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Dendritic cells in Sickle Cell Anemia: molecular mechanisms involved in regulating inflammation and adaptive immune response

Abstract

Sickle Cell Anemia (SCA) is one of the most common hemoglobinopathies in the world. Patients with SCA present reduced quality of life due to complications resulting from the change in the shape and physical properties of erythrocytes. These complications consist of chronic Hemolytic Anemia, pain crisis, organ dysfunction, susceptibility to infections, among others. SCA can be considered a chronic inflammatory disease, with the systemic release of proinflammatory cytokines such as TNF-, IL-6 and IL-8. In addition, patients have a change in the distribution and function of T and B lymphocytes. Although Dendritic Cells (DCs) are the major cells responsible for modulating lymphocyte function and able to produce the cytokines present in the patients' serum, the function of these cells in the development or regulation of inflammation during SCA has been poorly observed. It is also known that genes induced by IFN-I are among the genes most expressed in PBMCs of patients with SCA, but there is no report on the role of IFN-I or plasmacytoid DCs, the main producers of these cytokines, in the pathology of the disease. Our preliminary data show that patients with SCA present a greater amount and proportion of total DCs in the blood than healthy individuals. Among these cells, there is an increase in the proportion of pre-DCs and a reduction of circulating cDCs1, which indicates greater generation of DCs in the bone marrow and suggests differential activation and migration among the DCs subtypes during the inflammatory process of SCA. Our data also show that patients' monocytes are capable of generating inflammatory DCs that express CD14, unlike healthy individuals. Whether these cells are responsible, totally or partially, for the production of inflammatory cytokines and the polarization of the T lymphocytes to the Th17 profile, observed in our data, still needs to be discovered. Another fundamental question lies in the stimuli released during SCA capable of activating the DCs, in addition to the molecular mechanisms involved in the activation of these cells, which can lead to an activator or tolerogenic profile. In the present work, we intend to investigate the distribution, activation and functions of the different subpopulations of DCs in the blood of patients with SCA, as well as in the animal model of SCA, to discover the possible released PAMPs or DAMPs capable of activating them and investigate the signaling pathways involved in the process. We hope that the data will reveal more information about the establishment of the chronic inflammatory state and immune dysfunction presented by the patients with SCA and that they expose new therapeutic targets for specific regulation of the pathology. Finally, with the development of this project, I intend to establish my research area in the country, creating new collaborations and strengthening those already founded. In addition, I expect to collaborate with the formation of new scientists and with the publication of the works generated in high impact journals. (AU)