Alterações imunológicas na mucosa intestinal de camundongos com diabetes tipo 1

Abstract

Type 1 diabetes is a chronic autoimmune disease that affects genetically susceptible individuals. It can manifest in the early years of life, and a large percentage of individuals with diabetes are children. The disease leads to massive loss of pancreatic β cells producing insulin caused by an inflammatory response mediated by CD4+ and CD8+ T cells. Development diabetes is characterized by the breakdown of immunological tolerance to self antigens, and several factors such as dietary components and changes in the microbiota play a crucial role in the onset of pancreatitis and diabetes. The contact of imune system with the external antigens occurs mostly through the intestinal mucosa, and the integrity of its components is critical for the establishment of tolerance to these antigens, the classical phenomenon known as oral tolerance. In the presente study, we showed that NOD mice, a mouse that develops spontaneously type 1 diabetes, presented defects in the intestinal mucosa that lead to the breakdown of oral tolerance. A morphological analises of the small intestine of these mice did not show clinical signs of inflammation neither change in intraeptelial T lymphocytes frequency, but this strain presented defects in the intestinal barrier such as reduced production of mucus and the secretion of IgA in the intestinal lumen. The reduction in the frequency of B1 lymphocytes (CD19+ CD5+

) seen in these mice may contribute to the diminished sIgA found. The impaired oral tolerance was not due to a change in frequency of regulatory T cells (CD4+ FoxP3+

) in mesenteric lymph nodes. Furthermore we demonstrate that the development of diabetes was associated with an imbalance of resident macrophages which secrete IL-10 and monocyte-derived macrophages with a pro-inflammatory profile in small intestine. Because of the close relationship between the pancreas and the intestine, and the communication between them through the pancreatic lymph node, disturbances in intestinal mucosa can interfere with the development of type 1 diabetes. To understand the factors and changes in intestinal mucosa related to pathogenesis of type 1 diabetes is the first step for creation of new therapeutic strategies that are safe and successful for type 1 diabetes.