RESUMEN
Deep mycosis (aspergillus pneumonia (AsP)) and carinii pneumonitis (PCP) are complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The objective was to clarify the clinical significance of plasma titer of antibody against beta-glucans (anti-BG antibody) as a predictor of complications such as AsP or PCP and the prognosis of patients. Enzyme-linked immunosorbent assay was used to measure the plasma titer of antibodies against beta-glucans (BG) from Candida albicans in 22 healthy subjects and 52 patients with various stages of AAV. The mean plasma titer of the anti-BG antibody was 2,677 +/- 1,686 U in healthy subjects, 691 +/- 522 U in patients with untreated active vasculitis (n = 14), and 547 +/- 416 U in patients soon after immunosuppressive treatment (n = 24). Healthy subjects had significantly higher antibody titers than the other two groups (P < 0.05). Repeated measurements over the clinical course of AAV revealed an increase during remission to 1,180 +/- 130 U (n = 11), while there was a significant rapid decrease to 369 +/- 441 U (P < 0.01) concomitantly with elevation in plasma C-reactive protein and BG levels in patients with AAV that had AsP or PCP infection. Antifungal therapy resulted in a rapid rise of anti-BG antibody titer. Experiments in mice suggested that the anti-BG antibody neutralizes BG. Rapid decrease of the anti-BG antibody titer may be a useful indicator for diagnosis of the presence of AsP or PCP and for estimating the prognosis of patients with these opportunistic infections during immunosuppressive treatment of AAV.
Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/química , Antifúngicos/farmacología , Candida albicans/metabolismo , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Micosis/inmunología , Neumonía/diagnóstico , Vasculitis/inmunología , beta-Glucanos/química , Anciano de 80 o más Años , Aspergillus/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Reproducibilidad de los Resultados , beta-Glucanos/metabolismoRESUMEN
SKG mice are a recently established experimental model for rheumatoid arthritis (RA). Although they spontaneously develop chronic autoimmune arthritis under conventional conditions, SKG mice failed to develop chronic arthritis in a strictly controlled specific pathogen-free (SPF) environment. Beta-glucan (BG) from Laminaria digitata, laminarin (LAM), induced arthritis under SPF conditions, thus BG would be a pathogenic factor for arthritis in SKG mice. Therefore, we prepared BG from Candida albicans, a pathogenic fungus and investigated whether BG from C. albicans induced arthritis in SKG mice under SPF conditions. SKG mice were injected intraperitoneally with particulate BG (oxidative-Candida albicans (OX-CA)), soluble BG (Candida soluble beta-glucan (CSBG)) from C. albicans and LAM as a positive control. In addition, schizophyllan (SPG) from Schizophyllum commune or Mycobacterium whole cells were injected into SKG mice to induce arthritis. Mice injected with OX-CA, CSBG and SPG had more severe arthritis than with LAM, and whole Mycobacterium cells. IL-6 concentration in sera from SKG mice injected with OX-CA or CSBG was high, whereas not detected in sera from mice treated with LAM. In histological analysis, infiltration of inflammatory cells was observed in SKG mice injected with BG. These results suggest that fungal infection may be a factor to induce and exacerbate autoimmune diseases such as RA.
Asunto(s)
Artritis/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Candida albicans/química , Pared Celular/química , beta-Glucanos/toxicidad , Adyuvantes Inmunológicos/química , Animales , Femenino , Interleucina-6/sangre , Masculino , Ratones , Ratones Endogámicos , Mycobacterium tuberculosis/química , Sizofirano/química , beta-Glucanos/químicaRESUMEN
Collagen-induced arthritis (CIA) is an experimental model of rheumatoid arthritis (RA) and has helped researchers to analyze the pathogenesis of inflammatory joint disease. In classical CIA, Freund's complete adjuvant (FCA), which contains heat-killed Mycobacterium tuberculosis, is used as an adjuvant. In our previous study, we reported that particles of beta-glucan, OX-CA, derived from Candida albicans, acted as a proper adjuvant in the CIA model. In this study, to establish pure beta-glucan as an adjuvant for CIA, we tested a commercially available preparation of Zymosan A (ZYM) and modified its products. beta-Glucan fractions of ZYM were prepared by oxidation with various concentrations of NaClO. The oxidized ZYM (OX-ZYM) was mainly composed of beta-glucan. In this study, we examined its effect as an adjuvant for CIA. DBA/1 mice injected with CII and OX-CA developed arthritis 7-10 days after receiving booster injections; the OX-ZYM fractions induced arthritis with the same time course. 0.01% OX-ZYM (oxidized with a 0.01% NaClO solution) caused arthritis faster than 0.1% OX-ZYM or 0.5% OX-ZYM. In conclusion, beta-glucan derived from ZYM by brief oxidation with NaClO is a suitable adjuvant for a CIA model with anti-CII antibody production.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Artritis Experimental/etiología , Colágeno Tipo II/inmunología , Zimosan/farmacología , beta-Glucanos/farmacología , Animales , Células Cultivadas , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos DBA , Hipoclorito de Sodio/farmacologíaRESUMEN
Collagen-induced arthritis (CIA) is an experimental model of rheumatoid arthritis (RA) used for studying the clinical, immunological and genetic factors of the disease. Many studies of genetic susceptibility to CIA have been performed, usually with two strains of mice, DBA/1 and B10.RIII, since they are highly susceptible to CIA. Furthermore, F1 hybrid mice of susceptible and resistant strains reportedly develop arthritis. Recently, we reported that particles of beta-glucan, OX-CA, prepared from Candida albicans by NaClO-oxidation, acted as an adjuvant for CIA. Although, there have been many studies about the relationship between antigen and the major histocompatibility complex (MHC) in F1 hybrid mice, little is known argument about susceptibility to adjuvants. Therefore, we checked the susceptibility of F1 hybrids to CIA using OX-CA as an adjuvant. BALB/c and DBA/1 were mated to generate F1 hybrids which were then immunized with type II collagen (CII) plus Freund's complete adjuvant (FCA) or OX-CA. The results showed that F1 hybrids injected with CII plus FCA developed severe arthritis at an incidence ratio 80%, versus only 20% in mice injected with CII plus OX-CA. Furthermore, levels of anti-CII antibody, especially of the IgG2a subclass, in sera from mice treated with CII plus OX-CA were significantly low. Susceptibility to CIA might depend on not only MHC but also the adjuvant used for immunoactivation.
Asunto(s)
Adyuvantes Inmunológicos , Artritis Experimental/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Colágeno Tipo II , beta-Glucanos , Adyuvantes Inmunológicos/administración & dosificación , Animales , Formación de Anticuerpos/efectos de los fármacos , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Colágeno Tipo II/administración & dosificación , Adyuvante de Freund/administración & dosificación , Predisposición Genética a la Enfermedad , Masculino , Ratones , Ratones Endogámicos , Especificidad de la Especie , beta-Glucanos/administración & dosificaciónRESUMEN
Collagen-induced arthritis (CIA) is an experimental model of rheumatoid arthritis (RA) and has aided research into the pathogenesis of inflammatory joint disease. Typically, Type II collagen (CII) emulsified with Freund's complete adjuvant (FCA) is injected into DBA/1 mice. After a booster injection, the mice develop inflammation of the paws. But the fact that the immunization of CII alone does not induce arthritis suggests that activation of the immune system by an adjuvant is necessary for induction of the arthritis. In the present study, we investigated the ability of beta-glucans derived from Candida albicans to act as an adjuvant to induce autoimmune arthritis. DBA/1 mice were injected with CII emulsified with FCA or particulate beta-glucan, OX-CA, on day 0 and given a booster at day 21. Mice immunized with CII plus OX-CA developed arthritis at around 7-10 days after the booster injection. Similarly, mice administered CII emulsified with FCA developed arthritis with the same time course. The mice immunized with CII and OX-CA had a more severe arthritis than those immunized with CII and FCA. Histological changes and production of anti-CII antibody were observed regardless of the type of injection. In addition, components of C. albicans were also tested for their ability to induce arthritis as an adjuvant. The results showed that CSBG, which is a soluble beta-glucan, acted as an adjuvant for CIA but CAWS, which is a mannoprotein-beta-glucan complex, did not. In conclusion, beta-glucan derived from C. albicans acted as an adjuvant and the injection with CII resulted in arthritis with the production of anti-CII autoantibody. The results strongly suggested that fungal metabolites such as beta-glucans have the capacity to induce and exacerbate autoimmune diseases such as RA.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Artritis Experimental/inmunología , Enfermedades Autoinmunes/inmunología , Candida albicans/inmunología , beta-Glucanos/administración & dosificación , Animales , Artritis Experimental/microbiología , Artritis Experimental/patología , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/microbiología , Pared Celular/química , Pared Celular/inmunología , Colágeno Tipo II/administración & dosificación , Colágeno Tipo II/inmunología , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , beta-Glucanos/inmunologíaRESUMEN
Invasive mycosis has significantly increased in frequency among immunocompromised hosts leading to excessive morbidity and mortality. The combination of sulfamethoxazole (SMX) and trimethoprim (TMP) has been used extensively for the treatment and prophylaxis of infections by various microbes. The purpose of this study is to estimate the anti-fungal activity of SMX-TMP and examine the mechanism of activity. To investigate the antimicrobial activity of SMX-TMP in vitro, a mixture of SMX and TMP at 5:1 was serially diluted and added to potato dextrose agar medium or C-limiting agar medium. Aspergillus species were inoculated on the medium plate with SMX-TMP. The growth of A. fumigatus and A. oryzae was inhibited by addition of SMX-TMP. The anti-Aspergillus effect depended on not TMP but SMX and that was inhibited by p-aminobenzoic acid (PABA). A. niger was not sensitive against SMX-TMP in PDA medium, but sensitive in C-limiting medium. Those results showed that the activity depends on culture medium. Furthermore, addition of human serum did not influence the activity of SMX. The finding in this study suggested that SMX might be effective against Aspergillus species in clinical practice and prophylaxis treatment.
Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Sulfametoxazol/farmacología , Aspergillus/crecimiento & desarrollo , Recuento de Colonia Microbiana/métodos , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Autoreactivity is controlled at various steps by numerous mechanisms and is a key to understanding and treating autoimmune disease. Recently, an antibody against deiminated fibrinogen (DI-FBG) was detected in patients with rheumatoid arthritis (RA) with high specificity and sensitivity. DI-FBG converted enzymically by peptidyl arginine deiminase, was also detected in synovial membrane. In the present study, we investigated whether antibody to DI-FBG is produced in mice immunized with DI-FBG. Mice were immunized with DI-FBG in the presence or absence of adjuvant. Production of the specific antibody was only induced with adjuvant. The resulting antibody was specific for DI-FBG and did not react with intact/native fibrinogen. Furthermore, it recognized deiminated human fibrinogen and cyclic citrullinated peptide (CCP). These results suggested that mouse fibrinogen acquires antigenicity in mice through deimination and therefore, autoantibody such as that detected in RA patients specifically may be induced.