RESUMEN
T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection.
Asunto(s)
Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Interleucina-5/biosíntesis , Schistosoma haematobium/inmunología , Esquistosomiasis Urinaria/inmunología , Linfocitos T Colaboradores-Inductores/clasificación , Animales , Antihelmínticos/uso terapéutico , Línea Celular , Niño , Ensayo de Inmunoadsorción Enzimática , Estudios de Seguimiento , Humanos , Interferón gamma/análisis , Interleucina-4/análisis , Interleucina-5/análisis , Recuento de Huevos de Parásitos , Praziquantel/uso terapéutico , Esquistosomiasis Urinaria/tratamiento farmacológico , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/clasificación , Células TH1/metabolismo , Células Th2/clasificación , Células Th2/metabolismo , VolumetríaRESUMEN
T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection
Asunto(s)
Humanos , Animales , Niño , Citocinas/biosíntesis , Schistosoma haematobium/inmunología , Esquistosomiasis Urinaria/inmunología , Linfocitos T Colaboradores-Inductores/clasificación , Antihelmínticos/uso terapéutico , Antígenos Helmínticos , Línea Celular , Células Clonales/clasificación , Células Clonales/metabolismo , Citocinas/análisis , Citocinas/aislamiento & purificación , Ensayo de Inmunoadsorción Enzimática , Estudios de Seguimiento , Recuento de Huevos de Parásitos , Praziquantel/uso terapéutico , Esquistosomiasis Urinaria/tratamiento farmacológico , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/clasificación , Células TH1/metabolismo , Células Th2/clasificación , Células Th2/metabolismo , VolumetríaRESUMEN
Human susceptibility to Schistosoma mansoni infections is controlled by the SM1 locus on chromosome 5 in q31-q33. This genetic region encodes cytokines which regulate the development of helper T lymphocytes. In the present work, a clonal analysis of CD4(+) T lymphocytes of homozygous resistant and homozygous susceptible subjects was undertaken to evaluate whether SM1 controls helper T-cell differentiation. Of 121 CD4(+) T-cell clones (TCC) from three susceptible (S) and three resistant (R) subjects, 68 proliferated when stimulated by parasite antigens. Parasite-specific TCC derived from susceptible subjects (33 STCC) produced 10- to 1,000-fold less interleukin-4 and -5 than TCC from resistant subjects (25 RTCC). Clones from both patient groups produced, however, the same amount of gamma interferon. Parasite-specific STCC were type 1 helper (Th1) or Th0/1, whereas RTCC were either Th2 or Th0/2. These results, together with the localization of SM1 in 5q31-q33, indicate that the SM1 locus controls the differentiation of Th2 lymphocytes.
Asunto(s)
Cromosomas Humanos Par 5 , Esquistosomiasis mansoni/genética , Células Th2/inmunología , Adolescente , Adulto , Animales , Diferenciación Celular , Niño , Predisposición Genética a la Enfermedad/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inmunofenotipificación , Interleucina-4/biosíntesis , Interleucina-5/biosíntesis , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunologíaRESUMEN
A study of GB-C virus/Hepatitis G virus (GBV-C/ HGV) infection was carried out in a rural population of Northeastern Brazil, in which the prevalence of schistosomiasis is 80-90%. Despite the absence of parenteral risk exposure, the prevalence of GBV-C/HGV markers of infection was found to be unusually increased: viremia, 16.4%; specific antibody, 18.3%. It is therefore suspected that helminth infection influenced the immune response to GBV-C/HGV infection by shifting the balance of cytokine responses from Th1 to Th2, resulting in a delayed viral clearance. Phylogenetic analysis of viral isolates did not provide evidence for high rates of sexual or mother-to-infant viral transmission. The study revealed that viral strains belonged to types 1 and 2 only (predominant in Africa and Europe, respectively), suggesting that GBV-C/HGV was introduced into the New World by white conquerors and black slaves since the 16th century.
Asunto(s)
Flaviviridae , Hepatitis Viral Humana/epidemiología , Esquistosomiasis/complicaciones , Regiones no Traducidas 5'/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Brasil/epidemiología , Niño , ADN Viral/análisis , Salud de la Familia , Femenino , Flaviviridae/clasificación , Flaviviridae/genética , Flaviviridae/inmunología , Anticuerpos Antihepatitis/sangre , Hepatitis Viral Humana/complicaciones , Hepatitis Viral Humana/transmisión , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Prevalencia , ARN Viral/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esquistosomiasis/epidemiologíaRESUMEN
Three hundred million individuals are at risk of infection by schistosomes and around 200,000 die each year of this disease. Severe clinical disease in schistosomiasis is often the consequence of heavy infection which, in several endemic areas, are determined largely by the susceptibility/resistance of individuals. Previously, we reported evidence, based on a segregation analysis in Brazilian pedigrees, that intensity of infection by Schistosoma mansoni was influenced by a major gene, indicating that host genetic factors are probably critical in controlling schistosome infection and disease development. To localize this gene, referred to as SM1, we performed a genome-wide study on 142 Brazilian subjects belonging to 11 informative families Our results show a linkage to only one region, on chromosome 5q31-q33, with maximum two-point lod scores of +4.74 and +4.52 for D5S636 and the colony stimulating factor-1 receptor marker (CSF1R), respectively. This was corroborated by multipoint analysis, indicating a close proximity to CSF1R as the most likely location of SM1. This region contains several candidate genes encoding immunological molecules that were shown to play important roles in human protection against schistosomes.
Asunto(s)
Cromosomas Humanos Par 5/genética , Ligamiento Genético , Esquistosomiasis mansoni/genética , Brasil , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Receptor de Factor Estimulante de Colonias de Macrófagos/genéticaRESUMEN
The interleukine-5 (IL-5) is a hormone of the immune system that is the main regulator of eosinopoiesis, eosinophil maturation and activation, and immunoglobulin A production. Thus, IL-5 contributes in several ways to human immune defenses against various pathogens, including helminths and infectious agents of the digestive and respiratory tracts. On the other hand, the increase in eosinophil number and the activation of these cells, which both have been related to elevated IL-5 production, are the cause of severe pathological disorders, as in asthma or hypereosinophilic syndromes. Although the immunological pathways leading to IL-5 synthesis have been identified, the reasons for the large variability observed in IL-5 production among subjects exposed to comparable antigenic stimulation are unknown. To investigate the role of genetic factors in this variability, we conducted a segregation analysis in a Brazilian population infected by the helminth parasite Schistosoma mansoni. The analysis was performed on IL-5 levels produced by blood mononuclear cells of these subjects after in vitro restimulation with either parasite extracts (IL-5/schistosomula sonicates [SS] phenotype) or a T-lymphocyte mitogen (IL-5/phytohemagglutin [PHA]). The results provide clear evidence for the segregation of a codominant major gene controlling IL-5/SS and IL-5/PHA production and accounting for 70% and 73% of the phenotypic variance, respectively; the frequency of the allele predisposing to low IL-5 production was approximately .22 for both phenotypes. No significant relationship was found between these genes and the gene controlling infection intensities by S. mansoni detected in a previous study. Linkage studies are ongoing to locate those genes that would help to characterize the genetic factors involved in pathological conditions such as severe helminth infections and allergic diseases.
Asunto(s)
Interleucina-5/biosíntesis , Interleucina-5/genética , Leucocitos Mononucleares/metabolismo , Esquistosomiasis mansoni/metabolismo , Adolescente , Adulto , Factores de Edad , Brasil/epidemiología , Células Cultivadas , Niño , Preescolar , Variación Genética , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Modelos Lineales , Escala de Lod , Meiosis , Persona de Mediana Edad , Esquistosomiasis mansoni/inmunología , Factores SexualesRESUMEN
Vaccine-induced immunity to Schistosoma mansoni infection depends on the specific priming of certain T cell subsets and on the recall of this response by natural infections months or years after vaccine administration. Thus, those schistosome proteins that activate T cells in individuals stimulated by natural infections are potential candidate vaccine antigens. In the present study, we identified and purified one such T cell-stimulating antigen and evaluated its immunological properties in subjects living in an area endemic for Schistosoma mansoni. Chromatography fractions (gel filtration, followed by ion exchange chromatography) of soluble extracts of schistosomula were screened for their ability to stimulate schistosome-specific T cell clones derived from a subject sensitized by natural infection. A fraction stimulating most clones was identified and characterized. A few nanograms of this fraction, containing a major 9-10-kDa component, stimulated the T helper cells of most adults living in an endemic area of Brazil, and was able to trigger a strong cutaneous immediate hypersensitivity reaction. In contrast, children reacted weakly to this antigen preparation both in blastogenesis and in skin tests, although they mounted a significant reaction to crude larval antigen preparations. In conclusion, this work identifies a schistosomula antigen that induces a strong T cell response in adults sensitized by natural infections. This T cell response develops gradually in children and adolescents, is apparently not restricted by the HLA haplotypes common in the study area, and allows the production of parasite-specific IgE antibodies. Thus, this T cell response has some features of the immune response that is believed to protect chronically exposed humans from reinfection.
Asunto(s)
Antígenos Helmínticos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Linfocitos T/inmunología , Adulto , Animales , Formación de Anticuerpos , Antígenos Helmínticos/aislamiento & purificación , Brasil/epidemiología , División Celular/inmunología , Células Clonales , Humanos , Inmunofenotipificación , Masculino , Esquistosomiasis mansoni/epidemiología , Esquistosomiasis mansoni/prevención & controlRESUMEN
Cell-mediated immunity to Schistosoma mansoni antigens, unrelated antigens and mitogens was evaluated in 50 subjects with the same degree of exposure to infection living in an endemic area of schistosomiasis. The degree of infection, assessed by the number of eggs/g of stool, was variable in this population (0-5604), suggesting differences in susceptibility to infection. Absence of lymphoproliferative response was observed in 56% of this group, despite having a response to purified protein derivative of tuberculin (PPD) and tetanus toxoid (TT) antigens and to pokeweed mitogen. The 50 subjects were divided into two groups, according to their degree of infection. The lymphoproliferative responses to schistosomula and adult worm antigens in the group with a low degree of infection (< 400 eggs/g of stool) were higher than the ones documented in patients with a high degree of infection (> 400 eggs/g of stool), and these differences were statistically significant (p < 0.001). An inverse correlation between the lymphocyte proliferation in response to S. mansoni antigens and the degree of infection was also observed (p = 0.02), indicating that subjects with a lower degree of infection have a higher lymphoproliferative response to schistosomula and adult worm antigens. No differences in the lymphocyte reactivity to other antigens (PPD and TT) were detected in these groups. An impairment of interferon-gamma in vitro production was observed when the lymphocytes from these subjects were stimulated with S. mansoni adult worm antigen, although they produced gamma interferon in response to phytohemagglutinin.