Participação de anticorpos anti-DENV na imunopatogênese da dengue e produção de anticorpos monoclonais anti-flavivírus

Abstract

Dengue is a viral disease with different clinical manifestations, which symptoms vary from a mild infection to a more severe syndrome characterized by haematological disorders that can endanger patient's life. Several mechanisms are proposed to be involved in dengue severity, among them, the antibody dependent enhancement (ADE) and virus-induced autoimmunity phenomena. According to ADE theory, in DENV secondary infections, heterologous antibodies would fail in neutralizing the virus and form DENV-immunocomplexes that bind to Fcγ receptors bearing-cells, facilitating viral internalization and replication, with consequent disease aggravation. The DENVinduced autoimmunity theory suggests that antibodies against viral particles would react with components of host organism due to molecular mimicry between platelets, endothelial cells and molecules of the coagulatory system with viral proteins, resulting in these cells depletion, contributing with the increase in capillary permeability and/or thrombocytopenia that are typical in this disease. In addition to the search for understanding the mechanisms involved in dengue pathogenesis it is also necessary the development of a specific antiviral therapy. To date, patients’ treatment is restricted to the relief of symptoms and supportive care. A possible treatment strategy would be the utilization of monoclonal antibodies in immunotherapy. Therefore, with this work, we proposed to study these two distinct mechanisms possibly involved in dengue immunopathogenesis, through the analysis of the profile of IgG DENV-specific antibodies and serum/DENV-specific IgG1 and IgG3 and the correlation between platelet and leukocyte counts with DENV-specific IgG and IgM antibodies concentration in patients with dengue different clinical manifestations. Furthermore, we proposed the production of an anti-flavivirus monoclonal antibody. Our results point to a possible involvement of antibodies in different mechanisms of dengue immunopathogenesis and suggest monitoring these antibodies kinetics for signaling a less favorable prognosis for the disease. DENV-specific IgG dosage, one of the severity biomarkers reveled in this study, requires in the immunoenzymatic-standardized assay the addition of anti-flavivirus antibodies in the solid phase. The anti-flavivirus antibodies produced in this study demonstrated a potential employment for this purpose or in a future human therapy.