RESUMEN
Human immunodeficiency virus (HIV)-1 protease is a known target of CD8+ T cell responses, but it is the only HIV-1 protein in which no fully characterized HIV-1 protease CD4 epitopes have been identified to date. We investigated the recognition of HIV-1 protease by CD4+ T cells from 75 HIV-1-infected, protease inhibitor (PI)-treated patients, using the 5,6-carboxyfluorescein diacetate succinimidyl ester-based proliferation assay. In order to identify putative promiscuous CD4+ T cell epitopes, we used the TEPITOPE algorithm to scan the sequence of the HXB2 HIV-1 protease. Protease regions 4-23, 45-64 and 73-95 were identified; 32 sequence variants of the mentioned regions, encoding frequent PI-induced mutations and polymorphisms, were also tested. On average, each peptide bound to five of 15 tested common human leucocyte antigen D-related (HLA-DR) molecules. More than 80% of the patients displayed CD4+ as well as CD8+ T cell recognition of at least one of the protease peptides. All 35 peptides were recognized. The response was not associated with particular HLA-DR or -DQ alleles. Our results thus indicate that protease is a frequent target of CD4+ along with CD8+ proliferative T cell responses by the majority of HIV-1-infected patients under PI therapy. The frequent finding of matching CD4(+) and CD8+ T cell responses to the same peptides may indicate that CD4+ T cells provide cognate T cell help for the maintenance of long-living protease-specific functional CD8+ T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Epítopos de Linfocito T/inmunología , Proteasa del VIH/inmunología , VIH-1/inmunología , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Mapeo Epitopo/métodos , Epítopos de Linfocito T/metabolismo , Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Proteasa del VIH/genética , Proteasa del VIH/metabolismo , VIH-1/metabolismo , Antígenos HLA-DR/inmunología , Antígenos HLA-DR/metabolismo , Humanos , Datos de Secuencia Molecular , Mutación , Péptidos/inmunología , Péptidos/metabolismo , Unión ProteicaRESUMEN
Paramyosin, a Schistosoma mansoni myoprotein associated with human resistance to infection and reinfection, is a candidate antigen to compose a subunit vaccine against schistosomiasis. In this study, 11 paramyosin peptides selected by TEPITOPE algorithm as promiscuous epitopes were produced synthetically and tested in proliferation and in vitro human leucocyte antigen (HLA)-DR binding assays. A differential proliferative response was observed in individuals resistant to reinfection compared to individuals susceptible to reinfection in response to Para (210-226) peptide stimulation. In addition, this peptide was able to bind to all HLA-DR molecules tested in HLA-DR binding assays, confirming its promiscuity. Para (6-22) and Para (355-371) were also shown to be promiscuous peptides, because they were able to bind to the six and eight most prevalent HLA-DR alleles used in HLA-DR binding assays, respectively, and were also recognized by T cells of the individuals studied. These results suggest that these paramyosin peptides are promising antigens to compose an anti-schistosomiasis vaccine.
Asunto(s)
Epítopos de Linfocito T/inmunología , Proteínas del Helminto/inmunología , Esquistosomiasis mansoni/inmunología , Tropomiosina/inmunología , Adolescente , Adulto , Anciano , Algoritmos , Antígenos Helmínticos/inmunología , División Celular/inmunología , Niño , Femenino , Antígenos HLA-DR/inmunología , Humanos , Inmunidad Celular/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Péptidos/inmunología , Linfocitos T/inmunologíaRESUMEN
AIMS: To investigate the consequences of improvement in the workplace environment over six decades (1940-96) in asbestos miners and millers from a developing country (Brazil). METHODS: A total of 3634 Brazilian workers with at least one year of exposure completed a respiratory symptoms questionnaire, chest radiography, and a spirometric evaluation. The study population was separated into three groups whose working conditions improved over time: group I (1940-66, n = 180), group II (1967-76, n = 1317), and group III (1977-96, n = 2137). RESULTS: Respiratory symptoms were significantly related to spirometric abnormalities, smoking, and latency time. Breathlessness, in particular, was also associated with age, pleural abnormality and increased cumulative exposure to asbestos fibres. The odds ratios (OR) for parenchymal and/or non-malignant pleural disease were significantly lower in groups II and III compared to group I subjects (0.29 (0.12-0.69) and 0.19 (0.08-0.45), respectively), independent of age and smoking status. Similar results were found when groups were compared at equivalent latency times (groups I v II: 30-45 years; groups II v III: 20-25 years). Ageing, dyspnoea, past and current smoking, and radiographic abnormalities were associated with ventilatory impairment. Lower spirometric values were found in groups I and II compared to group III: lung function values were also lower in higher quartiles of latency and of cumulative exposure in these subjects. CONCLUSIONS: Progressive improvement in occupational hygiene in a developing country is likely to reduce the risk of non-malignant consequences of dust inhalation in asbestos miners and millers.
Asunto(s)
Amianto/toxicidad , Enfermedades Pulmonares/etiología , Minería/tendencias , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Adulto , Anciano , Amianto/administración & dosificación , Amianto/análisis , Brasil/epidemiología , Países en Desarrollo , Humanos , Exposición por Inhalación/efectos adversos , Exposición por Inhalación/análisis , Modelos Logísticos , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Minería/normas , Enfermedades Profesionales/diagnóstico por imagen , Enfermedades Profesionales/epidemiología , Exposición Profesional/análisis , Salud Laboral/estadística & datos numéricos , Radiografía , Pruebas de Función Respiratoria , Mecánica Respiratoria , Estudios Retrospectivos , Fumar/efectos adversos , EspirometríaRESUMEN
T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81-96) peptide] was most frequently recognized by PBMC from HLA-DR7+ DR53+ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81-103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.
Asunto(s)
Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Portadoras/inmunología , Miocardio/inmunología , Cardiopatía Reumática/inmunología , Linfocitos T/inmunología , Presentación de Antígeno , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Antígenos HLA-DR/metabolismo , Antígeno HLA-DR7/metabolismo , Cadenas HLA-DRB4 , Humanos , Epítopos Inmunodominantes , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Miosinas/inmunología , Péptidos/síntesis química , Péptidos/química , Péptidos/inmunología , Péptidos/metabolismo , Streptococcus pyogenes/inmunologíaAsunto(s)
Humanos , Masculino , Adulto , Neoplasias de la Médula Espinal , Condrosarcoma , Hemotórax/etiologíaRESUMEN
The Ia binding regions were analyzed for three unrelated peptide Ag (sperm whale myoglobin 106-118, influenza hemagglutinin 130-142, and lambda repressor protein 12-26) for which binding to more than one Ia molecule has previously been demonstrated. By determining the binding profile of three separate series of truncated synthetic peptides, it was found that in all three cases the different Ia reactivities mapped to largely overlapping regions of the peptides; although, for two of the peptides, the regions involved in binding the different Ia specificities were distinct. Moreover, subtle differences were found to dramatically influence some, but not other, Ia reactivities. Using a large panel of synthetic peptides it was found that a significant correlation exists between the capacity of peptides to interact with different alleles of the same molecule (i.e., IAd and IAk), but no correlation was found with the capacity of peptides to interact with different isotypes within the same haplotype (i.e., IAd and IEd). These data suggest that different alleles of the same MHC molecule may actually recognize closely related structures, whereas different isotypes may recognize unrelated, albeit non-mutually exclusive, structures on an Ag molecule.