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Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases, characterized by progressive cytopenias and propensity to develop acute myeloid leukemia. MDS is characterized by the presence of ineffective hematopoiesis with production of aberrant clones and elevated levels of cellular apoptosis in the bone marrow (BM). The myelodysplastic clone would arise as a result of genetic/ epigenetic changes in susceptible individuals during the aging process, favored by exposure to various types of stress, or to the presence of molecules or mediators generated by an existing or past inflammatory condition. It has been observed that both changes in gene expression or pre-exposure to inflammatory molecules are capable of triggering the activation of signaling pathways of innate immunity with the subsequent secretion of cytokines, chemokines and growth factors, which create an inflammatory microenvironment in BM. As a consequence, hematopoietic progenitor cells increase their rate of proliferation, expression of Fas and other receptors on their surface by recruiting immune cells such as CD8 + cytotoxic NK and T lymphocytes. Expression of death receptors, persistent signaling of inflammatory pathways, and T cell-mediated cytotoxicity induce apoptosis of some progenitor cells. However, it is not clear whether the cells that die belong to the normal clone, myelodysplastic, or both. Intramedullary apoptosis decreases the number of functional progenitors in BM, resulting in a smaller number of completely differentiated cells. In addition, the intrinsic defects in the differentiation potential of the myelodysplastic clone and sustained signaling of the inflammatory pathways produce a deregulated and biased differentiation towards the myeloid lineage. Increased rate of proliferation in MDS makes myeloid progenitor cells more prone to accumulation of additional epigenetic/genetic aberrations. In addition, unknown mechanisms produce changes in the expression of cellular receptors, and probably also in the expression of other molecules, leading to resistance to apoptosis of malignant cells. Together, all these alterations confer the SMD clone a survival advantage and contribute to its aberrant proliferation. The alteration of these cellular processes that prevail in BM is accompanied by the recruitment of immunomodulatory cells, which are probably caused by changes in the cytokine/chemokine environment (IL-4, IL-10 and TGFβ) and growth factors (VEGF, TNFα, thrombopoietin, etc.) and by modulating Tregs regulatory T cell activity. Tregs cells confer immune resistance to the myelodysplastic clone, allowing the abnormal proliferation of cells that escape the surveillance of the immune system and increasing the risk of progression to AML. There is much evidence that immunity plays a complex and ambiguous role in MDS. The chronic inflammation that results from the immune response has a systemic effect that worsens the syndrome. The immune activity is certainly variable according to the different stages of the disease. Understanding the dual role of the immune system in MDS is a challenge and rigorous clinical studies are needed to establish the value of manipulation of the immune system as a possible way of treating this pathology.
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