RESUMO
OBJECTIVE: To determine the differences between clinical, manometric, and neuroimmunological profile of esophagogastric junction outflow obstruction (EGJOO) and achalasia patients. METHODS: Seven EGJOO and 27 achalasia patients were enrolled in a blind cross-sectional study. Peripheral blood (PB) of 10 healthy donors and 10 lower esophageal sphincter (LES) muscle biopsies from organ transplant donors were included as controls. The presence of ganglion cells, cells of Cajal, Th22/Th7/Th2/Th1/Tregs/Bregs/pDCregs in tissue, and PB was assessed by immunohistochemistry and flow cytometry. Serum concentration of IL-22/IL-17A/IL-17F/IL-4/IFN-γ/IL-1ß/IL-6/IL-23/IL-33/TNF-α/IL-10 was determined using bioplex plates. ANAs and antineuronal antibodies were evaluated by immunofluorescence and Western blot. KEY RESULTS: EGJOO and achalasia patients had lower ganglion cells and cells of Cajal percentage vs. controls, while fibrosis was present only in achalasia patients. EGJOO and controls had lower cell percentage of Th22/Th17/Th2 vs. achalasia. EGJOO tissue had lower Th1/Treg cell number vs. achalasia, but higher levels vs. control group. Bregs and pDCregs percentage was higher in EGJOO vs. control group. Percentage of PB subpopulations in EGJOO was not significantly different from control group. Serum cytokine levels were higher for IL-1ß/IL-6/TNF-α, while IL-17A levels were lower in EGJOO vs. achalasia and control group. EGJOO group was negative for ANAs, while in achalasia group, 54% were positive. GAD65 and PNMa/Ta2 antibodies were present in achalasia, whereas Yo and recoverin were positive in EGJOO group. CONCLUSIONS AND INFERENCES: Although EGJOO shares some clinical characteristics with achalasia, the neuroimmunological profile is completely different, suggesting that EGJOO might be a different entity.
Assuntos
Acalasia Esofágica/diagnóstico , Transtornos da Motilidade Esofágica/diagnóstico , Junção Esofagogástrica/metabolismo , Esôfago/metabolismo , Adulto , Idoso , Estudos Transversais , Citocinas/sangue , Acalasia Esofágica/metabolismo , Transtornos da Motilidade Esofágica/metabolismo , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-IdadeRESUMO
Megaesophagus is one of the major causes of morbidity in chronic Chagas disease, and extensive denervation, associated with an inflammatory process, is recognized as the key factor for alterations in motility and disease development. Here, we analyzed esophagus samples from necropsied, infected individuals--6 cases with megaesophagus and 6 cases without megaesophagus--for the relative areas of expression of 2 neuromediators, substance P and vasoactive intestinal peptide, which are known to activate or inhibit, respectively, local immune cells. Samples from 6 noninfected individuals were used as controls. Esophageal sections were immunohistochemically stained for protein gene product 9.5, vasoactive intestinal peptide, and substance P, and the relative areas of expression of the latter 2 were calculated. Morphometric analyses revealed increased substance P and decreased vasoactive intestinal peptide relative areas in esophageal sections from patients with megaesophagus. Furthermore, in the group of patients without megaesophagus, the loss of vasoactive intestinal peptide positively correlated with the denervation process. We suggest that an imbalance between vasoactive intestinal peptide and substance P production results in the reestablishment and maintenance of the inflammatory process, leading to denervation and, consequently, promoting the development of megaesophagus.
Assuntos
Doença de Chagas/complicações , Acalasia Esofágica/metabolismo , Substância P/metabolismo , Trypanosoma cruzi/fisiologia , Peptídeo Intestinal Vasoativo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Chagas/patologia , Acalasia Esofágica/etiologia , Esôfago/inervação , Esôfago/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Plexo Mientérico/patologia , Neurônios/metabolismo , Neurônios/patologiaRESUMO
Trypanosoma cruzi presents a high degree of intraspecific variability, with possible implications for the pathogenesis of Chagas disease. The aim of this study was to evaluate T. cruzi kDNA minicircle gene signatures using the low-stringency single-specific-primer PCR technique in both peripheral blood and oesophageal mucosa from chronic chagasic patients, with or without megaesophagus, alone or in combination with cardiopathy and megacolon. It was not possible to identify a uniform pattern of shared bands between blood and oesophageal mucosa samples from individuals with the same clinical form or mixed forms, suggesting multiple T. cruzi infections with differential tissue tropism. Thus, the results indicate that there is an intense intraspecific variability in the hypervariable regions of T. cruzi kDNA, which has so far made it impossible to correlate the genetic profile of this structure with the clinical manifestations of Chagas disease.
Assuntos
Doença de Chagas/parasitologia , DNA de Cinetoplasto/análise , DNA de Protozoário/genética , Acalasia Esofágica/parasitologia , Trypanosoma cruzi/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Doença de Chagas/sangue , Doença de Chagas/genética , Doença Crônica , Impressões Digitais de DNA , DNA de Cinetoplasto/genética , DNA de Protozoário/sangue , DNA de Protozoário/metabolismo , Acalasia Esofágica/metabolismo , Feminino , Variação Genética , Interações Hospedeiro-Parasita , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Estatística como Assunto , Trypanosoma cruzi/parasitologiaRESUMO
Evidence accumulated by our investigations over the years give adequate proof for the existence of circulating antibodies in Chagas disease which bind to beta adrenergic and muscarinic cholinergic receptor of myocardium. The interaction of agonist-like antibodies with neurotransmitter receptors, triggers in the cells intracellular signal transductions that alter the physiological behaviour of the target organs. These events convert the normal cells into pathologically active cells. The interaction of antibodies with heart beta adrenergic and cholinergic receptors triggers physiologic, morphologic, enzymatic and molecular alterations, leading to tissue damage. The analysis of the prevalence and distribution of these antibodies reveals a strong association with cardiac and esophageal autonomic dysfunction in seropositive patients in comparison with those without alteration of the heart and esophagus autonomic disorders: therefore, the presence of these antibodies may partially explain the cardiomyoneurophathy and achalasia of Chagas disease, in which the sympathetic and parasympathetic systems are affected. The deposit of autoantibodies behaving like an agonist on neurotransmitter receptors, induceds desensitization and/or down regulation of the receptors. This in turn, could lead to a progressive blockade of neurotransmitter receptors, with sympathetic and parasympathetic dennervation, a phenomenon that has been described during the course of Chagas cardioneuropathy and achalasia. The clinical relevance of these findings is the demonstration, using biomolecules, of a strong association between the existence of circulating autoantibodies against peptides corresponding to the second extracellular loop of the human heart beta, adrenoceptor and M2 cholinoceptor in chagasic patients, and the presence of dysautonomic symptoms, making these autoantibodies a proper early marker of heart and digestive autonomic dysfunction.
Assuntos
Autoanticorpos/metabolismo , Cardiomiopatia Chagásica/imunologia , Acalasia Esofágica/imunologia , Doenças Neuromusculares/imunologia , Receptores Adrenérgicos beta/metabolismo , Receptores Colinérgicos/metabolismo , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/metabolismo , Cardiomiopatia Chagásica/complicações , Cardiomiopatia Chagásica/metabolismo , Acalasia Esofágica/complicações , Acalasia Esofágica/metabolismo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Doenças Neuromusculares/metabolismo , Receptores de Neurotransmissores/metabolismoRESUMO
1. Patients with chronic Chagas' disease have abnormally low gastric acid secretion and increased gastrin release both during fasting and after different stimuli. Regardless of the relationship between intragastric acidity and gastrin secretion, it is uncertain whether hypergastrinemia in Chagas' disease is caused by an increased population of antral gastrin (G) cells (hyperplasia) or by enhanced cell activity (hyperfunction). 2. We therefore estimated G cell number in antral biopsies from 16 chagasic patients and 13 control subjects using a peroxidase-anti-peroxidase immunohistochemical technique. All subjects underwent a gastric secretion test to determine peak acid output following intravenous pentagastrin instillation. 3. Antral G cell number in Chagas' disease patients was not significantly different from that observed in the control group (number of cells/mm2, median and (range): 128 (44-284) vs 138 (65-285)). 4. In chagasic patients, peak acid output was significantly lower than in controls (mmol/h, median and (range): 9.819 (3.024-21.564) vs 17.490 (9.423-25.848)). 5. These results suggest that the increase in gastrin release associated with reduced gastric acid secretion in Chagas' disease is mediated by antral G cell hyperfunction rather than by hyperplasia.
Assuntos
Doença de Chagas/patologia , Acalasia Esofágica/patologia , Mucosa Gástrica/patologia , Gastrinas/metabolismo , Megacolo/patologia , Adulto , Contagem de Células , Doença de Chagas/metabolismo , Doença Crônica , Acalasia Esofágica/metabolismo , Feminino , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Humanos , Masculino , Megacolo/metabolismo , Pessoa de Meia-Idade , Antro Pilórico/metabolismo , Antro Pilórico/patologiaRESUMO
1. Patients with chronic Chagas' disease have abnormally low gastric acid secretion and increased gastrin release both during fasting and after different stimuli. Regardless of the relationship between intragastric acidity and gastrin secretion, it is uncertain whether hypergastrinemia in Chagas' disease is caused by an increased population of antral gastrin (G) cells (hyperplasia) or by enhanced cell activity (hyperfunction). 2. We therefore estimated G cell number in antral biopsies from 16 chagasic patients and 13 control subjects using a peroxidase-anti-peroxidase immunohistochemical technique. All subjects underwent a gastric secretion test to determine peak acid output following intravenous pentagastrin instillation. 3. Antral G cell number in Chagas' disease patients was not significantly different from that observed in the control group (number of cells/mm2, median and (range): 128 (44-284) vs 138 (65-285)). 4. In chagasic patients, peak acid output was significantly lower than in controls (mmol/h, median and (range): 9.819 (3.024-21.564) vs 17.490 (9.423-25.848)). 5. These results suggest that the increase in gastrin release associated with reduced gastric acid secretion in Chagas' disease is mediated by antral G cell hyperfunction rather than by hyperplasia