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Analysis of Th17 response pattern, Regulatory T cells and proteomics in patients with digestive chronic chagas disease

Grant number: 14/04019-0
Support type:Regular Research Grants
Duration: October 01, 2014 - September 30, 2016
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Angela Maria Victoriano de Campos Soares
Grantee:Angela Maria Victoriano de Campos Soares
Home Institution: Faculdade de Medicina (FMB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi (T. cruzi). It is a neglected disease and considered a serious public health problem. It is endemic in Latin America, where there are still approximately 10 million people infected and over 25 million living in risk areas. The CD has two phases, acute, which lasts 2 to 4 months and is characterized by high parasitemia. Most often has no specific symptoms and signs, but if discovered and treated early can be cured, and the chronic phase characterized by low parasitemia, which persists throughout life and can be divided into three clinical forms: indeterminate, cardiac and digestive. The manifestations of digestive form of CD are attributed to the destruction of nerves in the myenteric plexus. The megaesophagus and megacolon are major causes of morbidity in the form of CD chronic gastrointestinal. Pathologically, both organs, esophagus and colon exhibit a large luminal enlargement and muscle hypertrophy. T cells use different mechanisms to regulate the immune response during Chagas disease, and host-parasite interactions may be influenced by the relationship T cell effector / regulatory. CD4 + T cells when cultured in the presence of TGF-², IL-6, IL-1b, IL-23 and IL-21 begin to express the transcription factor ROR³t and transform in the subpopulation Th17. These cells, which produce IL-17A, IL-17F, IL-21, IL-22 and TNF-±, promote an intense inflammatory process mediated by neutrophils and are associated with autoimmune diseases and to resistance against various bacterial and parasitic infections, but may also correlate with immunopathology in various other infections. Regulatory T cells (Treg) were described as a population of CD4 + CD25 + Foxp3 +, which regulates innate and adaptive immune responses and possess the ability to control excessive immune response. Tregs through the expression of IL-10 and TGF-² work benefiting patients with the indeterminate form of CD, keeping the balance between effector cells that kill the parasites and preventing the development of tissue immunopathology. Treg and Th17 cells have the same T cell precursors, but opposite effects on inflammation and immune tolerance. Furthermore, the Treg/Th17 imbalance has been demonstrated in various infections. Clinical Proteomics is defined as the proteome analysis which is intended to improve medical practice, for example, for the diagnosis, prevention, prognosis or therapy. Several proteomic biomarkers have been described for a variety of diseases, and various biomarkers have shown great value relative to current approaches for management of disease, based on validation studies. In chagasic patients with progression of disease severity, by an order of increasing gastrointestinal and cardiac injury or cell death may result in the release of intracellular proteins in the peripheral system, and thus alter the proteome profile. To date, there are no markers that predict the risk of developing megaesophagus or megacolon in patients with chronic asymptomatic CD, and still suspected that failures in the mechanisms that control the immune response may be involved in the development of digestive disease. Based on the absence of this information, we hypothesized that patients presenting with chronic digestive disease megacolon and megaesophagus produce high levels of IL-17, and have reduced frequency of Treg or suppressor activity, plus a proteome with different pattern when compared with those patients with the indeterminate form of the disease. Thus, the objective of this study is to analyze the participation of the response pattern Th17, Treg and proteomics in the development of clinical manifestations of chronic digestive Chagas disease. (AU)