the neonatal tolerance model. We report here that resistance to mercury disease is long lasting and not mercury-specific, suggesting that different CD8+ T cells are involved in resistance and neonatal tolerance, and that regulatory CD8+ Tc1 cells generated in tolerance are required to control the CD8- cell population from developing Th2-mediated autoimmunity. Upon mercury recall, CD8+ CD45RC(high) T cells, that represent the Tc1 subset in the rat, expanded and were polarized towards IFNgamma production. Interestingly, identical results were obtained with the CD8+ CD25+T cell population. Substantial amounts of FasL gene expression were detected in CD8+ T lymphocytes upon recall with the tolerogen. AICD may be one of the regulatory mechanisms used by these regulatory CD8+ Tc1 cells that control neonatal tolerance to a Th2-mediated autoimmune disorder.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Dimercaprol/análogos & derivados , Tolerancia Inmunológica/inmunología , Linfocitos T Citotóxicos/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Animales Recién Nacidos , Apoptosis/inmunología , Antígenos CD4/análisis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Antígenos CD8/análisis , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Dimercaprol/administración & dosificación , Dimercaprol/inmunología , Dimercaprol/farmacología , Proteína Ligando Fas , Expresión Génica , Inmunoglobulina E/sangre , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Antígenos Comunes de Leucocito/análisis , Transfusión de Linfocitos , Masculino , Glicoproteínas de Membrana/genética , Cloruro de Mercurio/administración & dosificación , Cloruro de Mercurio/inmunología , Compuestos Orgánicos de Oro , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/inmunología , Compuestos Organometálicos/farmacología , Propanoles , Ratas , Receptores de Interleucina-2/análisis , Bazo/citología , Bazo/inmunología , Compuestos de Sulfhidrilo , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Células Th2/efectos de los fármacosRESUMEN
After exposure to subtoxic doses of heavy metals such as mercury, H-2(s) mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we explore the role of two inhibitory immunoreceptors, CTLA-4 and FcgammaRIIB, in the regulation of mercury-induced autoimmunity. In susceptible mice treated with mercuric chloride (HgCl(2)), administration of a blocking anti-CTLA-4 Ab resulted in a further increase in anti-nucleolar autoantibodies and in total serum IgG1 levels. Furthermore, in some DBA/2 mice, which are normally resistant to heavy metal-induced autoimmunity, anti-CTLA-4 treatment leads to the production of anti-nucleolar Abs, thereby overcoming the genetic restriction of the disease. In mice deficient for the FcgammaRIIB, HgCl(2) administration did not trigger autoantibody production, but resulted in an increase in IgE serum levels. Taken together, these results indicate that different inhibitory mechanisms regulate various manifestations of this autoimmune syndrome.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Regulación hacia Abajo/inmunología , Cloruro de Mercurio/inmunología , Transducción de Señal/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Antígenos CD , Antígenos de Diferenciación/inmunología , Antígenos de Diferenciación/fisiología , Antígeno CTLA-4 , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/inmunología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Inyecciones Subcutáneas , Cloruro de Mercurio/administración & dosificación , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Receptores de IgG/deficiencia , Receptores de IgG/genética , Receptores de IgG/fisiología , Transducción de Señal/efectos de los fármacos , Síndrome , Factores de TiempoRESUMEN
BACKGROUND: In 97% of all patients with oral lichenoid reactions (OLR) associated with dental amalgam a removal of the fillings leads to a decline of the lesions, as a minimum. OBJECTIVES: The aim of this study was to determine if contact allergic or local toxic effects or both may contribute to OLR using an animal model with mercury-sensitive and non-sensitive rats. METHODS: Twenty Brown Norway rats, which have a genetic predisposition for an autoimmune syndrome after exposure to mercury and 20 Lewis rats, not mercury sensitive, were treated as follows: 10 animals of each group were sensitized with a low dose of mercuric chloride. Half of all animals received local exposure of the right buccal mucosa to amalgam (left: control), the others to amalgam alloy free of mercury. All rats were patch tested with an amalgam series. RESULTS: After 20 days of exposure 96% of all animals showed white mucosal lesions restricted to the contact zone of the alloy on the treated side, but only up to 25% had a positive patch test reaction to amalgam or inorganic mercury (INM). The lesions showed no relation to species, alloy, sensitization or patch test reaction. CONCLUSIONS: While allergic mechanisms may contribute to mucosal contact lesions in Brown Norway rats, this is less probable in Lewis rats. Mercury in general appears to be irrelevant in the development of ORL in this study. If this holds true for humans as well, patch testing with an amalgam series may be helpful in a minor fraction of all patients with OLR.
Asunto(s)
Amalgama Dental/toxicidad , Liquen Plano Oral/inducido químicamente , Animales , Mejilla , Dermatitis Alérgica por Contacto/complicaciones , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Liquen Plano Oral/patología , Cloruro de Mercurio/inmunología , Mucosa Bucal/patología , Pruebas del Parche , Ratas , Ratas Endogámicas BN , Ratas Endogámicas LewRESUMEN
Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8(+) T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8(+) T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8(+) T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8(+)CD45RC(high) T cells and the emergence of a high percentage of IFN-gamma-synthesizing CD8(+) T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8(+) cell-mediated regulatory response.
Asunto(s)
Animales Recién Nacidos/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD8-positivos/inmunología , Tolerancia Inmunológica , Subgrupos de Linfocitos T/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Anticuerpos Monoclonales/administración & dosificación , Enfermedades Autoinmunes/inducido químicamente , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Tolerancia Inmunológica/efectos de los fármacos , Inmunofenotipificación , Inyecciones Subcutáneas , Líquido Intracelular/inmunología , Líquido Intracelular/metabolismo , Masculino , Cloruro de Mercurio/administración & dosificación , Cloruro de Mercurio/inmunología , Ratas , Ratas Endogámicas BN , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/trasplanteRESUMEN
It is clear that functional heterogeneity of T cells may be explained by differential cytokine production. The aim of this paper was to review evidence for regulatory cells, generated after HgCl(2)-exposure. They differ from classical Th1 and Th2 cells, produce transforming growth factor-beta and interleukin-10 and exert their regulatory functions in a Th1/Th2-unrestricted fashion.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Enfermedades Autoinmunes/fisiopatología , Regulación hacia Abajo , Humanos , Cloruro de Mercurio/inmunología , Ratas , Ratas Endogámicas LewRESUMEN
Although evidence indicates that environmental factors play a major role in precipitating systemic autoimmunity in genetically susceptible individuals, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae, including lymphoproliferation, hypergammaglobulinemia, and overt systemic autoimmunity. Predisposition to such metal-induced immunopathology has been shown to be influenced by both MHC and non-MHC genes, as well as susceptibility to spontaneous lupus, in mice and other experimental animals. Among the various mouse strains examined to date, the DBA/2 appears to uniquely lack susceptibility to mercury-induced autoimmunity (HgIA), despite expressing a susceptible H-2 haplotype (H-2d). To define the genetic basis for this trait, two genome-wide scans were conducted using F2 intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are highly susceptible to HgIA. A single major quantitative trait locus on chromosome 1, designated Hmr1, was shown to be common to both crosses and encompassed a region containing several lupus susceptibility loci. Hmr1 was linked to glomerular immune complex deposits and not autoantibody production, suggesting that DBA/2 resistance to HgIA may primarily involve the later stages of disease pathogenesis. Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury-induced autoimmunity should provide important insights into the pathogenesis of autoimmunity and may reveal novel targets for intervention.
Asunto(s)
Enfermedades Autoinmunes/genética , Mapeo Cromosómico , Inmunidad Innata/genética , Cloruro de Mercurio/inmunología , Xenobióticos/inmunología , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Mapeo Cromosómico/métodos , Cruzamientos Genéticos , Femenino , Ligamiento Genético/inmunología , Marcadores Genéticos/inmunología , Predisposición Genética a la Enfermedad/genética , Ratones , Ratones Endogámicos DBA , Ratones Endogámicos NZB , Ratones Endogámicos , Carácter Cuantitativo Heredable , Especificidad de la EspecieRESUMEN
Previous studies have shown that genetic factors control the susceptibility to mercury-induced immunoglobulin (Ig)G1 antibody formation, IgE synthesis, renal IgG deposits and antinucleolar autoantibodies (ANolA) production in the susceptible mice. In this study, we examined the genetic control of resistance to these characteristics after HgCl2 injection in F1 hybrid crosses between the highly mercury resistant DBA/2 and mercury susceptible NZB (H-2d), SJL (H-2 s), A.CA (H-2f) and DBA/1 (H-2q) mice and also in backcross hybrids between (DBA/2 x SJL)F1 and SJL mice. We observed that mercury-induced immune/autoimmune manifestations were profoundly downregulated in most (if not all) of the F1 hybrids, indicating that the resistance to mercury was a dominant trait. Analysis of mercury-induced immune/autoimmune responses in the (DBA/2 x SJL) x SJL backcross hybrids suggested that only one gene or a cluster of genes determined the resistance to the ANolA production, whereas the resistance to other characteristics was controlled by two and/or three gene loci. By H-2 genotyping the backcross mice, it was found that H-2d haplotype per se could confer resistance to ANolA production. However, we did not find any significant association between the H-2d haplotype and the resistance to increase of IgG1 and IgE synthesis and the development of renal IgG1 deposits. Thus, while in DBA/2 mice, gene(s) in the H-2 loci strictly contribute to the inheritance of resistance to ANolA production; non-H-2 genes mainly govern the inheritance of unresponsiveness regarding other characteristics.
Asunto(s)
Autoinmunidad/genética , Cloruro de Mercurio/inmunología , Animales , Autoinmunidad/inmunología , Cruzamientos Genéticos , Femenino , Genes Dominantes , Antígenos H-2/genética , Masculino , Cloruro de Mercurio/administración & dosificación , Ratones , Ratones Endogámicos DBARESUMEN
Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Autoinmunidad/inmunología , Metales Pesados/efectos adversos , Adyuvantes Inmunológicos , Animales , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Oro/inmunología , Estado de Salud , Humanos , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades del Sistema Inmune/inmunología , Interferón gamma/inmunología , Interleucina-4/inmunología , Antígenos Comunes de Leucocito/inmunología , Cloruro de Mercurio/inmunología , Metales Pesados/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Células Th2/inmunología , Xenobióticos/inmunologíaRESUMEN
Suppression of IgE responses is a major goal for immunotherapy, especially in the field of allergy. The Th2 subset of helper T cells plays a vital role in class switching of B cells to IgE production by releasing IL-4. In susceptible rat strains, mercuric chloride (HgCl2) induces activation of Th2 cells, with enhanced expression of IL-4, polyclonal B cell activation and very high levels of circulating IgE. We have previously shown that spontaneous regulation of this response coincides with enhanced expression of Th1/type-1 cytokines, including interferon-gamma (IFN-gamma) and IL-12. We now report the effects of administration of exogenous type-1 cytokines on HgCl2-induced Th2 responses. At high doses, recombinant rat IFN-gamma markedly reduced serum IgE levels. Recombinant mouse IL-12 was less effective at suppressing the IgE response following HgCl2, although it caused marked up-regulation of IFN-gamma gene expression in the spleen. In Lewis rats, which are resistant to HgCl2-induced autoimmunity, a rise in serum IFN-gamma was observed after HgCl2, but administration of polyclonal anti-IFN-gamma antibodies did not render them susceptible to induction of a Th2 response by HgCl2. Our data show that individual type-1 cytokines are capable of suppressing the dramatic Th2 response induced by HgCl2 in the rat, even when they are not given until after starting HgCl2 administration. IFN-gamma is a pivotal cytokine in ameliorating the Th2 response and measures aimed at selective up-regulation of this cytokine may be of therapeutic value in suppression of unwanted IgE responses.