RESUMO
The association between inflammatory processes and intestinal neuronal destruction during the progression of Chagasic megacolon is well established. However, many other components play essential roles, both in the long-term progression and control of the clinical status of patients infected with Trypanosoma cruzi. Components such as neuronal subpopulations, enteric glial cells, mast cells and their proteases, and homeostasis-related proteins from several organic systems (serotonin and galectins) are differentially involved in the progression of Chagasic megacolon. This review is aimed at revealing the characteristics of the intestinal microenvironment found in Chagasic megacolon by using different types of already used biomarkers. Information regarding these components may provide new therapeutic alternatives and improve the understanding of the association between T. cruzi infection and immune, endocrine, and neurological system changes.
Assuntos
Biomarcadores/metabolismo , Doença de Chagas/diagnóstico , Inflamação/diagnóstico , Megacolo/diagnóstico , Trypanosoma cruzi/fisiologia , Animais , Microambiente Celular , Doença de Chagas/imunologia , Sistema Endócrino , Humanos , Sistema Imunitário , Inflamação/imunologia , Megacolo/imunologia , Sistema Nervoso , NeuroimunomodulaçãoRESUMO
Chagas disease is caused by the parasite, Trypanosoma cruzi that causes chronic cardiac and digestive dysfunction. Megacolon, an irreversible dilation of the left colon, is the main feature of the gastrointestinal form of Chagas disease. Patients have severe constipation, a consequence of enteric neuron degeneration associated with chronic inflammation. Dysmotility, infection, neuronal loss and a chronic exacerbated inflammation, all observed in Chagas disease, can affect enteroendocrine cells (EEC) expression, which in turn, could influence the inflammatory process. In this study, we investigated the distribution and chemical coding of EEC in the dilated and non-dilated portion of T. cruzi-induced megacolon and in non-infected individuals (control colon). Using immunohistochemistry, EECs were identified by applying antibodies to chromogranin A (CgA), glucagon-like peptide 1 (GLP-1), 5-hydroxytryptamine (5-HT), peptide YY (PYY) and somatostatin (SST). Greater numbers of EEC expressing GLP-1 and SST occurred in the dilated portion compared to the non-dilated portion of the same patients with Chagas disease and in control colon, but numbers of 5-HT and PYY EEC were not significantly different. However, it was noticeable that EEC in which 5-HT and PYY were co-expressed were common in control colon, but were rare in the non-dilated and absent in the dilated portion of chagasic megacolon. An increase in the number of CgA immunoreactive EEC in chagasic patients reflected the increases in EEC numbers summarised above. Our data suggests that the denervation and associated chronic inflammation are accompanied by changes in the number and coding of EEC that could contribute to disorders of motility and defence in the chagasic megacolon.
Assuntos
Doença de Chagas/patologia , Células Enteroendócrinas/patologia , Megacolo/patologia , Trypanosoma cruzi/isolamento & purificação , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Feminino , Humanos , Imuno-Histoquímica , Inflamação/imunologia , Inflamação/parasitologia , Inflamação/patologia , Masculino , Megacolo/imunologia , Megacolo/parasitologiaRESUMO
After acute infestation with the Chagas disease parasite, Trypanosoma cruzi, some patients who are serologically positive develop chronic megacolon and megaesophagus, whereas others are symptom-free. Chagas disease with gastrointestinal involvement involves an inflammatory invasion of the enteric plexuses and degeneration of enteric neurons. It is known that glial cells can be involved in enteric inflammatory responses. The aims were to determine the nature of any difference in lymphocytic invasion, enteric neurons, and enteric glial cells in seropositive individuals with and without megacolon. We have compared colonic tissue from serologically positive individuals with and without symptoms and from seronegative controls. Subjects with megacolon had significantly more CD-57 natural killer cells and TIA-1 cytotoxic lymphocytes within enteric ganglia, but numbers of CD-3 and CD-20 immunoreactive cells were not significantly elevated. The innervation of the muscle was substantially reduced to about 20% in megacolon, but asymptomatic seropositive subjects were not different to seronegative controls. Glial cell loss occurred equally in symptomatic and unaffected seropositive subjects, although the proportion with glial fibrillary acidic protein was greater in seropositive, nonsymptomatic subjects. Development of megacolon after acute infection with T cruzi is associated with maintained invasion of enteric ganglia with cytotoxic T cells and loss of muscle innervation, but changes in glial cell numbers are not associated with progression of enteric neuropathy.
Assuntos
Doença de Chagas/patologia , Colo/patologia , Megacolo/patologia , Plexo Mientérico/patologia , Neuroglia/patologia , Plexo Submucoso/patologia , Biomarcadores/metabolismo , Contagem de Células , Doença de Chagas/complicações , Doença de Chagas/imunologia , Colo/inervação , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Técnicas Imunoenzimáticas , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/patologia , Megacolo/imunologia , Megacolo/parasitologia , Plexo Mientérico/imunologia , Neuroglia/imunologia , Neuroglia/metabolismo , Proteínas de Ligação a Poli(A)/metabolismo , Plexo Submucoso/imunologia , Antígeno-1 Intracelular de Células T , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologiaRESUMO
BACKGROUND AND AIMS: Gastrointestinal disorders is one of the clinical manifestations of chronic Chagas' disease. The pathogenesis seems to be associated with autonomic dysfunction. Here, we consider the muscarinic cholinoceptor mediated alteration in distal colon function in chagasic megacolon. PATIENTS: Patients were divided into four groups: group I, chronic chagasic patients with megacolon; group II, chronic chagasic patients without megacolon; group III, non-chagasic patients with megacolon; and group IV, normal healthy volunteers (control). METHODS: Binding assay and immunoblot of cholinoceptors from human and rat colon and enzyme immunoassay (ELISA) using a synthetic 24mer peptide corresponding to the second extracellular loop of human M2 muscarinic acetylcholine receptors (mAChR) were used to detect the presence of serum antibodies. The effect of antibodies on basal tone and 3',5'-cyclic monophosphate (cAMP) production of human and rat distal colon strips were also tested. RESULTS: Group I but not the other groups had circulating antibodies capable of interacting with human colon activating M2 mAChR, as they competed with binding of specific radioligand to mAChR and interacted with the second extracellular loop of human M2 mAChR. Moreover, affinity purified anti-M2 peptide IgG from group I, in common with monoclonal antihuman M2 mAChR, recognised bands with a molecular weight corresponding to colon mAChR. This antibody also displayed an agonist-like activity, increasing basal tone and decreasing cAMP accumulation. Both effects were blunted by AF-DX 116 and neutralised by the synthetic peptide. CONCLUSIONS: In chagasic patients with megacolon there are antibodies that can recognise and activate M2 mAChR. The implications of these autoantibodies in the pathogenesis of chagasic megacolon is discussed.
Assuntos
Doença de Chagas/imunologia , Imunoglobulina G/fisiologia , Megacolo/imunologia , Receptores Colinérgicos/fisiologia , Adulto , Idoso , Análise de Variância , Animais , Anticorpos Monoclonais/fisiologia , Autoanticorpos/fisiologia , Western Blotting/métodos , Estudos de Casos e Controles , Doença de Chagas/complicações , AMP Cíclico/metabolismo , Eletroforese em Gel de Poliacrilamida/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Megacolo/etiologia , Pessoa de Meia-Idade , Músculo Liso/metabolismo , Ratos , Ratos WistarRESUMO
PURPOSE: The mechanisms that control chronic infection in vivo and the immunologic mechanisms involved in the pathogenesis of chagasic megacolon are not completely characterized. Although autoimmunity may play a role in the pathogenesis of Chagas' disease, recent studies, both in mice and in humans, suggest a positive association of tissue parasitism, inflammation, and severity of lesions. The aim of this study was to evaluate the role of inflammatory cells and the subclasses of lymphocytes involved in neuropathic lesions in the colon of patients who underwent resection for advanced megacolon. METHODS: Specimens from 23 patients were selected based on histopathologic analysis. Paraffin-embedded tissue blocks were sectioned and evaluated by immunohistochemistry for cluster of differentiation 3, cluster of differentiation 8, cluster of differentiation 20, and natural killer cell antibodies by an avidin-biotin peroxidase method. RESULTS: Almost all myenteric plexuses were damaged, characterized by degenerative changes, necrosis of ganglion cells, and inflammatory response. Mild lymphocytic infiltration around degenerated and normal ganglion cells was observed in all cases. Collagen fibers and mononuclear cells surrounded some ganglion cells. Most of the inflammatory cells were lymphocytes, identified as cluster of differentiation 3-positive cells. Cluster of differentiation 8-positive lymphocytes were associated with degenerated ganglion cells. Natural killer cell antibodies were detected in a lower proportion of cells and were distributed between muscle layers or in proximity to the myenteric plexus. All these findings were also observed in the submucosal plexus. Cluster of differentiation 20-positive lymphocytes were not present in muscle layers or in the vicinity of either plexus. CONCLUSION: Pathogenesis of the megacolon is based on a continuous process of ganglion cell damage with participation of T lymphocytes expressing cluster of differentiation 8 and natural killer cell membrane antigens. B lymphocytes do not take part in the chronic inflammatory reaction.